藤田　至彦 （フジタ　ヨシヒコ）

コミュニケーション情報 byコメンテータガイド

• コメント

  腫瘍関連の遺伝子、タンパク質、薬剤の機能、化学的性質など

研究者情報

学位

• 医学博士（1993年05月 京都大学）

ホームページURL

https://jglobal.jst.go.jp/detail?JGLOBAL_ID=201401005484222525

科研費研究者番号

• 80192730

J-Global ID

• 201401005484222525

研究キーワード

• がん分子標的治療   分子標的薬   

現在の研究分野（キーワード）

腫瘍関連の遺伝子、タンパク質、薬剤の機能、化学的性質など

所属学協会

• 日本臨床腫瘍学会   American association for Cancer Research   日本がん分子標的治療学会   日本癌学会   

研究活動情報

論文

• Novel single nucleotide polymorphism biomarkers to predict opioid effects for cancer pain.

  Yoshihiko Fujita; Hiromichi Matsuoka; Yasutaka Chiba; Junji Tsurutani; Takeshi Yoshida; Kiyohiro Sakai; Miki Nakura; Ryo Sakamoto; Chihiro Makimura; Yoichi Ohtake; Kaoru Tanaka; Hidetoshi Hayashi; Masayuki Takeda; Tatsuya Okuno; Naoki Takegawa; Koji Haratani; Takayuki Takahama; Junko Tanizaki; Atsuko Koyama; Kazuto Nishio; Kazuhiko Nakagawa

  Oncology letters 26 2 355 - 355 2023年08月 [査読有り]
   

  There have been few studies on predictive biomarkers that may be useful to select the most suitable opioids to optimize therapeutic efficacy in individual patients with cancer pain. We recently investigated the efficacy of morphine and oxycodone using single nucleotide polymorphisms (SNPs) of the catechol-O-methyltransferase (COMT) rs4680 gene as a biomarker (RELIEF study). To explore additional biomarkers that may enable the selection of an appropriate opioid for individual patients with cancer pain, three SNPs were examined: C-C motif chemokine ligand 11 (CCL11; rs17809012), histamine N-methyltransferase (HNMT; rs1050891) and transient receptor potential V1 (TRPV1; rs222749), which were screened from 74 pain-related SNPs. These SNPs, which were identified as being significantly associated with the analgesic effect of morphine, were then used to genotype the 135 patients in the RELIEF study who had been randomized into a morphine group (n=69) or an oxycodone group (n=66). The present study then assessed whether the SNPs could also be used as selective biomarkers to predict which opioid(s) might be the most suitable to provide pain relief for patients with cancer. Oxycodone tended to provide superior analgesic effects over morphine in patients carrying the genotype AA for the CCL11 rs17809012 SNP (P=0.012 for interaction), suggesting that it could serve as a potential biomarker for personalized analgesic therapy for patients suffering with cancer pain.
• Morphine Versus Oxycodone for Cancer Pain Using a Catechol-O-methyltransferase Genotype Biomarker: A Multicenter, Randomized, Open-Label, Phase III Clinical Trial (RELIEF Study)

  Hiromichi Matsuoka; Junji Tsurutani; Yasutaka Chiba; Yoshihiko Fujita; Kiyohiro Sakai; Takeshi Yoshida; Miki Nakura; Ryo Sakamoto; Chihiro Makimura; Yoichi Ohtake; Kaoru Tanaka; Hidetoshi Hayashi; Masayuki Takeda; Tatsuya Okuno; Naoki Takegawa; Koji Haratani; Atsuko Koyama; Kazuto Nishio; Kazuhiko Nakagawa

  The Oncologist 2022年11月 [査読有り]
   

  Abstract Background We hypothesized that the high-dose opioid requirement in patients carrying the rs4680-GG variant in the COMT gene encoding catechol-O-methyltransferase would be greater for patients taking morphine than for those taking oxycodone, thus providing a much-needed biomarker to inform opioid selection for cancer pain. Methods A randomized, multicenter, open-label trial was conducted at a Japanese hospital’s palliative care service. Patients with cancer pain treated with regular doses of nonsteroidal anti-inflammatory drugs or acetaminophen were enrolled and randomized (1:1) into morphine (group M) and oxycodone (group O) groups. The minimum standard dose of immediate-release (IR) oral opioids was repeatedly administered by palliative care physicians to achieve pain-reduction goals (Pain reduction ≥ 33% from baseline and up to ≤ 3 on a numerical rating scale). The primary endpoint was the proportion of subjects requiring high-dose opioids on day 0 with the GG genotype. Results Of 140 participants who developed cancer-related pain among 378 subjects registered and pre-screened for the genotype, 139 were evaluated in the current study. Among patients carrying a COMT rs4680-GG genotype, 48.3% required high-dose opioids in group M, compared with the 20.0% in group O (95% CI, 3.7%-50.8%; P = .029). Of those with the non-GG genotype, 41.5% treated with morphine and 23.1% with oxycodone required high-dose opioids (95% CI, 3.3%-38.3%; P = 0.098). Conclusion Using the COMT rs4680 genotype alone is not recommended for selecting between morphine and oxycodone for pain relief.
• クルクミンモノグルクロニドのPten欠損前立腺癌マウスに対する化学予防の可能性(Chemopreventive potential of curcumin monoglucuronide in mouse Pten-null prostate cancer)

  倉 由吏恵; デベラスコ・マルコ; 坂井 和子; 藤田 和利; 坂野 恵里; 藤田 至彦; 橋本 士; 西本 光寿; 野澤 昌弘; 吉村 一宏; 掛谷 秀昭; 植村 天受; 西尾 和人

  日本癌学会総会記事 81回 P - 2387 2022年09月
• がん疼痛に対するオピオイド選択のための多型バイオマーカーの探索

  藤田 至彦; 松岡 弘道; 鶴谷 純司; 千葉 康敬; 酒井 清裕; 吉田 健史; 大武 陽一; 小山 敦子; 西尾 和人; 中川 和彦

  Palliative Care Research 17 Suppl. S.179 - S.179 (NPO)日本緩和医療学会 2022年07月
• PDZK1 induces resistance to apoptosis in esophageal adenocarcinoma cells.

  Osamu Handa; Kyousuke Goda; Yukiko Handa; Shinya Fukushima; Motoyasu Osawa; Takahisa Murao; Hiroshi Matsumoto; Eiji Umegaki; Yoshihiko Fujita; Kazuto Nishio; Akiko Shiotani

  Esophagus : official journal of the Japan Esophageal Society 18 3 655 - 662 2021年07月 [査読有り]
   

  BACKGROUND: Esophageal cancer is a lethal malignancy with a poor prognosis. The incidence of esophageal adenocarcinoma, which develops from Barrett's esophagus (BE), has recently been increasing. In a previous study, we found that PDZK1 expression is higher in long segment BE compared to that in short-segment BE. However, the function of PDZK1 in the mucosa of BE is unclear. AIMS: Clarify the role of PDZK1 in BE mucosa using PDZK1 overexpressed cells. METHODS: Human adenocarcinoma-derived OE33 cells were used as a parental cell line and transfected to generate PDZK1 overexpressed OE33 cells (PC cells) or transfected with empty vector as control cells (NC cells). Cell growth of NC and PC cells in 10% fetal bovine serum was evaluated by cell counting. The effect of PDZK1 on proteasome inhibitor (PSI)-induced apoptosis was qualified by fluorescence microscopy and quantified by flow cytometry. Expression of apoptosis-related proteins was evaluated by western blotting. RESULTS: There were no significant differences in cell growth between NC and PC cells. PSI significantly increased apoptosis in NC cells, but not in PC cells. In response to PSI, increased levels of cleaved-caspase3 and decreased pro-caspase3 levels were found in NC cells, but not in PC cells. In NC cells, PSI significantly decreased Bcl-2 expression without affecting Bax levels. In contrast, high expression of both Bcl-2 and Bax was observed in PC cells. CONCLUSION: Overexpression of PDZK1 protein induces an apoptosis-resistant phenotype in BE cells, which may be a potential therapeutic target.
• Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site: A Nonrandomized Phase 2 Clinical Trial.

  Hidetoshi Hayashi; Yuichi Takiguchi; Hironobu Minami; Kohei Akiyoshi; Yoshihiko Segawa; Hiroki Ueda; Yasuo Iwamoto; Chihiro Kondoh; Koji Matsumoto; Shin Takahashi; Hisateru Yasui; Toshiyuki Sawa; Yusuke Onozawa; Yasutaka Chiba; Yosuke Togashi; Yoshihiko Fujita; Kazuko Sakai; Shuta Tomida; Kazuto Nishio; Kazuhiko Nakagawa

  JAMA oncology 6 12 1931 - 1938 2020年12月 [査読有り]
   

  Importance: Although profiling of gene expression and gene alterations by next-generation sequencing (NGS) to predict the primary tumor site and guide molecularly targeted therapy might be expected to improve clinical outcomes for cancer of unknown primary site (CUP), to our knowledge, no clinical trial has previously evaluated this approach. Objective: To assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP. Design, Setting, and Participants: This phase 2 clinical trial was conducted at 19 institutions in Japan and enrolled 111 previously untreated patients with the unfavorable subset of CUP between March 2015 and January 2018, with 97 patients being included in the efficacy analysis. Eligibility criteria included a diagnosis of unfavorable CUP after mandatory examinations, including pathological evaluation by immunohistochemistry, chest-abdomen-pelvis computed tomography scans, and a positron emission tomography scan. Interventions: RNA and DNA sequencing for selected genes was performed simultaneously to evaluate gene expression and gene alterations, respectively. A newly established algorithm was applied to predict tumor origin based on these data. Patients received site-specific therapy, including molecularly targeted therapy, according to the predicted site and detected gene alterations. Main Outcomes And Measures: The primary end point was 1-year survival probability. Secondary end points included progression-free survival (PFS), overall survival (OS), objective response rate, safety, efficacy according to predicted site, and frequency of gene alterations. Results: Of 97 participants, 49 (50.5%) were women and the median (range) age was 64 (21-81) years. The cancer types most commonly predicted were lung (21 [21%]), liver (15 [15%]), kidney (15 [15%]), and colorectal (12 [12%]) cancer. The most frequent gene alterations were in TP53 (45 [46.4%]), KRAS (19 [19.6%]), and CDKN2A (18 [18.6%]). The 1-year survival probability, median OS, and median PFS were 53.1% (95% CI, 42.6%-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Targetable EGFR mutations in tumor specimens were detected in 5 patients with predicted non-small-cell lung cancer (5.2%), 4 of whom were treated with afatinib; 2 of these patients achieved a durable PFS of longer than 6 months. Conclusions and Relevance: This study's findings suggest that site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by NGS, can contribute to treating patients with the unfavorable subset of CUP. Trial Registration: UMIN Identifier: UMIN000016794.
• Molecular biomarker identification for esophageal adenocarcinoma using endoscopic brushing and magnified endoscopy

  Kyosuke Goda; Takahisa Murao; Yukiko Handa; Ryo Katsumata; Shinya Fukushima; Rui Nakato; Motoyasu Osawa; Manabu Ishii; Minoru Fujita; Osamu Handa; Hiroshi Matsumoto; Yoshihiko Fujita; Kazuto Nishio; Timothy M. Wallace; Rene Gomez-Esquivel; Manuel Berzosa; Herbert C. Wolfsen; Michael B. Wallace; Eiji Umegaki; Akiko Shiotani

  Esophagus 18 2 306 - 314 2020年07月 [査読有り]
   

  BACKGROUND: Barrett's esophagus (BE) is a predisposing factor for esophageal adenocarcinoma (EAC); however, the precise mechanism underlying this association remains unclear. The identification of biomarkers that are associated with an increased risk of BE progression to EAC would facilitate diagnosis and early treatment. Toward this goal, we aimed to identify biomarkers associated with BE and EAC in patients. METHODS: In conjunction with high-resolution magnified endoscopy with narrow-band imaging (ME-NBI), we obtained brushing samples from the long-segment BE (LSBE) or short-segment BE (SSBE) of patients with EAC or without EAC (control). To identify candidate biomarker genes, microarray analysis was performed for a training set of 28 American samples. To confirm the microarray results, expression levels of the 16 candidate biomarkers were evaluated by real-time polymerase chain reaction analysis, using samples collected from an additional 53 American patients. In addition, we also performed a functional analysis for these genes using Gene Ontology (GO) enrichment analysis. RESULTS: Among the 16 genes identified as differentially expressed by microarray analysis, the GO analysis indicated matrix metalloproteinase (MMP) family associated with 'collagen metabolic process' and 'multicellular organismal macromolecule metabolic process' as the two top biological processes. Brushing samples of patients with EAC showed up-regulated expression of decay-accelerating factors (DAF and CD55) and topoisomerase type Iiα (TOP2A), and down-regulated expression of the sodium channel epithelial 1 beta subunit (SCNN1B). CONCLUSIONS: The up-regulation of CD55 and TOP2A, and the down-regulation of SCNN1B were common to the brushing samples and might serve as molecular biomarkers for identifying EAC in patients with SSBE. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) (000004004).
• Clinical and immune profiling for cancer of unknown primary site

  Koji Haratani; Hidetoshi Hayashi; Takayuki Takahama; Yasushi Nakamura; Shuta Tomida; Takeshi Yoshida; Yasutaka Chiba; Takahiro Sawada; Kazuko Sakai; Yoshihiko Fujita; Yosuke Togashi; Junko Tanizaki; Hisato Kawakami; Akihiko Ito; Kazuto Nishio; Kazuhiko Nakagawa

  Journal for ImmunoTherapy of Cancer 7 1 251 - 251 2019年12月 [査読有り]
   

  BACKGROUND: Immune checkpoint inhibitors (ICIs) confer a survival benefit in many cancer types. Given that the survival outcome for cancer of unknown primary site (CUP) remains poor, we investigated the potential of CUP for immunotherapy. METHODS: A total of 164 patients with CUP (favorable subset, 34 patients; unfavorable subset, 130 patients) who were treated between January 2009 and March 2017 was identified from a review of medical records at Kindai University Hospital. They included 92 patients for whom pretreatment tumor tissue was available both for determination of programmed cell death-ligand 1 expression and tumor-infiltrating lymphocyte (TIL) density by immunohistochemistry (IHC) and for immune-related gene expression profiling (irGEP). The results of irGEP for CUP were compared with published data for ICI-treated solid cancers classified into progressive disease (PD) and non-PD subsets according to their best response to ICIs. RESULTS: The median overall survival of all CUP patients was 29.3 months (95% confidence interval [CI], 15.7-not reached) and 7.1 months (95% CI, 5.0-9.4) for favorable and unfavorable subsets, respectively. IHC and irGEP revealed that pretreatment immune activity-including expression of immune checkpoint molecules-for CUP was similar to that for ICI-responsive malignancies (antitumor immune cell signatures: CUP versus PD, P = 0.002-0.067; CUP versus non-PD, P = 0.591-0.999), although VEGFA expression was associated with suppression of antitumor immunity in CUP (P = 0.008, false discovery rate = 0.010). In addition, one case of CUP in the unfavorable subset that was associated with prominent PD-L1 expression on TILs and showed a durable response to nivolumab is presented. CONCLUSIONS: The survival outcome of CUP remains unsatisfactory. However, our clinical and immune profiling of CUP has revealed a potential to benefit from immunotherapy, with ICIs thus being a potential option for CUP treatment.
• aCGH Analysis of Predictive Biomarkers for Response to Bevacizumab plus Oxaliplatin- or Irinotecan-Based Chemotherapy in Patients with Metastatic Colorectal Cancer.

  Yoshihiko Fujita; Masataka Taguri; Kentaro Yamazaki; Junji Tsurutani; Kazuko Sakai; Takahiro Tsushima; Michitaka Nagase; Hiroshi Tamagawa; Shinya Ueda; Takao Tamura; Yasushi Tsuji; Kohei Murata; Koichi Taira; Tadamichi Denda; Toshikazu Moriwaki; Sadao Funai; Takako Eguchi Nakajima; Kei Muro; Akihito Tsuji; Motoki Yoshida; Koichi Suyama; Takuya Kurimoto; Naotoshi Sugimoto; Eishi Baba; Nobuhiko Seki; Mikio Sato; Takaya Shimura; Narikazu Boku; Ichinosuke Hyodo; Takeharu Yamanaka; Kazuto Nishio

  The oncologist 24 3 327 - 337 2019年03月 [査読有り]
   

  BACKGROUND: The randomized phase III study (WJOG4407G) showed equivalent efficacy between FOLFOX and FOLFIRI in combination with bevacizumab as the first-line treatment for metastatic colorectal cancer (mCRC). We studied whole genome copy number profiles using array-based comparative genomic hybridization (aCGH) analysis of tumor tissue samples obtained in this study. The aim of this study was to identify gene copy number alterations that could aid in selecting either FOLFOX or FOLFIRI in combination with bevacizumab for patients with mCRC. MATERIALS AND METHODS: DNA was purified from 154 pretreatment formalin-fixed paraffin-embedded tissue samples (75 from the FOLFOX arm and 79 from the FOLFIRI arm) of 395 patients enrolled in the WJOG4407G trial and analyzed by aCGH. Genomic regions greater than 1.2-fold were regarded as copy number gain (CNG). RESULTS: Patient characteristics between the treatment arms were well balanced except for tumor laterality (left side; 64% in FOLFOX arm and 80% in FOLFIRI arm, p = .07). FOLFIRI showed a trend toward better response rate (RR), progression-free survival (PFS) and overall survival (OS) than FOLFOX in the patients with CNG of chromosome 8q24.1 (Fisher's exact test, p = .134 for RR; interaction test, p = .102 for PFS and p = .003 for OS) and 8q24.2 (Fisher's exact test, p = .179 for RR; interaction test, p = .144 for PFS and p = .002 for OS). CONCLUSION: Chromosome 8q24.1-q24.2 may contain genes that could potentially serve as predictive markers for selecting either FOLFOX or FOLFIRI in combination with bevacizumab for treatment of patients with mCRC. IMPLICATIONS FOR PRACTICE: Bevacizumab has been used as a standard first-line treatment for patients with metastatic colorectal cancer (mCRC) in combination with either oxaliplatin-based or irinotecan-based chemotherapy. Until now, there has been no predictive marker to choose between the two combination chemotherapies. This array-based comparative genomic hybridization analysis revealed that the difference in therapeutic effect between the two combination chemotherapies is prominent in patients with mCRC with gene copy number gain in chromosome 8p24.1-p24.2. Such patients showed more favorable response and survival when treated with irinotecan-based combination chemotherapy. Overlapping genes commonly found in this region may be predictive biomarkers of the efficacy of the combination chemotherapy with bevacizumab.
• Randomized Phase II Trial Comparing Site-Specific Treatment Based on Gene Expression Profiling With Carboplatin and Paclitaxel for Patients With Cancer of Unknown Primary Site

  Hidetoshi Hayashi; Takayasu Kurata; Yuichi Takiguchi; Makoto Arai; Koji Takeda; Kohei Akiyoshi; Koji Matsumoto; Takuma Onoe; Hirofumi Mukai; Nobuaki Matsubara; Hironobu Minami; Masanori Toyoda; Yusuke Onozawa; Akira Ono; Yoshihiko Fujita; Kazuko Sakai; Yasuhiro Koh; Ayano Takeuchi; Yasuo Ohashi; Kazuto Nishio; Kazuhiko Nakagawa

  Journal of Clinical Oncology 37 7 570 - 579 2019年03月 [査読有り]
   

  Although gene expression profiling is a promising diagnostic technique to determine the tissue of origin for patients with cancer of unknown primary site (CUP), no clinical trial has evaluated yet site-specific therapy directed by this approach compared with empirical chemotherapy. We therefore performed a randomized study to assess whether such site-specific therapy improves outcome compared with empirical chemotherapy in previously untreated patients with CUP. Comprehensive gene expression profiling was performed by microarray analysis, and an established algorithm was applied to predict tumor origin. Patients with CUP were randomly assigned (1:1) to receive standard site-specific therapy or empirical paclitaxel and carboplatin (PC). The primary end point was 1-year survival rate. One hundred thirty patients were randomly assigned and had sufficient biopsy tissue for molecular analysis. Efficacy analysis was performed for 50 and 51 patients in the site-specific therapy and empirical PC arms, respectively. Cancer types most commonly predicted were pancreatic (21%), gastric (21%), and lymphoma (20%). The 1-year survival rate was 44.0% and 54.9% for site-specific treatment and empirical PC ( P = .264), respectively. Median overall and progression-free survival were 9.8 and 5.1 months, respectively, for site-specific treatment versus 12.5 and 4.8 months for empirical PC ( P = .896 and .550, respectively). Median overall survival (16.7 v 10.6 months; P = .116) and progression-free survival (5.5 v 3.9 months; P = .018) were better for predicted more-responsive than less-responsive tumor types. Site-specific treatment that was based on microarray profiling did not result in a significant improvement in 1-year survival compared with empirical PC, although prediction of the original site seemed to be of prognostic value.
• Selection of opioids for cancer-related pain using a biomarker: a randomized, multi-institutional, open-label trial (RELIEF study)

  Hiromichi Matsuoka; Junji Tsurutani; Yasutaka Chiba; Yoshihiko Fujita; Masato Terashima; Takeshi Yoshida; Kiyohiro Sakai; Yoichi Otake; Atsuko Koyama; Kazuto Nishio; Kazuhiko Nakagawa

  BMC CANCER 17 1 674  2017年10月 [査読有り]
   

  Background: Cancer patients experience pain that has physiological, sensory, affective, cognitive, behavioral, and sociocultural dimensions. Opioids are used in treatment of pain in patients with various types of cancer. We previously showed that the catechol-O-methyltransferase (COMT) genotype is related to the plasma level of morphine and the required dose of morphine in an exploratory prospective study. The findings showed that a group of patients with a GG single nucleotide polymorphism (SNP) rs4680 in COMT required a significantly higher dose of morphine than a non-GG group. A biomarker for selection of opioids for cancer pain relief would be particularly useful clinically, and therefore we have planned a randomized comparative study of morphine and oxycodone, using the COMT rs4680 SNP as a biomarker. This study is aimed at verifying the assumption that patients in the GG group require an increased morphine dose for pain relief. Methods: The RELIEF study is a randomized, multi-institutional, open-label trial with a primary endpoint of the proportion of subjects requiring high-dose opioids, as calculated from the dose of a rescue preparation administered on day 0. Secondary endpoints include the Hospital Anxiety and Depression Scale, Short form McGill Pain Questionnaire-2, European Organization for Research and Treatment of Cancer QLQ-C15-PAL, Pain Catastrophizing Scale, and adverse events, Eligibility criteria are patients with advanced carcinoma with non-daily use of opioids in initial screening for registration; and cancer pain targeted for daily opioid treatment, NSAIDs or acetaminophen, NRS = >= 3(average over 24 h), opioid-treatment naive within 30 h, no chemotherapy, radiotherapy, or bisphosphonate administration newly started within 2 weeks, and written informed consent at the time of second registration. Between November 2014 and June 2017, an estimated 110 patients from two sites in Japan were randomized (1:1) to morphine or oxycodone in GG and non-GG groups. Discussion: A method for selection of appropriate opioids in cancer patients is a high unmet medical need. This study was designed to evaluate the efficacy of different opioids in patients with cancer based on gene polymorphism, as the first potential multi-institutional registration trial to be conducted in cancer patients with pain.
• Prospective replication study implicates the catechol-o-methyltransferase val158met polymorphism as a biomarker for the response to morphine in patients with cancer

  Hiromichi Matsuoka; Chihiro Makimura; Atsuko Koyama; Yoshihiko Fujita; Junji Tsurutani; Kiyohiro Sakai; Ryo Sakamoto; Kazuto Nishio; Kazuhiko Nakagawa

  Biomedical Reports 7 4 380 - 384 2017年10月 [査読有り]
   

  Genetic differences in humans cause clinical difficulties in opioid treatment. Previous studies indicate that a single nucleotide polymorphism in the catechol-O-methyltransferase (COMT) gene (rs4680 p.Val158Met) may present as a predictive biomarker for the response to morphine treatment. In our previous pilot exploratory study, patients with a G/G genotype were demonstrated to require a higher dose of morphine, compared with patients with A/A and A/G genotypes. In the present study, the aim was to replicate the findings in an independent cohort of opioid-treatment-naïve patients exhibiting various types of cancer. This prospective study was conducted from 2011 to 2012 at the Kindai University Faculty of Medicine. A total of 50 patients with opioid-treatment naïve and histologically confirmed malignant neoplasms who were scheduled to undergo opioid treatment were evaluated in the present study. Assessments were conducted pre-treatment (day 1), post-treatment (day 1), and one week after treatment (day 8). The required dose of morphine on day 1 was significantly higher for patients with the G/G genotype of COMT, compared with those with the A/A and A/G genotypes (P=0.013). The results of the present study provide additional evidence that the COMT genotype may be a predictive biomarker for the response to morphine treatment.
• Expectation of a Decrease in Pain Affects the Prognosis of Pain in Cancer Patients: a Prospective Cohort Study of Response to Morphine

  Hiromichi Matsuoka; Kazuhiro Yoshiuchi; Atsuko Koyama; Chihiro Makimura; Yoshihiko Fujita; Junji Tsurutani; Kiyohiro Sakai; Ryo Sakamoto; Kazuto Nishio; Kazuhiko Nakagawa

  INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE 24 4 535 - 541 2017年08月 [査読有り]
   

  Purpose Cancer pain is a multidimensional experience that includes physiological, sensory, affective, cognitive, behavioral, and sociocultural dimensions. Few prospective studies have examined the relationship between a patient's expectation of pain improvement and the pain prognosis. The aim of this prospective study was to investigate whether patients' expectation to pain reduction was associated with pain intensity after morphine treatment in opioid treatment-na < ve patients with various types of cancer. The subjects were patients scheduled for cancer pain treatment with morphine who were taking nonsteroidal anti-inflammatory drugs daily. Morphine treatment was performed according to the standard method, including titration (NCCN Guidelines (TM), Adult Cancer Pain). Simple regression analysis was performed between pain intensity numerical rating scale (NRS) (day 8) as the dependent variable, expectation of pain decrease NRS (day 1), tumor types, and the following covariates as independent variables: patients' characteristics such as age, gender, PS (day 1), genotype of catechol-O-methyltransferase, total scores of Hospital Anxiety and Depression Scale (day 1), and pain intensity NRS (day 1). Multiple regression analysis was performed using forced entry methods with pain intensity NRS (day 8) as the dependent variable, and expectation of pain decrease NRS (day 1) and the covariates as independent variables that had a p value < 0.05 in the simple regression models. A total of 100 patients with baseline data were included, and 97 patients (51% female) met the inclusion criteria. Patients with a high expectation of pain decrease NRS had a significantly lower pain intensity NRS (day 8) (p = 0.001). Non-pharmacological factors such as expectations for pain treatment could also be important factors to treat cancer pain, which might be associated with communication skills in physicians.
• Clinical significance of Akt2 in advanced pancreatic cancer treated with erlotinib

  Eri Banno; Yosuke Togashi; Marco A. De Velasco; Takuro Mizukami; Yu Nakamura; Masato Terashima; Kazuko Sakai; Yoshihiko Fujita; Ken Kamata; Masayuki Kitano; Masatoshi Kudo; Kazuto Nishio

  INTERNATIONAL JOURNAL OF ONCOLOGY 50 6 2049 - 2058 2017年06月 [査読有り]
   

  Akt2 is an isoform of Akt, and an association between Akt2 and resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been suggested in pancreatic cancer (PC) in vitro. In this study, we investigated the association between Akt2 expression as evaluated using immunohistochemistry and the outcome of patients with advanced PC who had received treatment with erlotinib (an EGFR-TKI). Although the difference was not significant, patients with high levels of Akt2 expression tended to have a poorer response and a shorter progression-free survival period after treatment with erlotinib plus gemcitabine than those with low expression levels (P=0.16 and 0.19, respectively). In vitro, an Akt2-amplified PC cell line and Akt2-overexpressed cell lines exhibited resistance to anti-EGFR therapies, including erlotinib, but combined treatment with BYL719 (a PI3K inhibitor) cancelled this resistance. Our findings suggest that Akt2 might be associated with the resistance to anti-EGFR therapies, especially the use of erlotinib against PC, and that this resistance can be overcome by combined treatment with a PI3K inhibitor. Akt2 expression could become a predictive biomarker for erlotinib resistance in PC.
• Efficacy of irreversible EGFR-TKIs for the uncommon secondary resistant EGFR mutations L747S, D761Y, and T854A

  Masato Chiba; Yosuke Togashi; Eri Bannno; Yoshihisa Kobayashi; Yu Nakamura; Hidetoshi Hayashi; Masato Terashima; Marco A. De Velasco; Kazuko Sakai; Yoshihiko Fujita; Tetsuya Mitsudomi; Kazuto Nishio

  BMC CANCER 17 1 281  2017年04月 [査読有り]
   

  Background: Non-small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) gene mutations (exon 19 deletion or exon 21 L858R) respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The secondary T790 M mutation in exon 20 of the EGFR gene is the most common type of acquired resistance mutation. Several reports have also shown that other secondary mutations (L747S, D761Y and T854A), while uncommon, can induce acquired resistance to first-generation EGFR-TKIs. However, little is known about the anticancer activities of second-or third-generation EGFR-TKIs. Methods: Uncommon secondary mutations were introduced into Ba/F3 cells along with the sensitive EGFR L858R mutation (Ba/F3-L858R/L747S, Ba/F3-L858R/D761Y, and Ba/F3-L858R/T854A), and the sensitivities to various EGFR-TKIs were then investigated. Results: Both the Ba/F3-L858R/L747S and Ba/F3-L858R/D761Y cell lines exhibited weak resistances to first-generation reversible EGFR-TKIs, while the Ba/F3-L858R/T854A cell line exhibited a strong resistance. In contrast, irreversible EGFR-TKIs, especially third-generation EGFR-TKIs, were capable of overcoming these resistances. Western blot analyses demonstrated that gefitinib (first-generation) inhibited the phosphorylation of EGFR to a lesser extent in cells with these secondary mutations than in cells with the sensitive L858R mutation alone. In contrast, afatinib and osimertinib (second-and third-generation) inhibited the phosphorylation of EGFR in cells with these secondary mutations to a similar extent as that seen in cells with the sensitive L858R mutation alone. Conclusions: Our experimental findings suggest that irreversible EGFR-TKIs, especially third-generation EGFR-TKIs, can be effective against uncommon secondary mutations and that switching to third-generation EGFR-TKIs could be a promising treatment strategy for patients with acquired resistance because of these uncommon secondary mutations.
• Incidence of carnitine deficiency in patients with cancer pain: A pilot study.

  Sakai K; Matsuoka H; Ohtake Y; Makimura C; Izumi H; Fujita Y; Otsuka M; Tsurutani J; Nishio K; Nakagawa K; Koyama A

  Molecular and clinical oncology 6 3 331 - 333 2017年03月 [査読有り]
   

  Carnitine deficiency is reportedly associated with increased pain sensation in diabetes mellitus and fibromyalgia, but the association between serum carnitine concentration and cancer pain has not been fully elucidated. We investigated the incidence of carnitine deficiency in patients with cancer pain, and examined the effect of the patients' demographic and clinical characteristics on pain intensity and carnitine deficiency. The serum carnitine concentration was measured in 50 patients with cancer pain receiving non-steroidal anti-inflammatory drugs, but not opioids. Multivariate regression analysis was used to determine the association of carnitine concentration, pain intensity, age and gender with hemoglobin and C-reactive protein (CRP) concentrations. Carnitine deficiency was detected in 9 of the patients (18.0%) and found to be significantly correlated with an elevated CRP concentration (P=0.039). In conclusion, although there does not appear to be an association between carnitine deficiency and cancer pain, it may be affected by inflammation or infection.
• Significance of FGF9 gene in resistance to anti-EGFR therapies targeting colorectal cancer: A subset of colorectal cancer patients with FGF9 upregulation may be resistant to anti-EGFR therapies

  Mizukami T; Togashi Y; Naruki S; Banno E; Terashima M; de Velasco MA; Sakai K; Yoneshige A; Hayashi H; Fujita Y; Tomida S; Nakajima TE; Fujino T; Boku N; Ito A; Nakagawa K; Nishio K

  Mol Carcinog 56 1 106 - 117 Wiley 2017年01月 [査読有り]
  
• MEK inhibitors against MET-amplified non-small cell lung cancer

  Masato Chiba; Yosuke Togashi; Shuta Tomida; Hiroshi Mizuuchi; Yu Nakamura; Eri Banno; Hidetoshi Hayashi; Masato Terashima; Marco A. De Velasc; Kazuko Sakai; Yoshihiko Fujita; Tetsuya Mitsudomi; Kazuto Nishio

  INTERNATIONAL JOURNAL OF ONCOLOGY 49 6 2236 - 2244 2016年12月 [査読有り]
   

  Several receptor tyrosine kinases (RTKs) including EGFR, ALK, and MET have been identified as therapeutic targets in non-small cell lung cancer (NSCLC). Among the downstream pathways of RTKs, the MAPK pathway is particularly important for cancer cell proliferation, differentiation, and survival. In this study, the effects of MEK inhibitors (trametinib and PD0325901) in several NSCLC cell lines with driver gene alterations, especially RTK genes, were tested in vitro using an MTT assay, and a wide range of sensitivities was found. In particular, all the EGFR-mutated cell lines were resistant to MEK inhibitors, whereas all the MET-amplified cell lines were sensitive. A bioinformatics technique and western blot analyses showed that the PI3K/AKT pathway is more activated in EGFRmutated NSCLC than in MET-amplified NSCLC, and a PI3K inhibitor enhanced the sensitivity to trametinib in the EGFR-mutated cell lines, suggesting that this pathway is associated with resistance to MEK inhibitors. Although the HCC827 cell line (EGFR mutation) was resistant to MEK inhibitors, the HCC827CNXR cell line, whose driver gene shifts from EGFR to MET, exhibited enhanced sensitivity to MEK inhibitors, indicating the biological importance of the MAPK pathway for MET-amplified NCSLC. Furthermore, a synergistic effect of crizotinib (a MET inhibitor) and trametinib was observed in MET-amplified NCLC cell lines. Our findings indicate that the MAPK pathway is biologically important for MET-amplified NSCLC and strongly encourage the development of combination therapy with a MET inhibitor and a MEK inhibitor against MET-amplified NSCLC.
• FGFR gene alterations in lung squamous cell carcinoma are potential targets for the multikinase inhibitor nintedanib

  Masaaki Hibi; Hiroyasu Kaneda; Junko Tanizaki; Kazuko Sakai; Yosuke Togashi; Masato Terashima; Marco Antonio De Velasco; Yoshihiko Fujita; Eri Banno; Yu Nakamura; Masayuki Takeda; Akihiko Ito; Tetsuya Mitsudomi; Kazuhiko Nakagawa; Isamu Okamoto; Kazuto Nishio

  CANCER SCIENCE 107 11 1667 - 1676 2016年11月 [査読有り]
   

  Fibroblast growth factor receptor (FGFR) gene alterations are relatively frequent in lung squamous cell carcinoma (LSCC) and are a potential targets for therapy with FGFR inhibitors. However, little is known regarding the clinicopathologic features associated with FGFR alterations. The angiokinase inhibitor nintedanib has shown promising activity in clinical trials for non-small cell lung cancer. We have now applied next-generation sequencing (NGS) to characterize FGFR alterations in LSCC patients as well as examined the antitumor activity of nintedanib in LSCC cell lines positive for FGFR1 copy number gain (CNG). The effects of nintedanib on the proliferation of and FGFR signaling in LSCC cell lines were examined invitro, and its effects on tumor formation were examined invivo. A total of 75 clinical LSCC specimens were screened for FGFR alterations by NGS. Nintedanib inhibited the proliferation of FGFR1 CNG-positive LSCC cell lines in association with attenuation of the FGFR1-ERK signaling pathway invitro and invivo. FGFR1 CNG (10.7%), FGFR1 mutation (2.7%), FGFR2 mutation (2.7%), FGFR4 mutation (5.3%), and FGFR3 fusion (1.3%) were detected in LSCC specimens by NGS. Clinicopathologic features did not differ between LSCC patients positive or negative for FGFR alterations. However, among the 36 patients with disease recurrence after surgery, prognosis was significantly worse for those harboring FGFR alterations. Screening for FGFR alterations by NGS warrants further study as a means to identify patients with LSCC recurrence after surgery who might benefit from nintedanib therapy.
• Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC

  Yu Nakamura; Yosuke Togashi; Hirokazu Nakahara; Shuta Tomida; Eri Banno; Masato Terashima; Hidetoshi Hayashi; Marco A. de Velasco; Kazuko Sakai; Yoshihiko Fujita; Takatsugu Okegawa; Kikuo Nutahara; Suguru Hamada; Kazuto Nishio

  MOLECULAR CANCER THERAPEUTICS 15 8 1988 - 1997 2016年08月 [査読有り]
   

  The prognosis for patients with advanced esophageal or head-and-neck squamous cell carcinoma (ESCC or HNSCC) remains poor, and the identification of additional oncogenes and their inhibitors is needed. In this study, we evaluated the sensitivities of several ESCC and HNSCC cell lines to HER inhibitors (cetuximab, erlotinib, and afatinib) in vitro and found two cell lines that were hypersensitive to afatinib. Sequence analyses for the afatinib-targeted HER family genes in the two cell lines revealed that one cell line had a previously reported activating EGFR L861Q mutation, whereas the other had an HER4 G1109C mutation of unknown function. No amplification of HER family genes was found in either of the two cell lines. The phosphorylation level of HER4 was elevated in the HER4 G1109C mutation-overexpressed HEK293 cell line, and the mutation had a transforming potential and exhibited tumorigenicity in an NIH3T3 cell line, indicating that this HER4 mutation was an activating oncogenic mutation. Afatinib dramatically reduced the phosphorylation level of EGFR or HER4 and induced apoptosis in the two cell lines. In vivo, tumor growth was also dramatically decreased by afatinib. In a database, the frequencies of HER family gene mutations in ESCC or HNSCC ranged from 0% to 5%. In particular, HER4 mutations have been found relatively frequently in HNSCC. Considering the addiction of cancer cells to activating oncogenic EGFR or HER4 mutations for proliferation, HNSCC or ESCC with such oncogenic mutations might be suitable for targeted therapy with afatinib. (C) 2016 AACR.
• Sensitivities to various epidermal growth factor receptor-tyrosine kinase inhibitors of uncommon epidermal growth factor receptor mutations L861Q and S768I: What is the optimal epidermal growth factor receptor-tyrosine kinase inhibitor?

  Eri Banno; Yosuke Togashi; Yu Nakamura; Masato Chiba; Yoshihisa Kobayashi; Hidetoshi Hayashi; Masato Terashima; Marco A. de Velasco; Kazuko Sakai; Yoshihiko Fujita; Tetsuya Mitsudomi; Kazuto Nishio

  CANCER SCIENCE 107 8 1134 - 1140 2016年08月 [査読有り]
   

  Most patients with non-small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) mutations, such as deletions in exon 19 or the L858R mutation in exon 21, respond dramatically to EGFR tyrosine kinase inhibitors (EGFR-TKI), and their sensitivities to various EGFR-TKI have been well characterized. Our previous article showed the in vitro sensitivities of EGFR exon 18 mutations to EGFR-TKI, but little information regarding the sensitivities of other uncommon EGFR mutations is available. First, stable transfectant Ba/F3 cell lines harboring EGFR L858R (Ba/F3-L858R), L861Q (Ba/F3-L861Q) or S768I (Ba/F3-S768I) mutations were created and their drug sensitivities to various EGFR-TKI were examined. Both the Ba/F3-L861Q and Ba/F3-S768I cell lines were less sensitive to erlotinib, compared with the Ba/F3-L858R cell line, but their sensitivities to afatinib were similar to that of the Ba/F3-L858R cell line. The Ba/F3-L861Q cell line was similarly sensitive and the Ba/F3-S768I cell line was less sensitive to osimertinib, compared with the Ba/F3-L858R cell line. The results of western blot analyses were consistent with these sensitivities. Next, similar experiments were also performed using the KYSE270 (L861Q) and KYSE 450 (S768I) cell lines, and their results were compatible with those of the transfectant Ba/F3 cell lines. Our findings suggest that NSCLC harboring the EGFR L861Q mutation might be sensitive to afatinib or osimertinib and that NSCLC harboring the EGFR S768I mutation might be sensitive to afatinib. Overall, afatinib might be the optimal EGFR-TKI against these uncommon EGFR mutations.
• Functional Analyses of Mutations in Receptor Tyrosine Kinase Genes in Non-Small Cell Lung Cancer: Double-Edged Sword of DDR2

  Masato Terashima; Yosuke Togashi; Katsuaki Sato; Hiroshi Mizuuchi; Kazuko Sakai; Kenichi Suda; Yu Nakamura; Eri Banno; Hidetoshi Hayashi; Marco A. De Velasco; Yoshihiko Fujita; Shuta Tomida; Tetsuya Mitsudomi; Kazuto Nishio

  CLINICAL CANCER RESEARCH 22 14 3663 - 3671 2016年07月 [査読有り]
   

  Purpose: This study investigated whether mutations of receptor tyrosine kinase (RTK) genes detected using next-generation sequencing (NGS) are suitable therapeutic targets. Experimental design: Fifty surgically resected non-small cell lung cancer (NSCLC) samples were target resequenced using NGS. We then investigated the functions of the identified RTK gene mutations, including their oncogenic potential, in vitro. Results: Mutations in RTK genes were found in 20 samples (EGFR, 15; ERBB4, 1; ALK, 1; DDR2, 2; FGFR1, 1), mutations in MAPK pathway genes were found in nine samples (KRAS, 7; NRAS, 1; BRAF, 2), and mutations in PI3K pathway genes were found in three samples (PIK3CA, 1; PTEN, 3). Among the mutations in RTKs, the functions of four mutations were unclear (ERBB4 D245G; DDR2 H246R and E655K; FGFR1 A263V). These mutations did not exhibit any transformational activities. Neither the phosphorylation nor the protein expressions of RTKs were changed by the DDR2 H246R, ERBB4 D245G, and FGFR1 A263V mutations, although the expression level of the DDR2 protein harboring the E655K mutation was particularly low. Collagen stimulation decreased cellular proliferation through p38 activation in the DDR2 wild-type-overexpressed cell lines, whereas the growth-suppressive effect was weakened in DDR2 E655K-overex-pressed cell lines. Furthermore, the DDR2 E655K protein strongly bound to ubiquitin ligase E3 (Cbl-b), and the mutant protein expression was increased after treatment with a proteasome inhibitor. Conclusions: Our experimental findings suggest that RTK mutations are not always suitable as therapeutic targets. The DDR2 E655K mutation can play a role in cancer progression by reducing the growth-inhibitory effect of collagen. (C) 2016 AACR.
• Characterization of the cytotoxic activity of [2]rotaxane (TRO-A0001), a novel supramolecular compound, in cancer cells

  Yoshihiko Fujita; Masahiko Kimura; Hiroki Sato; Toshikazu Takata; Nobufumi Ono; Kazuto Nishio

  ARCHIVES OF PHARMACAL RESEARCH 39 6 825 - 832 2016年06月 [査読有り]
   

  Rotaxanes comprise a class of interlocked molecules containing a wheel threaded onto an axle with blocking groups on the ends to keep the wheel from sliding off. Here, we show that [2][bis(2-(3,5-dimethylphenylcarbonyloxy)ethyl) ammoniumtrifluoromethanesulfonate]-[dibenzo-24-crown-8] rotaxane (TRO-A0001), a rotaxane compound, exerted a growth inhibitory effect on several human cancer cell lines. An MTT assay revealed an IC50 of 14-830 nM for TRO-A0001 in these cells. Neither the wheel nor the axle part alone inhibited tumor cell growth, suggesting that the complete rotaxane molecule with its unique "intramolecular mobility" is required to inhibit cell growth. Annexin-V/PI staining provided evidence of the induction of apoptosis, which was further confirmed by the observation of poly (ADP-ribose) polymerase cleavage. Furthermore, a cell cycle analysis using flow cytometry showed that TRO-A0001 treatment resulted in G(1) arrest in glioblastoma T98G and melanoma G361 cells. An immunoblot analysis revealed that in both cell lines, TRO-A0001 treatment caused the induction of p21/Cip1, thereby down-regulating Cdks 2, 4 and 6 and reducing Cyclins D1 and E. The results presented in this study demonstrate cytotoxicity of the rotaxane compound and its potential as a lead compound for the development of a chemotherapeutic agent against cancer.
• Impact of Tight Junction Protein ZO-1 and TWIST Expression on Postoperative Survival of Patients with Hepatocellular Carcinoma

  Tomoyuki Nagai; Tokuzo Arao; Kazuto Nishio; Kazuko Matsumoto; Satoru Hagiwara; Toshiharu Sakurai; Yasunori Minami; Hiroshi Ida; Kazuomi Ueshima; Naoshi Nishida; Kazuko Sakai; Nagahiro Saijo; Kanae Kudo; Hiroyasu Kaneda; Daisuke Tamura; Keiichi Aomatsu; Hideharu Kimura; Yoshihiko Fujita; Seiji Haji; Masatoshi Kudo

  DIGESTIVE DISEASES 34 6 702 - 707 2016年 [査読有り]
   

  Background: Epithelial-mesenchymal transition (EMT) is considered to play a critical role in cancer progression and metastasis. However, the impact of EMT on the prognosis of hepatocellular carcinoma (HCC) is still elusive. In this study, we examined the relationship between the expression of EMT markers and recurrence-free survival (RFS) and overall survival (OS) in HCC patients after hepatic resection. Summary:The mRNA expression of 15 genes related to EMT was assessed by quantitative real-time polymerase chain reaction in cancerous tissues from 72 patients who underwent hepatic resection of HCC between January 2005 and December 2010 at our hospital. The upregulation of TWIST and the downregulation of tight junction protein ZO-1 (TJP1) were significantly associated with shorter RFS as well as OS. Increased levels of TWIST and decreased levels of TJP1 should be predictive markers for poor prognosis in patients with HCC after hepatectomy; those could serve as potential biomarkers for the treatment of HCC. Key Messages: A low level of TJP1 and high level of TWIST expression were prognostic factors predicting HCC after hepatic resection. (C) 2016 S. Karger AG, Basel
• Overexpression of CD55 from Barrett's esophagus is associated with esophageal adenocarcinoma risk

  Takahisa Murao; Akiko Shiotani; Yoshihiko Fujita; Yoshiyuki Yamanaka; Tomoari Kamada; Noriaki Manabe; Jiro Hata; Kazuto Nishio; Ken Haruma

  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 31 1 99 - 106 2016年01月 [査読有り]
   

  Background and Aim: Although several molecular biomarkers for esophageal adenocarcinoma (EAC) have been shown to be useful disease indicators, none has been established as a reliable indicator for risk of EAC or have progressed to routine use. The aim was to identify biomarkers of high risk for EAC in patients with Barrett's esophagus (BE). Methods: Following endoscopic observation by magnified endoscopy with narrow band imaging (ME-NBI), brushing was followed by obtaining biopsy samples from columnarlined esophagus (CLE) and from EAC lesions of EAC patients, and from age-and sexmatched non-EAC controls with BE. Total RNA was extracted for microarray analysis using Affymetrix GeneChip Human Genome U133 plus 2.0 Array. Real-time-PCR analysis of identified candidate genes was used to confirm the results. Results: Overall, 9 EAC patients and 50 patients with BE were studied. Seventy-nine candidate genes were identified by microarray analysis based on a proportional hazards model (P < 0.005). Six genes exhibited significantly differential expressions in both BE and cancer lesions of the EAC group compared to BE of the controls. In the brushing samples, median CD55 relative expression levels in cancer lesions were highest and decreased in BE of EAC group and BE of the controls, in that order (P < 0.001). Conclusion: Over expression of CD55 in brushing samples taken from BE may be associated with the risk of EAC.
• Clinicopathological and Genetic Differences Between Low-Grade and High-Grade Colorectal Mucinous Adenocarcinomas

  Yasumasa Yoshioka; Yosuke Togashi; Takaaki Chikugo; Akihiro Kogita; Masataka Taguri; Masato Terashima; Takuro Mizukami; Hidetoshi Hayashi; Kazuko Sakai; Marco A. de Velasco; Shuta Tomida; Yoshihiko Fujita; Tadao Tokoro; Akihiko Ito; Kiyotaka Okuno; Kazuto Nishio

  CANCER 121 24 4359 - 4368 2015年12月 [査読有り]
   

  BACKGROUND: Although colorectal mucinous adenocarcinomas (MCs) are conventionally regarded as exhibiting high-grade differentiation, they can be divided by differentiation into 2 groups according to the glandular appearance: low-grade mucinous adenocarcinoma (low-MC) and high-grade mucinous adenocarcinoma (high-MC). METHODS: Patients with colorectal cancer (CRC) who underwent surgical resection between 2000 and 2012 were enrolled in this study. Among the cases with MC, the clinicopathological and genetic differences between low-MC and high-MC were investigated with next-generation sequencing. RESULTS: A total of 1373 patients with CRC were analyzed. Forty patients (2.9%) had MC, and 13 patients had high-MC. Patients with MC had significantly shorter disease-free survival (DFS) and overall survival (OS) periods than those with nonmucinous carcinoma. When low-MC patients and high-MC patients were compared, those with high-MC had significantly shorter DFS and OS periods than those with low-MC. Multivariate analyses revealed that high-MC was significantly associated with both shorter DFS and shorter OS, but low-MC was not. A genome analysis revealed that low-MC had a considerably larger number of mutations than high-MC, and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and adenomatous polyposis coli mutations were particularly frequently found in low-MC. In contrast, SMAD family member 4 (SMAD4) mutations were frequently found in high-MC. CONCLUSIONS: High-MC is an independent prognostic factor in CRC (but low-MC is not), and it is genetically different from other CRCs, including low-MC. Both the clinicopathological differences and the genetic differences suggest that low-MC and high-MC should be distinguished in clinical settings. (C) 2015 American Cancer Society.
• An activating ALK gene mutation in ALK IHC-positive/FISH-negative non-small cell lung cancer.

  Togashi Y; Mizuuchi H; Kobayashi Y; Hayashi H; Terashima M; Sakai K; Bannno E; Mizukami T; Nakamura Y; de Velasco MA; Fujita Y; Tomida S; Mitsudomi T; Nishio K

  Ann Oncol 26 8 1800 - 1801 2015年08月 [査読有り]
  
• EGFR and HER2 signals play a salvage role in MEK1-mutated gastric cancer after MEK inhibition

  Takuro Mizukami; Yosuke Togashi; Shunsuke Sogabe; Eri Banno; Masato Terashima; Marco A. de Velasco; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Takako Eguchi Nakajima; Narikazu Boku; Kazuto Nishio

  INTERNATIONAL JOURNAL OF ONCOLOGY 47 2 499 - 505 2015年08月 [査読有り]
   

  Since the prognosis of unresectable advanced gastric cancer remains poor, novel therapeutic strategies are needed. Somatic MEKI gene mutations have been reported as oncogenic activating mutations in gastric cancer, and MEK inhibitors can be effective against such gastric cancers. In the present study, however, activated EGFR and HER2 signals after treatment with a MEK inhibitor (trametinib) were found in a MEK1-mutated gastric cancer cell line (OCUM-1 cell line) using a phospho-receptor tyrosine kinase array. The phosphorylation of EGFR and HER2 reactivated ERK1/2, which had been inhibited by trametinib, and EGF stimulation led to resistance to trametinib in this cell line. Lapatinib, an EGFR and an HER2 inhibitor, reversed the activation of ERK1/2 by inhibiting the phosphorylation of EGFR and HER2 and cancelled the resistance. The combination of trametinib and lapatinib synergistically inhibited the cell growth of the OCUM-1 cell line and strongly induced apoptosis by inhibiting the activated EGFR and HER2 signals. These results suggest that the EGFR and HER2 signals play a salvage role and are related to resistance to MEK inhibitors in MEK1-mutated gastric cancer. Moreover, combination therapy with trametinib and lapatinib can exhibit a synergistic effect and may contribute to overcoming the resistance to MEK inhibitors.
• Extended RAS and BRAF Mutation Analysis Using Next-Generation Sequencing

  Kazuko Sakai; Junji Tsurutani; Takeharu Yamanaka; Azusa Yoneshige; Akihiko Ito; Yosuke Togashi; Marco A. De Velasco; Masato Terashima; Yoshihiko Fujita; Shuta Tomida; Takao Tamura; Kazuhiko Nakagawa; Kazuto Nishio

  PLOS ONE 10 5 e0121891  2015年05月 [査読有り]
   

  Somatic mutations in KRAS, NRAS, and BRAF genes are related to resistance to anti-EGFR antibodies in colorectal cancer. We have established an extended RAS and BRAF mutation assay using a next-generation sequencer to analyze these mutations. Multiplexed deep sequencing was performed to detect somatic mutations within KRAS, NRAS, and BRAF, including minor mutated components. We first validated the technical performance of the multiplexed deep sequencing using 10 normal DNA and 20 formalin-fixed, paraffin-embedded (FFPE) tumor samples. To demonstrate the potential clinical utility of our assay, we profiled 100 FFPE tumor samples and 15 plasma samples obtained from colorectal cancer patients. We used a variant calling approach based on a Poisson distribution. The distribution of the mutation-positive population was hypothesized to follow a Poisson distribution, and a mutation-positive status was defined as a value greater than the significance level of the error rate (alpha = 2 x 10(-5)). The cut-off value was determined to be the average error rate plus 7 standard deviations. Mutation analysis of 100 clinical FFPE tumor specimens was performed without any invalid cases. Mutations were detected at a frequency of 59% (59/100). KRAS mutation concordance between this assay and Scorpion-ARMS was 92% (92/100). DNA obtained from 15 plasma samples was also analyzed. KRAS and BRAF mutations were identified in both the plasma and tissue samples of 6 patients. The genetic screening assay using next-generation sequencer was validated for the detection of clinically relevant RAS and BRAF mutations using FFPE and liquid samples.
• Collateral Chemoresistance to Anti-Microtubule Agents in a Lung Cancer Cell Line with Acquired Resistance to Erlotinib

  Hiroshi Mizuuchi; Kenichi Suda; Katsuaki Sato; Shuta Tomida; Yoshihiko Fujita; Yoshihisa Kobayashi; Yoshihiko Maehara; Yoshitaka Sekido; Kazuto Nishio; Tetsuya Mitsudomi

  PLOS ONE 10 4 e0123901  2015年04月 [査読有り]
   

  Various alterations underlying acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have been described. Although treatment strategies specific for these mechanisms are under development, cytotoxic agents are currently employed to treat many patients following failure of EGFR-TKIs. However, the effect of TKI resistance on sensitivity to these cytotoxic agents is mostly unclear. This study investigated the sensitivity of erlotinib-resistant tumor cells to five cytotoxic agents using an in vitro EGFR-TKI-resistant model. Four erlotinib-sensitive lung adenocarcinoma cell lines and their resistant derivatives were tested. Of the resistant cell lines, all but one showed a similar sensitivity to the tested drugs as their parental cells. HCC4006ER cells with epithelial mesenchymal transition features acquired resistance to the three microtubule-targeting agents, docetaxel, paclitaxel and vinorelbine, but not to cisplatin and gemcitabine. Gene expression array and immunoblotting demonstrated that ATP-binding cassette subfamily B, member 1 (ABCB1) was up-regulated in HCC4006ER cells. ABCB1 knockdown by siRNA partially restored sensitivity to the anti-microtubule agents but not to erlotinib. Moreover, the histone deacetylase inhibitor entinostat sensitized HCC4006ER cells to anti-microtubule agents through ABCB1 suppression. Our study indicates that sensitivity of tumor cells to cytotoxic agents in general does not change before and after failure of EGFR-TKIs. However, we describe that two different molecular alterations confer acquired resistance to EGFR-TKIs and cytotoxic agents, respectively. This phenomenon should be kept in mind in selection of subsequent therapy after failure of EGFR-TKIs.
• Chronic nicotine exposure mediates resistance to EGFR-TKI in EGFR-mutated lung cancer via an EGFR signal

  Yosuke Togashi; Hidetoshi Hayashi; Kunio Okamoto; Soichi Fumita; Masato Terashima; Marco A. de Velasco; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Kazuhiko Nakagawa; Kazuto Nishio

  LUNG CANCER 88 1 16 - 23 2015年04月 [査読有り]
   

  Background: Some of patients with non-small cell lung cancer (NSCLC) harboring somatic activating mutations of the epidermal growth factor receptor gene (EGFR mutations) show poor responses to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) treatment. Cigarette smoking is the strongest documented risk factor for the development of lung cancer. Nicotine, while not carcinogenic by itself, has been shown to induce proliferation, angiogenesis, and the epithelial-mesenchymal transition; these effects might be associated with EGFR-TKI resistance. Materials and methods: PC-9 and 11-18 cell lines (EGFR-mutated NSCLC cell lines) were cultured with 1 mu M nicotine for 3 months and were designated as PC-9/N and 11-18/N cell lines, respectively. The sensitivities of these cell lines to EGFR-TKI were then tested in vitro. Moreover, the association between the smoking status and the progression-free survival (PFS) period was investigated in patients with EGFR-mutated NSCLC who were treated with gefitinib. Results: The PC-9/N and 11-18/N cell lines were resistant to EGFR-TKI, compared with controls. The phosphorylation of EGFR in these cell lines was reduced by EGFR-TKI to a smaller extent than that observed in controls, and a higher concentration of EGFR-TKI was capable of further decreasing the phosphorylation. Clinically, smoking history was an independent predictor of a poor PFS period on gefitinib treatment. Conclusions: Chronic nicotine exposure because of cigarette smoking mediates resistance to EGFR-TKI via an EGFR signal. Smoking cessation is of great importance, while resistance may be overcome through the administration of high-dose EGFR-TKI. (c) 2015 Elsevier Ireland Ltd. All rights reserved.
• Activated MET acts as a salvage signal after treatment with alectinib, a selective ALK inhibitor, in ALK-positive non-small cell lung cancer

  Akihiro Kogita; Yosuke Togashi; Hidetoshi Hayashi; Eri Banno; Masato Terashima; Marco A. De Velasco; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Yoshifumi Takeyama; Kiyotaka Okuno; Kazuhiko Nakagawa; Kazuto Nishio

  INTERNATIONAL JOURNAL OF ONCOLOGY 46 3 1025 - 1030 2015年03月 [査読有り]
   

  Non-small cell lung cancer (NSCLC) carrying echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements is hypersensitive to ALK inhibitors, including crizotinib and alectinib. Crizotinib was initially designed as a MET inhibitor, whereas alectinib is a selective ALK inhibitor. The MET signal, which is inhibited by crizotinib but not by alectinib, is dysregulated in many human cancers. However, the role of the MET signal in ALK-positive NSCLC remains unclear. In this study, we found that hepatocyte growth factor (HGF), ligand of MET, mediated the resistance to alectinib, but not to crizotinib, via the MET signal in ALK-positive NSCLC cell lines (H3122 and H2228 cell lines). In addition, alectinib activated the MET signal even in the absence of HGF and the inhibition of the MET signal enhanced the efficacy of alectinib. These findings suggest that activated MET acts as a salvage signal in ALK-positive NSCLC. This novel role of the MET signal in ALK-positive NSCLC may pave the way for further clinical trials examining MET inhibitors.
• Low-Dose Aspirin-Associated Upper and Mid Gastrointestinal Tract Damage and Gene Polymorphism

  Akiko Shiotani; Yoshihiko Fujita; Kazuto Nishio

  CURRENT PHARMACEUTICAL DESIGN 21 35 5066 - 5072 2015年 [査読有り]
   

  The risk of gastrointestinal (GI) bleeding is increased in association with the use of low-dose aspirin (LDA). There are few studies of the association between genetic polymorphisms and the risks of aspirin-induced ulcer or its complications. Individuals with two single nucleotide polymorphisms (SNPs) of cyclooxygenase-1 (COX-1), A-842G and C50T, exhibit increased sensitivity to aspirin and lower prostaglandin synthesis capacity but the polymorphism lacked statistical significance in relation to an association with bleeding peptic ulcer. In our previous Japanese study, SLCO1B1 521TT genotype and the SLCO1B1 *1b haplotype were significantly associated with the risk of peptic ulcer and ulcer bleeding in patients taking LDA, especially in the patients with angiotensin converting enzyme inhibitor (ACEI), angiotensin type 1 receptor blocker (ARB), or statin co-treatment. Protonpump inhibitors (PPIs) are recommended for patients who require antiplatelet therapy and have a history of upper GI bleeding. The interaction between PPIs and consequent impaired effectiveness of clopidogrel has caused concern regarding the effect of genetic polymorphisms of the CYP2C19 which mediates conversion of clopidogrel to its active metabolite. The later recent genome-wide analysis of SNPs indicated the association of several SNPs with small bowel bleeding in Japanese patients taking LDA. The data are still lacking and further prospective studies are needed to identify the specific gene polymorphisms as risk or protective factors for GI bleeding associated with LDA.
• Performance of a novel KRAS mutation assay for formalin-fixed paraffin embedded tissues of colorectal cancer

  Kazuko Sakai; Azusa Yoneshige; Akihiko Ito; Yoji Ueda; Satoshi Kondo; Hitoshi Nobumasa; Yoshihiko Fujita; Yosuke Togashi; Masato Terashima; Marco A. De Velasco; Shuta Tomida; Kazuto Nishio

  SPRINGERPLUS 4 7  2015年01月 [査読有り]
   

  We compared the performance of the 3D-Gene (R) mutation assay (3D-Gene (R) KRAS mutation assay kit) with the Scorpion-ARMS (therascreen (R) KRAS RGQ PCR Kit) and Luminex (MEBGEN (TM) KRAS kit) assays for the detection of KRAS mutations in formalin-fixed, paraffin-embedded tissue samples from 150 patients diagnosed with colorectal cancer. DNA was extracted from the paraffin-embedded tissue samples with or without macrodissection under hematoxylin and eosin staining and the KRAS mutation status was independently determined using these assays. Discordant results were re-analyzed by Sanger sequencing. Mutation detection analysis was successfully performed in all 150 specimens using the 3D-Gene (R) mutation assay without an invalid case. The concordance rate between the 3D-Gene (R) mutation assay and Scorpion-ARMS or Luminex was 98.7% (148/150). KRAS mutations were detected at a frequency of 35.3% (53/150) in colorectal cancer specimens. Three discrepant cases were found between the three assays. Overall, our results demonstrate a high concordance rate of between the 3D-Gene (R) mutation assay and the two existing in-vitro diagnostics kits. All three assays proved to be validated methods for detecting clinically significant KRAS mutations in paraffin-embedded tissue samples.
• Activin signal promotes cancer progression and is involved in cachexia in a subset of pancreatic cancer

  Yosuke Togashi; Akihiro Kogita; Hiroki Sakamoto; Hidetoshi Hayashi; Masato Terashima; Marco A. de Velasco; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Masayuki Kitano; Kiyotaka Okuno; Masatoshi Kudo; Kazuto Nishio

  CANCER LETTERS 356 2 819 - 827 2015年01月 [査読有り]
   

  We previously reported that activin produces a signal with a tumor suppressive role in pancreatic cancer (PC). Here, the association between plasma activin A and survival in patients with advanced PC was investigated. Contrary to our expectations, however, patients with high plasma activin A levels had a significantly shorter survival period than those with low levels (median survival, 314 days vs. 482 days, P = 0.034). The cellular growth of the MIA PaCa-2 cell line was greatly enhanced by activin A via non-SMAD pathways. The cellular growth and colony formation of an INHBA (beta subunit of inhibin)overexpressed cell line were also enhanced. In a xenograft study, INHBA-overexpressed cells tended to result in a larger tumor volume, compared with a control. The bodyweights of mice inoculated with INHBA-overexpressed cells decreased dramatically, and these mice all died at an early stage, suggesting the occurrence of activin-induced cachexia. Our findings indicated that the activin signal can promote cancer progression in a subset of PC and might be involved in cachexia. The activin signal might be a novel target for the treatment of PC. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
• Inhibition of β-Catenin enhances the anticancer effect of irreversible EGFR-TKI in EGFR-mutated non-small-cell lung cancer with a T790M mutation.

  Togashi Y; Hayashi H; Terashima M; de Velasco MA; Sakai K; Fujita Y; Tomida S; Nakagawa K; Nishio K

  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 10 1 93 - 101 2015年01月 [査読有り]
   

  Introduction: Patients with non-small-cell lung cancer (NSCLC) with somatic activating mutations of the epidermal growth factor receptor gene (EGFR mutations) generally respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs). beta-Catenin is a key component of the Wnt/beta-Catenin signal and is an important oncogene that is involved in the pathogenesis and progression of malignant tumors, especially cancer stem cells. Methods and Results: We found that EGFR-mutated NSCLC cell lines exhibited a high expression level of beta-Catenin, compared with cell lines with the wild-type EGFR gene, and XAV939 (a beta-Catenin inhibitor) enhanced the sensitivities to EGFR-TKI in EGFR-mutated NSCLC cell lines. In EGFR-mutated NSCLC cell lines with the acquired resistance threonine-to-methionine mutation in codon 790 (T790M) mutation, XAV939 enhanced the sensitivity of the cells to an irreversible EGFR-TKI but not a reversible EGFR-TKI. The combination of XAV939 and EGFR-TKIs strongly inhibited the beta-Catenin signal and strongly decreased the phosphorylation of EGFR, compared with the use of EGFR-TKIs alone, suggesting an interaction between EGFR and the beta-Catenin signal. The stem cell-like properties of the EGFR-mutated cell line carrying the T790M mutation were inhibited by XAV939 and BIBW2992 (an irreversible EGFR-TKI). Furthermore, the stem cell-like properties were strongly inhibited by a combination of both the agents. A xenograft study demonstrated that beta-Catenin knockdown enhanced the antitumor effect of BIBW2992 in the EGFR-mutated NSCLC cell line carrying the T790M mutation. Conclusion: Our findings indicate that beta-Catenin might be a novel therapeutic target in EGFR-mutated NSCLC carrying the T790M mutation.
• Single nucleotide polymorphism markers for low-dose aspirin-associated peptic ulcer and ulcer bleeding

  Akiko Shiotani; Takahisa Murao; Yoshihiko Fujita; Yoshinori Fujimura; Takashi Sakakibara; Kazuto Nishio; Ken Haruma

  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 29 47 - 52 2014年12月 [査読有り]
   

  Background and AimIn our previous study, the SLCO1B1 521TT genotype and the SLCO1B1*1b haplotype were significantly associated with the risk of peptic ulcer in patients taking low-dose aspirin (LDA). The aim of the present study was to investigate pharmacogenomic profile of LDA-induced peptic ulcer and ulcer bleeding. MethodsPatients taking 100mg of enteric-coated aspirin for cardiovascular diseases and with a peptic ulcer or ulcer bleeding and patients who also participated in endoscopic surveillance were studied. Genome-wide analysis of single nucleotide polymorphisms (SNPs) was performed using the Affymetrix DME Plus Premier Pack. SLCO1B1*1b haplotype and candidate genotypes of genes associated with ulcer bleeding or small bowel bleeding identified by genome-wide analysis were determined using TaqMan SNP Genotyping Assay kits, polymerase chain reaction-restriction fragment length polymorphism, and direct sequencing. ResultsOf 593 patients enrolled, 111 patients had a peptic ulcer and 45 had ulcer bleeding. The frequencies of the SLCO1B1*1b haplotype and CHST2 2082 T allele were significantly greater in patients with peptic ulcer and ulcer bleeding compared to the controls. After adjustment for significant factors, the SLCO1B1*1b haplotype was associated with peptic ulcer (OR 2.20, 95% CI 1.24-3.89) and CHST2 2082 T allele with ulcer bleeding (2.57, 1.07-6.17). ConclusionThe CHST2 2082 T allele as well as SLCO1B1*1b haplotype may identify patients at increased risk for aspirin-induced peptic ulcer or ulcer bleeding.
• MEK Inhibitor for Gastric Cancer with MEK1 Gene Mutations

  Shunsuke Sogabe; Yosuke Togashi; Hiroaki Kato; Akihiro Kogita; Takuro Mizukami; Yoichi Sakamoto; Eri Banno; Masato Terashima; Hidetoshi Hayashi; Marco A. de Velasco; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Takushi Yasuda; Yoshifumi Takeyama; Kiyotaka Okuno; Kazuto Nishio

  MOLECULAR CANCER THERAPEUTICS 13 12 3098 - 3106 2014年12月 [査読有り]
   

  The prognosis for patients with unresectable advanced or recurrent gastric cancer remains poor. The identification of additional oncogenes with influences similar to those of epidermal growth factor receptor gene mutations, upon which the growth of cancer cells is dependent, is needed. In this study, we evaluated sensitivity to MEK inhibitors (GSK1120212 and PD0325901) in several gastric cancer cell lines in vitro and found three poorly differentiated gastric cancer cell lines that were hypersensitive to the inhibitors. The sequence analyses in these three cell lines revealed that one cell line had a novel MEK1 mutation, while the other two had previously reported KRAS and MEK1 mutations, respectively; the gene statuses of the other resistant cell lines were all wild-type. Experiments using MEK1 expression vectors demonstrated that the MEK1 mutations induced the phosphorylation of ERK1/2 and had a transforming potential, enhancing the tumorigenicity. The MEK inhibitor dramatically reduced the phosphorylation of ERK1/2 and induced apoptosis in the cell lines with MEK1 mutations. In vivo, tumor growth was also dramatically decreased by an inhibitor. One of the 46 gastric cancer clinical samples that were examined had a MEK1 mutation; this tumor had a poorly differentiated histology. Considering the addiction of cancer cells to active MEK1 mutations for proliferation, gastric cancer with such oncogenic MEK1 mutations might be suitable for targeted therapy with MEK inhibitors. (C)2014 AACR.
• Hypoxia induces resistance to ALK inhibitors in the H3122 non-small cell lung cancer cell line with an ALK rearrangement via epithelial-mesenchymal transition

  Akihiro Kogita; Yosuke Togashi; Hidetoshi Hayashi; Shunsuke Sogabe; Masato Terashima; Marco A. De Velasco; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Yoshifumi Takeyama; Kiyotaka Okuno; Kazuhiko Nakagawa; Kazuto Nishio

  INTERNATIONAL JOURNAL OF ONCOLOGY 45 4 1430 - 1436 2014年10月 [査読有り]
   

  Patients with non-small cell lung cancer (NSCLC) with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements generally respond to ALK inhibitors such as crizotinib. However, some patients with EML4-ALK rearrangements respond poorly to crizotinib. Hypoxia is involved in the resistance to chemotherapeutic treatments in several cancers, and we investigated the association between the responses to ALK inhibitors and hypoxia. Sensitivity of the H3122 NSCLC cell line (EML4-ALK rearrangement) to ALK inhibitors (crizotinib or alectinib) was investigated during a normoxic or hypoxic state using an MTT assay. We found that the cell line was resistant to the inhibitors during hypoxia. Hypoxia mediated morphologic changes, including cell scattering and the elongation of the cell shape, that are characteristic of the epithelial-mesenchymal transition (EMT). A migration assay demonstrated that the number of migrating cells increased significantly during hypoxia, compared with during normoxia. Regarding EMT-related molecules, the expressions of slug, vimentin, and fibronectin were increased while that of E-cadherin was decreased by hypoxia. In addition, hypoxia inducible factor 1A-knockdown cancelled the hypoxia-induced EMT and resistance. Our findings indicate that hypoxia induces resistance to ALK inhibitors in NSCLC with an EML4-ALK rearrangement via the EMT.
• KIAA1199 interacts with glycogen phosphorylase kinase β-subunit (PHKB) to promote glycogen breakdown and cancer cell survival.

  Terashima M; Fujita Y; Togashi Y; Sakai K; De Velasco MA; Tomida S; Nishio K

  Oncotarget 5 16 7040 - 7050 2014年08月 [査読有り]
   

  The KIAA1199 gene was first discovered to be associated with non-syndromic hearing loss. Recently, several reports have shown that the up-regulation of KIAA1199 is associated with cancer cell migration or invasion and a poor prognosis. These findings indicate that KIAA1199 may be a novel target for cancer therapy. Therefore, we explored in detail the function of KIAA1199 in cancer cells. In this study, we investigated the interaction of KIAA1199 protein with intracellular proteins in cancer cells. To this end, we expressed KIAA1199-MBP fusion protein and performed a pull-down assay. In addition, KIAA1199-overexpressing cancer cell lines were constructed using a retroviral vector and were used for further experiments. A pull-down analysis showed that the glycogen phosphorylase kinase beta-subunit (PHKB) interacted with the C-terminal region of KIAA1199 protein. Furthermore, we observed the interaction of KIAA1199 with glycogen phosphorylase brain form (PYGB) under serum-free conditions. The interaction promoted glycogen breakdown and cancer cell survival. Our findings indicate that KIAA1199 plays an important role in glycogen breakdown and cancer cell survival and that it may represent a novel target for cancer therapy.
• Frequent amplification of ORAOV1 gene in esophageal squamous cell cancer promotes an aggressive phenotype via proline metabolism and ROS production

  Yosuke Togashi; Tokuzo Arao; Hiroaki Kato; Kazuko Matsumoto; Masato Terashima; Hidetoshi Hayashi; Marco A. de Velasco; Yoshihiko Fujita; Hideharu Kimura; Takushi Yasuda; Hitoshi Shiozaki; Kazuto Nishio

  ONCOTARGET 5 10 2962 - 2973 2014年05月 [査読有り]
   

  Chromosomal band 11q13 seems to be one of the most frequently amplified lesions in human cancer, including esophageal squamous cell cancer (ESCC). The oral cancer overexpressed 1 (ORAOV1) gene has been identified within this region, but its detailed biological function in human ESCC remains largely unclear. In our clinical samples of stage III ESCC, ORAOV1 amplification was observed in 49 of 94 cases (53%). ORAOV1 amplification was significantly associated with a poorly differentiated histology and tumors located in the upper or middle esophagus. Patients with ORAOV1 amplification tended to have a shorter survival period, although the difference was not significant. To investigate the function of ORAOV1, we created ORAOV1-overexpressed ESCC cell lines that exhibited increased cellular proliferation and colony formation, compared with in vitro controls. In vivo, ORAOV1-overexpressed cells exhibited a significantly increased tumorigenicity and a significantly larger tumor volume and poorer differentiation than controls. The peptide mass fingerprinting technique demonstrated that ORAOV1 bound to pyrroline-5-carboxylate reductase (PYCR), which is associated with proline metabolism and reactive oxygen species (ROS) production. Then, ORAOV1-overexpressed cell lines were resistant to stress treatment, which was cancelled by PYCR-knockdown. In addition, the ORAOV1-overexpressed cell line had a higher intracellular proline concentration and a lower ROS level. Our findings indicate that the ORAOV1 gene is frequently amplified in ESCC, enhances tumorigenicity and tumor growth, and is associated with a poorly differentiated tumor histology via proline metabolism and ROS production. ORAOV1 could be a novel target for the treatment of ESCC.
• Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic cancer

  Yosuke Togashi; Hiroki Sakamoto; Hidetoshi Hayashi; Masato Terashima; Marco A. de Velasco; Yoshihiko Fujita; Yasuo Kodera; Kazuko Sakai; Shuta Tomida; Masayuki Kitano; Akihiko Ito; Masatoshi Kudo; Kazuto Nishio

  MOLECULAR CANCER 13 126  2014年05月 [査読有り]
   

  Background: Transforming growth factor, beta (TGFB) signal is considered to be a tumor suppressive pathway based on the frequent genomic deletion of the SMAD4 gene in pancreatic cancer (PC); however; the role of the activin signal, which also belongs to the TGFB superfamily, remains largely unclear. Methods and results: We found a homozygous deletion of the activin A receptor, type IB (ACVR1B) gene in 2 out of 8 PC cell lines using array-comparative genomic hybridization, and the absence of ACVR1B mRNA and protein expression was confirmed in these 2 cell lines. Activin A stimulation inhibited cellular growth and increased the phosphorylation level of SMAD2 and the expression level of p21(CIP1/WAF1) in the Sui66 cell line (wild-type ACVR1B and SMAD4 genes) but not in the Sui68 cell line (homozygous deletion of ACVR1B gene). Stable ACVR1B-knockdown using short hairpin RNA cancelled the effects of activin A on the cellular growth of the PC cell lines. In addition, ACVR1B-knockdown significantly enhanced the cellular growth and colony formation abilities, compared with controls. In a xenograft study, ACVR1B-knockdown resulted in a significantly elevated level of tumorigenesis and a larger tumor volume, compared with the control. Furthermore, in clinical samples, 6 of the 29 PC samples (20.7%) carried a deletion of the ACVR1B gene, while 10 of the 29 samples (34.5%) carried a deletion of the SMAD4 gene. Of note, 5 of the 6 samples with a deletion of the ACVR1B gene also had a deletion of the SMAD4 gene. Conclusion: We identified a homozygous deletion of the ACVR1B gene in PC cell lines and clinical samples and proposed that the deletion of the ACVR1B gene may mediate an aggressive cancer phenotype in PC. Our findings provide novel insight into the role of the activin signal in PC.
• Melanoma Transition Is Frequently Accompanied by a Loss of Cytoglobin Expression in Melanocytes: A Novel Expression Site of Cytoglobin

  Yoshihiko Fujita; Satoshi Koinuma; Marco A. De Velasco; Jan Bolz; Yosuke Togashi; Masato Terashima; Hidetoshi Hayashi; Takuya Matsuo; Kazuto Nishio

  PLOS ONE 9 4 e94772  2014年04月 [査読有り]
   

  The tissue distribution and function of hemoglobin or myoglobin are well known; however, a newly found cytoglobin (CYGB), which also belongs to the globin family, remains to be characterized. To assess its expression in human malignancies, we sought to screen a number of cell lines originated from many tissues using northern blotting and real time PCR techniques. Unexpectedly, we found that several, but not all, melanoma cell lines expressed CYGB mRNA and protein at much higher levels than cells of other origins. Melanocytes, the primary origin of melanoma, also expressed CYGB at a high level. To verify these observations, immunostaining and immunoblotting using anti-CYGB antibody were also performed. Bisulfite-modified genomic sequencing revealed that several melanoma cell lines that abrogated CYGB expression were found to be epigenetically regulated by hypermethylation in the promoter region of CYGB gene. The RNA interference-mediated knockdown of the CYGB transcript in CYGB expression-positive melanoma cell lines resulted in increased proliferation in vitro and in vivo. Flow cytometric analysis using 2'-, 7'-dichlorofluorescein diacetate (DCFH-DA), an indicator of reactive oxygen species (ROS), revealed that the cellular ROS level may be involved in the proliferative effect of CYGB. Thus, CYGB appears to play a tumor suppressive role as a ROS regulator, and its epigenetic silencing, as observed in CYGB expression-negative melanoma cell lines, might function as an alternative pathway in the melanocyte-to-melanoma transition.
• 【消化器疾患の病態生理】 低用量アスピリン内服患者における小腸出血と遺伝子多型の検討

  塩谷 昭子; 村尾 高久; 藤田 穣; 藤村 宜憲; 榊原 敬; 藤田 至彦; 西尾 和人; 春間 賢

  Progress in Medicine 34 3 416 - 419 (株)ライフ・サイエンス 2014年03月 

  低用量アスピリン内服患者における小腸出血と遺伝子多型について検討した。消化管内視鏡を予定している低用量アスピリン内服患者、および内服中に消化管出血をきたした患者で、小腸出血37例(網羅酌遺伝子多型解析17例を含む)と対照群400例(網羅的遺伝子多型解析18例を含む)を対象とした。臨床背景の比較では、喫煙者が小腸出血群で有意に多かった。併用薬剤の検討では、小腸出血群でワルファリン内服およびNSAIDs内服で有意に多かったが、PPI内服率は両群で差を認めなかった。DMET解析により、小腸出血と関連性を認めた23遺伝子27SNPsを検出した。437例に対する特定された遺伝子多型解析の結果、4遺伝子5SNPsが小腸出血と有意に関連した。多変量解析で、喫煙、心臓以外の動脈硬化性疾患、ワルファリン併用、CYP2D6-2178 rs28360521GGホモは有意に小腸出血と関連した。
• A Supramolecular Substance, [2] Rotaxane, Induces Apoptosis in Human Molt-3 Acute Lymphoblastic Leukemia Cells.

  Kimura M; Makio K; Hara K; Hiruma W; Fujita Y; Takata T; Nishio K; Ono N

  Drug Res 65 11 614 - 616 2014年 [査読有り]
  
• Novel Single Nucleotide Polymorphism Markers for Low Dose Aspirin-Associated Small Bowel Bleeding

  Akiko Shiotani; Takahisa Murao; Yoshihiko Fujita; Yoshinori Fujimura; Takashi Sakakibara; Kazuto Nishio; Ken Haruma

  PLOS ONE 8 12 e84244  2013年12月 [査読有り]
   

  Background: Aspirin-induced enteropathy is now increasingly being recognized although the pathogenesis of small intestinal damage induced by aspirin is not well understood and related risk factors have not been established. Aim: To investigate pharmacogenomic profile of low dose aspirin (LDA)-induced small bowel bleeding. Methods: Genome-wide analysis of single nucleotide polymorphisms (SNPs) was performed using the Affymetrix DMET (TM) Plus Premier Pack. Genotypes of candidate genes associated with small bowel bleeding were determined using TaqMan SNP Genotyping Assay kits and direct sequencing. Results: In the validation study in overall 37 patients with small bowel bleeding and 400 controls, 4 of 27 identified SNPs: CYP4F11 (rs1060463) GG (p=0.003), CYP2D6 (rs28360521) GG (p=0.02), CYP24A1 (rs4809957) T allele (p=0.04), and GSTP1 (rs1695) G allele (p=0.04) were significantly more frequent in the small bowel bleeding group compared to the controls. After adjustment for significant factors, CYP2D6 (rs28360521) GG (OR 4.11, 95% CI. 1.62 -10.4) was associated with small bowel bleeding. Conclusions: CYP4F11 and CYP2D6 SNPs may identify patients at increased risk for aspirin-induced small bowel bleeding.
• The OCT4 pseudogene POU5F1B is amplified and promotes an aggressive phenotype in gastric cancer.

  Hayashi H; Arao T; Togashi Y; Kato H; Fujita Y; Develasco MA; Kimura H; Matsumoto K; Tanaka K; Okamoto I; Ito A; Yamada Y; Nakagawa K; Nishio K

  Oncogene 34 2 199 - 208 2013年11月 [査読有り]
   

  POU5F1B (POU domain class 5 transcription factor 1B), a processed pseudogene that is highly homologous to OCT4, was recently shown to be transcribed in cancer cells, but its clinical relevance and biological function have remained unclear. We now show that POU5F1B, which is located adjacent to MYC on human chromosome 8q24, is frequently amplified in gastric cancer (GC) cell lines. POU5F1B, but not OCT4, was also found to be expressed at a high level in GC cell lines and clinical specimens. In addition, the DNA copy number and mRNA abundance for POU5F1B showed a positive correlation in both cancer cell lines and GC specimens. Overexpression of POU5F1B in GC cells promoted colony formation in vitro as well as both tumorigenicity and tumor growth in vivo, and these effects were enhanced in the additional presence of MYC overexpression. Furthermore, knockdown of POU5F1B expression with a short hairpin RNA confirmed a role for the endogenous pseudogene in the promotion of cancer cell growth in vitro and tumor growth in vivo. POU5F1B overexpression induced upregulation of various growth factors in GC cells as well as exhibited mitogenic, angiogenic and antiapoptotic effects in GC xenografts. Finally, amplification of POU5F1B was detected in 17 (12%) of 145 cases of GC and was a significant predictor of poor prognosis in patients with stage IV disease. In conclusion, we found that the POU5F1B pseudogene is amplified and expressed at a high level in, as well as confers an aggressive phenotype on, GC, and that POU5F1B amplification is associated with a poor prognosis in GC patients.
• Overexpression of heparan sulfate 6-O-sulfotransferase-2 in colorectal cancer.

  Shigeru Hatabe; Hideharu Kimura; Tokuzo Arao; Hiroaki Kato; Hidetoshi Hayashi; Tomoyuki Nagai; Kazuko Matsumoto; Marco DE Velasco; Yoshihiko Fujita; Go Yamanouchi; Masao Fukushima; Yasuhide Yamada; Akihiko Ito; Kiyotaka Okuno; Kazuto Nishio

  Molecular and clinical oncology 1 5 845 - 850 2013年09月 [査読有り]
   

  The heparan sulfate sulfotransferase gene family catalyzes the transfer of sulfate groups to heparan sulfate and regulates various growth factor-receptor signaling pathways. However, the involvement of this gene family in cancer biology has not been elucidated. It was demonstrated that the heparan sulfate D-glucosaminyl 6-O-sulfotransferase-2 (HS6ST2) gene is overexpressed in colorectal cancer (CRC) and its clinical significance in patients with CRC was investigated. The mRNA levels of HS6ST2 in clinical CRC samples and various cancer cell lines were assessed using a microarray analysis and quantitative RT-PCR, respectively. An immunohistochemical (IHC) analysis of the HS6ST2 protein was performed using 102 surgical specimens of CRC. The correlations between the HS6ST2 expression status and clinicopathological characteristics were then evaluated. HS6ST2 mRNA was significantly overexpressed by 37-fold in CRC samples compared to paired colonic mucosa. High levels of HS6ST2 mRNA expression were also observed in colorectal, esophageal and lung cancer cell lines. The IHC analysis demonstrated that HS6ST2 was expressed in the cytoplasmic region of CRC cells, but not in normal colonic mucosal cells. Positive staining for HS6ST2 was detected in 40 patients (39.2%). There was no significant association between the clinicopathological characteristics and HS6ST2 expression. However, positive staining for HS6ST2 was associated with a poor survival (P=0.074, log-rank test). In conclusion, HS6ST2 was found to be overexpressed in CRC and its expression tended to be a poor prognostic factor, although the correlation was not significant. These findings indicate that HS6ST2 may be a novel cancer-related marker that may provide insight into the glycobiology of CRC.
• Detection of epidermal growth factor receptor T790M mutation in plasma DNA from patients refractory to epidermal growth factor receptor tyrosine kinase inhibitor

  Kazuko Sakai; Atsushi Horiike; Darryl L. Irwin; Keita Kudo; Yoshihiko Fujita; Azusa Tanimoto; Toshio Sakatani; Ryota Saito; Kyohei Kaburaki; Noriko Yanagitani; Fumiyoshi Ohyanagi; Makoto Nishio; Kazuto Nishio

  Cancer Science 104 9 1198 - 1204 2013年09月 [査読有り]
   

  A secondary epidermal growth factor receptor (EGFR) mutation, the substitution of threonine 790 with methionine (T790M), leads to acquired resistance to reversible EGFR-tyrosine kinase inhibitors (EGFR-TKIs). A non-invasive method for detecting T790M mutation would be desirable to direct patient treatment strategy. Plasma DNA samples were obtained after discontinuation of gefitinib or erlotinib in 75 patients with non-small cell lung cancer (NSCLC). T790M mutation was amplified using the SABER (single allele base extension reaction) technique and analyzed using the Sequenom MassARRAY platform. We examined the T790M mutation status in plasma samples obtained after treatment with an EGFR-TKI. The SABER assay sensitivity using mixed oligonucleotides was determined to be 0.3%. The T790M mutation was detected in 21 of the 75 plasma samples (28%). The presence of the T790M mutation was confirmed by subcloning into sequencing vectors and sequencing in 14 of the 21 samples (66.6%). In this cohort of 75 patients, the median progression-free survival (PFS) of the patients with the T790M mutation (n = 21) was not statistically different from that of the patients without the mutation (n = 54, P = 0.94). When patients under 65 years of age who had a partial response were grouped according to their plasma T790M mutation status, the PFS of the T790M-positive patients (n = 11) was significantly shorter than that of the T790M-negative patients (n = 29, P = 0.03). The SABER method is a feasible means of determining the plasma T790M mutation status and could potentially be used to monitor EGFR-TKI therapy. © 2013 Japanese Cancer Association.
• Influence of Novel Supramolecular Substance, [2] Rotaxane, on the Caspase Signaling Pathway in Melanoma and Colon Cancer Cells In Vitro

  Kazuki Hara; Tatsuya Beppu; Masahiko Kimura; Yoshihiko Fujita; Toshikazu Takata; Kazuto Nishio; Nobufumi Ono

  JOURNAL OF PHARMACOLOGICAL SCIENCES 122 2 153 - 157 2013年06月 [査読有り]
   

  We studied the influence of novel supramolecular substance, [2] rotaxane (TRO-A0001), on caspase signaling and cell viability in cancer cell lines. TRO-A0001 suppressed concentration-dependently cell proliferation. Expression of the cleaved-form caspase-3 and PARP was significantly increased in cells exposed to TRO-A0001. The expression of Bax was increased by TRO-A0001. Furthermore, the down-regulation of Bax by siRNA resulted in growth activation significantly. The morphological analysis demonstrated that TRO-A0001 increased the levels of apoptotic cells in human cancer cell lines. These results suggest that TRO-A0001 induces apoptosis in cancer cells and holds potential as a new anti-tumor medicine.
• A Microarray-Based Gene Expression Analysis to Identify Diagnostic Biomarkers for Unknown Primary Cancer

  Issei Kurahashi; Yoshihiko Fujita; Tokuzo Arao; Takayasu Kurata; Yasuhiro Koh; Kazuko Sakai; Koji Matsumoto; Maki Tanioka; Koji Takeda; Yuichi Takiguchi; Nobuyuki Yamamoto; Asuka Tsuya; Nobuaki Matsubara; Hirofumi Mukai; Hironobu Minami; Naoko Chayahara; Yasuhiro Yamanaka; Keisuke Miwa; Shin Takahashi; Shunji Takahashi; Kazuhiko Nakagawa; Kazuto Nishio

  PLOS ONE 8 5 e63249  2013年05月 [査読有り]
   

  Background: The biological basis for cancer of unknown primary (CUP) at the molecular level remains largely unknown, with no evidence of whether a common biological entity exists. Here, we assessed the possibility of identifying a common diagnostic biomarker for CUP using a microarray gene expression analysis. Methods: Tumor mRNA samples from 60 patients with CUP were analyzed using the Affymetrix U133A Plus 2.0 GeneChip and were normalized by asinh (hyperbolic arc sine) transformation to construct a mean gene-expression profile specific to CUP. A gene-expression profile specific to non-CUP group was constructed using publicly available raw microarray datasets. The t-tests were performed to compare the CUP with non-CUP groups and the top 59 CUP specific genes with the highest fold change were selected (p-value<0.001). Results: Among the 44 genes that were up-regulated in the CUP group, 6 genes for ribosomal proteins were identified. Two of these genes (RPS7 and RPL11) are known to be involved in the Mdm2-p53 pathway. We also identified several genes related to metastasis and apoptosis, suggesting a biological attribute of CUP. Conclusions: The protein products of the up-regulated and down-regulated genes identified in this study may be clinically useful as unique biomarkers for CUP.
• Gene amplification of EGFR, HER2, FGFR2 and MET in esophageal squamous cell carcinoma

  Hiroaki Kato; Tokuzo Arao; Kazuko Matsumoto; Yoshihiko Fujita; Hideharu Kimura; Hidetoshi Hayashi; Kouhei Nishiki; Mitsuru Iwama; Osamu Shiraishi; Atsushi Yasuda; Masayuki Shinkai; Motohiro Imano; Haruhiko Imamoto; Takushi Yasuda; Kiyotaka Okuno; Hitoshi Shiozaki; Kazuto Nishio

  INTERNATIONAL JOURNAL OF ONCOLOGY 42 4 1151 - 1158 2013年04月 [査読有り]
   

  Molecular targeted therapy is expected to be a promising therapeutic approach for the treatment of esophageal squamous cell carcinoma (ESCC); however, the gene amplification status of molecular targeted genes in ESCC remains largely unclear. The gene amplification of EGFR, HER2, FGFR2 and MET was examined using a real-time PCR-based copy number assay of 245 ESCC surgical specimens of formalin-fixed, paraffin-embedded samples. Fluorescence in situ hybridization (FISH) and comparative genomic hybridization analyses verified the results of the copy number assay. EGFR mutation was detected using the Scorpions-ARMS method. The EGFR status and drug sensitivity to an EGFR tyrosine kinase inhibitor was then evaluated in vitro. Gene amplification of EGFR and HER2 was observed in 7% (16/244) and 11% (27/245) of the ESCC specimens. A multivariate analysis revealed that HER2 amplification was a significant predictor of a poor prognosis in patients with stage III post-operative ESCC. The L861Q type of EGFR mutation with hypersensitivity to EGFR tyrosine kinase inhibitor was found in one of the eight ESCC cell lines and one de1745 type of EGFR mutation was identified in 107 clinical samples. In addition, we demonstrated for the first time that FGFR2 amplification was observed in 4% (8/196) of the ESCC specimens. MET amplification was observed in 1% (2/196). In conclusion, the frequent gene amplification of EGFR, HER2 and FGFR2 and the presence of active EGFR mutations were observed in ESCC specimens. Our results strongly encourage the development of molecular targeted therapy for ESCC.
• Slug increases sensitivity to tubulin-binding agents via the downregulation of βIII and βIVa-tubulin in lung cancer cells.

  Tamura D; Arao T; Nagai T; Kaneda H; Aomatsu K; Fujita Y; Matsumoto K; De Velasco MA; Kato H; Hayashi H; Yoshida S; Kimura H; Maniwa Y; Nishio W; Sakai Y; Ohbayashi C; Kotani Y; Nishimura Y; Nishio K

  Cancer medicine 2 2 144 - 154 2 2013年04月 [査読有り]
   

  Transcription factor Slug/SNAI2 (snail homolog 2) plays a key role in the induction of the epithelial mesenchymal transition in cancer cells; however, whether the overexpression of Slug mediates the malignant phenotype and alters drug sensitivity in lung cancer cells remains largely unclear. We investigated Slug focusing on its biological function and involvement in drug sensitivity in lung cancer cells. Stable Slug transfectants showed typical morphological changes compared with control cells. Slug overexpression did not change the cellular proliferations; however, migration activity and anchorage-independent growth activity with an antiapoptotic effect were increased. Interestingly, stable Slug overexpression increased drug sensitivity to tubulin-binding agents including vinorelbine, vincristine, and paclitaxel (5.8- to 8.9-fold increase) in several lung cancer cell lines but did not increase sensitivity to agents other than tubulin-binding agents. Real-time RT-PCR (polymerase chain reaction) and western blotting revealed that Slug overexpression downregulated the expression of beta III and beta IVa-tubulin, which is considered to be a major factor determining sensitivity to tubulin-binding agents. A luciferase reporter assay confirmed that Slug suppressed the promoter activity of beta IVa-tubulin at a transcriptional level. Slug overexpression enhanced tumor growth, whereas Slug overexpression increased drug sensitivity to vinorelbine with the downregulation of beta III and beta IV-tubulin in vivo. Immunohistochemistry of Slug with clinical lung cancer samples showed that Slug overexpression tended to be involved in response to tubulin-binding agents. In conclusion, our data indicate that Slug mediates an aggressive phenotype including enhanced migration activity, anoikis suppression, and tumor growth, but increases sensitivity to tubulin-binding agents via the downregulation of beta III and beta IVa-tubulin in lung cancer cells.
• Highly Sensitive Detection of EGFR T790M Mutation Using Colony Hybridization Predicts Favorable Prognosis of Patients with Lung Cancer Harboring Activating EGFR Mutation

  Yoshihiko Fujita; Kenichi Suda; Hideharu Kimura; Kazuko Matsumoto; Tokuzo Arao; Tomoyuki Nagai; Nagahiro Saijo; Yasushi Yatabe; Tetsuya Mitsudomi; Kazuto Nishio

  JOURNAL OF THORACIC ONCOLOGY 7 11 1640 - 1644 2012年11月 [査読有り]
   

  Introduction: Approximately 50% of lung cancer patients with epidermal growth factor receptor (EGFR)-mutations (deletion in exon 19 or L858R) who develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) reportedly carry a secondary EGFR T790M mutation. This mutation has been suggested to be present in tumor cells before EGFR-TKI treatment in a small population of individuals. Here, we use a highly sensitive colony hybridization technique in an attempt to evaluate the actual incidence of T790M in pretreatment tumor specimens. Methods: DNA was extracted from surgically resected tumor tissues of 38 patients with the EGFR mutation and examined for the presence of T790M, using a standard polymerase chain reaction based method followed by a modified colony hybridization (CH) technique with an analytical sensitivity of approximately 0.01%. Associations between the T790M status and clinical characteristics including time to treatment failure (TTF) for EGFR-TKI were evaluated. Results: The T790M mutation analysis of the specimens from the 38 patients detected 30 mutants (79%). The median TTF was 9 months for the patients with pretreatment T790M and 7 months for the patients without the T790M mutation (p = 0.44). When the patients with T790M were divided into strongly positive and modestly positive subgroups in terms of the frequency of positive signals observed using CH technique, the 7 patients with strong positivity had a TTF that was significantly longer than that of the 8 patients without T790M (p = 0.0097) and of the 23 patients with modest positivity (p = 0.0019). Conclusions: Our highly sensitive CH method showed that a subgroup of non-small-cell lung cancer patients with the EGFR mutation harbored the rare T790M allele before EGFR-TKI treatment. A high proportion of T790M allele may define a clinical subset with a relatively favorable prognosis.
• Aza-derivatives of resveratrol are potent macrophage migration inhibitory factor inhibitors

  Yoshihiko Fujita; Rafiqul Islam; Kazuko Sakai; Hiroyasu Kaneda; Kanae Kudo; Daisuke Tamura; Keiichi Aomatsu; Tomoyuki Nagai; Hidekazu Kimura; Kazuko Matsumoto; Marco A. de Velasco; Tokuzo Arao; Tadashi Okawara; Kazuto Nishio

  INVESTIGATIONAL NEW DRUGS 30 5 1878 - 1886 2012年10月 [査読有り]
   

  Resveratrol (3, 4', 5-trihydroxy-trans-stilbene), a natural phytoalexin found in grapes and wine, has anti-proliferative activity on human-derived cancer cells. In our study, we used a conventional condensation reaction between aldehydes and amines to provide a number of aza-resveratrol (3, 4', 5-trihydroxy-trans- aza-stilbene) derivatives in an attempt to screen for compounds with resveratrol's action but with increased potency. Aza-resveratrol and its hydroxylated derivative (3, 4, 4', 5-tetrahydroxy-trans- aza-stilbene) showed a more enhanced anti-proliferative effect than resveratrol in an MCF-7 breast carcinoma cell line. To identify the cellular targets of the aza derivatives of resveratrol, we conjugated the latter aza-stilbene compound with epoxy-activated agarose and performed affinity purification. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, was identified as a major target protein in MCF-7 cell lysates using a matrix-assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI-TOF MS). The aza-resveratrol and its hydroxylated derivative, but not resveratrol, were also found to be potent inhibitors of MIF tautomerase activity, which may be associated with their inhibitory effects on MIF bioactivity for cell growth.
• Expression changes in arrestin β 1 and genetic variation in catechol-O-methyltransferase are biomarkers for the response to morphine treatment in cancer patients.

  Matsuoka H; Arao T; Makimura C; Takeda M; Kiyota H; Tsurutani J; Fujita Y; Matsumoto K; Kimura H; Otsuka M; Koyama A; Imamura CK; Tanigawara Y; Yamanaka T; Tanaka K; Nishio K; Nakagawa K

  Oncology reports 27 5 1393 - 1399 5 2012年05月 [査読有り]
   

  Genetic differences in individuals with regard to opioid-receptor signaling create clinical difficulties for opioid treatment; consequently, useful pharmacodynamic and predictive biomarkers are needed. In this prospective study, we studied gene expression changes in peripheral blood leukocytes using a microarray and real-time RT-PCR analysis to identify pharmacodynamic biomarkers for monitoring the effect of morphine in a cohort of opioid-treatment-naive cancer patients. We also examined genetic variations in opioid receptor mu 1 (OPRMI, 118A -> G) and catechol-O-methyltransferase (COMT, 472G -> A) to evaluate predictive biomarkers of the treatment outcome of morphine. The plasma concentration of morphine was measured using a liquid chromatography-tandem mass spectrometry method. Microarray analysis revealed that the m RNA expression levels of arrestin beta 1 (ARRB1) were significantly down-regulated by morphine treatment. Real-time RT-PCR analysis against independent samples confirmed the results (P=0.003) and changes during treatment were negatively correlated with the plasma morphine concentration (R=-0.42). No correlation was observed between the genotype of OPRMI and morphine treatrnent; however, the plasma concentration of morphine and the required dose of morphine were significantly lower for the A/A genotype of COMT (vs. A/G+G/G, P=0.008 and 0.03). We found that changes in the expression of ARRB1 may be a novel pharmacodynamic biomarker and the COMT 472G -> A genotype may be a predictive biomarker of the response to morphine treatment.
• A Novel Mass Spectrometry-Based Assay for Diagnosis of EML4-ALK-Positive Non-Small Cell Lung Cancer

  Kazuko Sakai; Isamu Okamoto; Ken Takezawa; Tomonori Hirashima; Hiroyasu Kaneda; Masayuki Takeda; Kazuko Matsumoto; Hideharu Kimura; Yoshihiko Fujita; Kazuhiko Nakagawa; Tokuzo Arao; Kazuto Nishio

  JOURNAL OF THORACIC ONCOLOGY 7 5 913 - 918 2012年05月 [査読有り]
   

  Introduction: The presence of the transforming fusion gene echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) in non-small-cell lung cancer (NSCLC) is a predictive marker for the efficacy of anaplastic lymphoma kinase inhibitors. However, the currently available assays for the detection of the different variants of EML4-ALK have limitations. Methods: We developed an assay system for the detection of EML4-ALK variants 1, 2, 3a, 3b, 4, 5a, 5b, 6, or 7 transcripts in total RNA obtained from formalin-fixed, paraffin-embedded (FFPE) specimens of NSCLC tissue. The assay is based on region-specific polymerase chain reaction amplification of EML4-ALK complementary DNA followed by specific single-base primer extension and analysis of the extension products by matrix-assisted laser desorption/ionization-time of flight mass spectrometry. The assay was validated by fluorescence in situ hybridization and the results confirmed by subcloning and sequencing of polymerase chain reaction products. Results: Evaluation of the analytic sensitivity of the assay with serial dilutions of plasmids containing EML4-ALK complementary DNA sequences revealed it to be capable of the reliable detection of one copy of each plasmid per reaction. The assay also detected EML4-ALK variants 1 or 3 in three FFPE samples of surgically resected NSCLC shown to be positive for anaplastic lymphoma kinase rearrangement by fluorescence in situ hybridization. Furthermore, the assay identified variant 1 of EML4-ALK in 3 of 20 FFPE biopsy samples from patients with advanced NSCLC. All positive samples were confirmed by subcloning and sequencing. Conclusions: Our novel assay is highly sensitive and effective for the detection of EML4-ALK in FFPE specimens.
• Integrated analysis of whole genome exon array and array-comparative genomic hybridization in gastric and colorectal cancer cells

  Kazuyuki Furuta; Tokuzo Arao; Kazuko Sakai; Hideharu Kimura; Tomoyuki Nagai; Daisuke Tamura; Keiichi Aomatsu; Kanae Kudo; Hiroyasu Kaneda; Yoshihiko Fujita; Kazuko Matsumoto; Yasuhide Yamada; Kazuyoshi Yanagihara; Masaru Sekijima; Kazuto Nishio

  CANCER SCIENCE 103 2 221 - 227 2012年02月 [査読有り]
   

  Whole genome-scale integrated analyses of exon array and array-comparative genomic hybridization are expected to enable the identification of unknown genetic features of cancer cells. Here, we evaluated this approach in 22 gastric and colorectal cancer cell lines, focusing on protein kinase genes and genes belonging to the cadherincatenin family. Regarding alternative splicing patterns, several cancer cell lines predominantly expressed isoform 1 of protein kinase A catalytic subunit beta (PRKACB). Paired gastric cancer specimens demonstrated that isoform 1 of PRKACB was a novel cancer-related variant transcript in gastric cancers. In addition, the exon array analysis clearly identified exon 3 or exon 34 skipping in catenin beta 1, a short intron insertion with exon 9 skipping in CDH1, and a deletional transcript of CDH13. These abnormal transcripts were shown to have arisen from small genomic deletions. Meanwhile, an integrated analysis of 11 gastric cancer cell lines revealed that four cell lines amplified fibroblast growth factor receptor 2, with truncated forms observed in two of the cell lines. Gene amplification, and not the truncated form, was found to determine the sensitivity to a fibroblast growth factor receptor inhibitor, indicating that our cell line panel might be useful for cell-based evaluations of specific inhibitors. Using an integrated analysis, we identified several abnormal transcripts and genomic alterations in gastric and colorectal cancer cells. Our approach might enable genetic changes to be identified more efficiently, and the present results warrant further investigation using clinical samples and integrated analyses. (Cancer Sci 2012; 103: 221227)
• Slug Is Upregulated during Wound Healing and Regulates Cellular Phenotypes in Corneal Epithelial Cells

  Keiichi Aomatsu; Tokuzo Arao; Kosuke Abe; Aya Kodama; Koji Sugioka; Kazuko Matsumoto; Kanae Kudo; Hideharu Kimura; Yoshihiko Fujita; Hidetoshi Hayashi; Tomoyuki Nagai; Yoshikazu Shimomura; Kazuto Nishio

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 53 2 751 - 756 2012年02月 [査読有り]
   

  PURPOSE. The involvement of the epithelial mesenchymal transition (EMT) in the process of corneal wound healing remains largely unclear. The purpose of the present study was to gain insight into Slug expression and corneal wound healing. METHODS. Slug expression during wound healing in the murine cornea was evaluated using fluorescence staining in vivo. Slug or Snail was stably introduced into human corneal epithelial cells (HCECs). These stable transfectants were evaluated for the induction of the EMT, cellular growth, migration activity, and expression changes in differentiation-related molecules. RESULTS. Slug, but not Snail, was clearly expressed in the nuclei of corneal epithelial cells in basal lesion of the corneal epithelium during wound healing in vivo. The overexpression of Slug or Snail induced an EMT-like cellular morphology and cadherin switching in HCECs, indicating that these transcription factors were able to mediate the typical EMT in HCECs. The overexpression of Slug or Snail suppressed cellular proliferation but enhanced the migration activity. Furthermore, ABCG2, TP63, and keratin 19, which are known as stemness-related molecules, were downregulated in these transfectants. CONCLUSIONS. It was found that Slug is upregulated during corneal wound healing in vivo. The overexpression of Slug mediated a change in the cellular phenotype affecting proliferation, migration, and expression levels of differentiation-related molecules. This is the first evidence that Slug is regulated during the process of corneal wound healing in the corneal epithelium in vivo, providing a novel insight into the EMT and Slug expression in corneal wound healing. (Invest Ophthalmol Vis Sci. 2012; 53: 751-756) DOI: 10.1167/iovs.11-8222
• SRPX2 Is a Novel Chondroitin Sulfate Proteoglycan That Is Overexpressed in Gastrointestinal Cancer

  Kaoru Tanaka; Tokuzo Arao; Daisuke Tamura; Keiichi Aomatsu; Kazuyuki Furuta; Kazuko Matsumoto; Hiroyasu Kaneda; Kanae Kudo; Yoshihiko Fujita; Hideharu Kimura; Kazuyoshi Yanagihara; Yasuhide Yamada; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio

  PLOS ONE 7 1 2012年01月 [査読有り]
   

  SRPX2 (Sushi repeat-containing protein, X-linked 2) has recently emerged as a multifunctional protein that is involved in seizure disorders, angiogenesis and cellular adhesion. Here, we analyzed this protein biochemically. SRPX2 protein was secreted with a highly posttranslational modification. Chondroitinase ABC treatment completely decreased the molecular mass of purified SRPX2 protein to its predicted size, whereas heparitinase, keratanase and hyaluroinidase did not. Secreted SRPX2 protein was also detected using an anti-chondroitin sulfate antibody. These results indicate that SRPX2 is a novel chondroitin sulfate proteoglycan (CSPG). Furthermore, a binding assay revealed that hepatocyte growth factor dose-dependently binds to SRPX2 protein, and a ligand-glycosaminoglycans interaction was speculated to be likely in proteoglycans. Regarding its molecular architecture, SRPX2 has sushi repeat modules similar to four other CSPGs/lecticans; however, the molecular architecture of SRPX2 seems to be quite different from that of the lecticans. Taken together, we found that SRPX2 is a novel CSPG that is overexpressed in gastrointestinal cancer cells. Our findings provide key glycobiological insight into SRPX2 in cancer cells and demonstrate that SRPX2 is a new member of the cancer-related proteoglycan family.
• An early event of EGFR mutation in pleomorphic carcinoma of the lung

  Miyako Saitoh; Mafumi Niijima; Yuichi Takiguchi; Kenzo Hiroshima; Yoshihiko Fujita; Kazuto Nishio; Koichiro Tatsumi

  INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 16 6 770 - 773 2011年12月 [査読有り]
   

  Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective in prolonging progression-free survival time of patients with non-small cell lung carcinoma, typically adenocarcinoma, bearing some active EGFR mutations in their tumors. However, the close relationship between the EGFR mutations and pleomorphic carcinoma of the lung, which is a very rare type of primary lung cancer, has never been elucidated. We present a 60-year-old Japanese woman with pleomorphic carcinoma of the lung that became resistant to cytotoxic chemotherapies including platinum-based chemotherapy, and her general condition seriously deteriorated. Thereafter, treatment with gefitinib was started and resulted in significant tumor shrinkage and a dramatic improvement in her general condition for up to 8.5 months. Analyses of the EGFR mutation in separately microdissected specimens from adenocarcinoma and spindle cell components revealed that both components possessed the L858R point mutation. These findings gave us some insight into the carcinogenesis of pleomorphic carcinoma of the lung in relation to EGFR gene alteration. Testing for EGFR mutation may be important in patients with advanced pleomorphic carcinoma including adenocarcinoma component that is usually chemoresistant.
• Prospective Study Evaluating the Plasma Concentrations of Twenty-six Cytokines and Response to Morphine Treatment in Cancer Patients

  Chihiro Makimura; Tokuzo Arao; Hiromichi Matsuoka; Masayuki Takeda; Hidemi Kiyota; Junji Tsurutani; Yoshihiko Fujita; Kazuko Matsumoto; Hideharu Kimura; Masatomo Otsuka; Atsuko Koyama; Chiyo K. Imamura; Takeharu Yamanaka; Kyoko Tanaka; Kazuto Nishio; Kazuhiko Nakagawa

  ANTICANCER RESEARCH 31 12 4561 - 4568 2011年12月 [査読有り]
   

  Cytokine signaling is involved in pain and opioid-receptor signaling. In this prospective study, we studied the plasma cytokine levels in order to identify candidate biomarkers for predicting resistance to morphine treatment in a cohort of opioid-treatment-naive cancer patients. We analyzed pain rating and the plasma concentrations of 26 cytokines at baseline and after morphine treatment using a multiplex immunoassay system for the following cytokines: eotaxin, colony stimulating factor, granulocyte (G-CSF), colony stimulating factor granulocyte-macrophage (GMCSF), interferon alpha 2 (IFN-alpha 2), IFN-gamma, interleukin 1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17, IP-10, monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1 alpha (MIP-1 alpha), MIP-1 beta, tumor necrosis factor-alpha (TNF-alpha) and TNF-beta. No correlation was observed between the clinical characteristics and the numerical rating scale for pain at baseline or among patients who developed resistance to morphine treatment. Interestingly, the plasma concentration of MIP-1 alpha significantly decreased during morphine treatment (day 8 vs. baseline, p=0.03). Regarding the baseline plasma cytokine concentrations, none of the cytokine levels were correlated with the numerical rating scale for pain at baseline; however, the baseline plasma concentrations of eotaxin, IL-8, IL-12 (p40), IL-12 (p70), MIP-1 alpha and MIP-1 beta were significantly lower in patients who required a high dose of morphine or who developed resistance to morphine treatment. In conclusion, this is the first report revealing that the plasma concentrations of several cytokines were significantly modulated during treatment and were correlated with treatment outcome of morphine. Our results suggest that plasma cytokine levels may be promising biomarkers for morphine treatment and that they warrant further study.
• Activin A inhibits vascular endothelial cell growth and suppresses tumour angiogenesis in gastric cancer

  H Kaneda; T Arao; K Matsumoto; M A De Velasco; D Tamura; K Aomatsu; K Kudo; K Sakai; T Nagai; Y Fujita; K Tanaka; K Yanagihara; Y Yamada; I Okamoto; K Nakagawa; K Nishio

  British Journal of Cancer 105 8 1210 - 1217 2011年10月 [査読有り]
  
• Acquired Drug Resistance to Vascular Endothelial Growth Factor Receptor 2 Tyrosine Kinase Inhibitor in Human Vascular Endothelial Cells

  Tokuzo Arao; Kazuko Matsumoto; Kazuyuki Furuta; Kanae Kudo; Hiroyasu Kaneda; Tomoyuki Nagai; Kazuko Sakai; Yoshihiko Fujita; Daisuke Tamura; Keiichi Aomatsu; Fumiaki Koizumi; Kazuto Nishio

  ANTICANCER RESEARCH 31 9 2787 - 2796 2011年09月 [査読有り]
   

  Acquired resistance to antiangiogenic drugs has emerged as a potentially important issue in clinical settings; however, the underlying molecular and cellular mechanism of resistance to vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitor (TKI) remains largely unclear. We evaluated the cellular characteristics of human umbilical vein endothelial cell (HUVEC) clones, which are resistant to VEGFR2-TKI (Ki8751) to elucidate this mechanism of resistance to antiangiogenic drugs. Resistant HUVEC clones were 10-fold more resistant to VEGFR2-TKI than the parental cells and they exhibited an almost complete absence of VEGF-mediated cellular proliferation. The mRNA expression analysis revealed that expression of VEGFR1, VEGFR2 and VEGFR3 was lower in resistant clones, while that of several angiogenic ligands was increased. The protein expression of VEGFR2 was markedly down-regulated in two (R5 and R6 clone) out of five resistant clones. Focusing on the R5 clone, VEGF stimulation did not increase the phosphorylation of VEGFR2 or the dimerization of VEGFR2. The inhibition of phospho-AKT by VEGFR2-TKI was also weakened more than 10-fold in the R5 clone. Finally, a microarray analysis revealed that some angiogenesis-associated, and some angiogenesis-specific genes, including platelet endothelial cell adhesion molecule 1 (PECAM1)/CD31, homeobox A9 (HOXA9), and endothelial cell-specific molecule 1 (ESM1), were remarkably down-regulated in all the resistant clones compared with the parental cells. HUVEC clones resistant to VEGFR2-TK1 exhibited down-regulation of VEGFR2, a decreased signal response to VEGF stimulation, and the loss of vascular endothelial markers. These results strongly suggest that an escape from VEGFR2 signaling-dependency is one of the cellular mechanisms of resistance to VEGFR2-TK1 in vascular endothelial cells.
• TGF-β induces sustained upregulation of SNAI1 and SNAI2 through Smad and non-Smad pathways in a human corneal epithelial cell line.

  Aomatsu K; Arao T; Sugioka K; Matsumoto K; Tamura D; Kudo K; Kaneda H; Tanaka K; Fujita Y; Shimomura Y; Nishio K

  Investigative ophthalmology & visual science 52 5 2437 - 2443 5 2011年04月 [査読有り]
   

  PURPOSE. The aim of this study was to investigate the expression changes of epithelial mesenchymal transition (EMT)-related molecules induced by TGF-beta signaling in a human corneal epithelial cell line (HCECs). METHODS. The cellular response to TGF-beta was evaluated by immunoblotting, quantitative real-time RT-PCR, and immunofluorescence microscopy in HCECs. RESULTS. TGF-beta significantly increased mRNA expression of SNAI1, SNAI2, VIM, and FN1, but not TWIST1 through Smad and non-Smad pathways in HCECs. Protein expression of a mesenchymal marker N-cadherin was dose-dependently increased and that of an epithelial marker of E-cadherin was decreased by TGF-beta. TGF-beta, but not EGF, mediated the EMT-like morphologic changes. Both TGF-beta and EGF were capable of upregulating SNAI1 and SNAI2 by about two-fold within a short response time. However, a detailed time course analysis revealed drastically different expression patterns, with TGF-beta mediating a sustained upregulation of SNAI1 and SNAI2 for at least for 6 days and EGF allowing a return to the baseline expression values after 8 similar to 12 h. These data indicate that TGF-beta, but not EGF, induces sustained upregulation of SNAI1 and SNAI2 in HCECs. CONCLUSIONS. TGF-beta induces sustained upregulation of SNAI1 and SNAI2 through Smad and non-Smad pathways, EMT-like morphologic changes, downregulation of E-cadherin, and upregulation of N-cadherin in HCECs. The authors' findings provide insight into the TGF-beta signaling and the temporal expression patterns of EMT-inducible transcription factors in HCECs. (Invest Ophthalmol Vis Sci. 2011; 52: 2437-2443) DOI: 10.1167/iovs.10-5635
• Antitumor Activity of BIBF 1120, a Triple Angiokinase Inhibitor, and Use of VEGFR2(+)pTyr(+) Peripheral Blood Leukocytes as a Pharmacodynamic Biomarker In Vivo

  Kanae Kudo; Tokuzo Arao; Kaoru Tanaka; Tomoyuki Nagai; Kazuyuki Furuta; Kazuko Sakai; Hiroyasu Kaneda; Kazuko Matsumoto; Daisuke Tamura; Keiichi Aomatsu; Marco A. De Velasco; Yoshihiko Fujita; Nagahiro Saijo; Masatoshi Kudo; Kazuto Nishio

  CLINICAL CANCER RESEARCH 17 6 1373 - 1381 2011年03月 [査読有り]
   

  Purpose: BIBF 1120 is a potent, orally available triple angiokinase inhibitor that inhibits VEGF receptors (VEGFR) 1, 2, and 3, fibroblast growth factor receptors, and platelet-derived growth factor receptors. This study examined the antitumor effects of BIBF 1120 on hepatocellular carcinoma (HCC) and attempted to identify a pharmacodynamic biomarker for use in early clinical trials. Experimental Design: We evaluated the antitumor and antiangiogenic effects of BIBF 1120 against HCC cell line both in vitro and in vivo. For the pharmacodynamic study, the phosphorylation levels of VEGFR2 in VEGF-stimulated peripheral blood leukocytes (PBL) were evaluated in mice inoculated with HCC cells and treated with BIBF 1120. Results: BIBF 1120 (0.01 mu mol/L) clearly inhibited the VEGFR2 signaling in vitro. The direct growth inhibitory effects of BIBF 1120 on four HCC cell lines were relatively mild in vitro (IC50 values: 2-5 mu mol/L); however, the oral administration of BIBF 1120 (50 or 100 mg/kg/d) significantly inhibited the tumor growth and angiogenesis in a HepG2 xenograft model. A flow cytometric analysis revealed that BIBF 1120 significantly decreased the phosphotyrosine (pTyr) levels of VEGFR2(+)CD45(dim) PBLs and the percentage of VEGFR2(+)pTyr(+) PBLs in vivo; the latter parameter seemed to be a more feasible pharmacodynamic biomarker. Conclusions: We found that BIBF 1120 exhibited potent antitumor and antiangiogenic activity against HCC and identified VEGFR2(+)pTyr(+) PBLs as a feasible and noninvasive pharmacodynamic biomarker in vivo. Clin Cancer Res; 17(6); 1373-81. (C)2010 AACR.
• Sorafenib Inhibits the Hepatocyte Growth Factor-Mediated Epithelial Mesenchymal Transition in Hepatocellular Carcinoma

  Tomoyuki Nagai; Tokuzo Arao; Kazuyuki Furuta; Kazuko Sakai; Kanae Kudo; Hiroyasu Kaneda; Daisuke Tamura; Keiichi Aomatsu; Hideharu Kimura; Yoshihiko Fujita; Kazuko Matsumoto; Nagahiro Saijo; Masatoshi Kudo; Kazuto Nishio

  MOLECULAR CANCER THERAPEUTICS 10 1 169 - 177 2011年01月 [査読有り]
   

  The epithelial mesenchymal transition (EMT) has emerged as a pivotal event in the development of the invasive and metastatic potentials of cancer progression. Sorafenib, a VEGFR inhibitor with activity against RAF kinase, is active against hepatocellular carcinoma (HCC); however, the possible involvement of sorafenib in the EMT remains unclear. Here, we examined the effect of sorafenib on the EMT. Hepatocyte growth factor (HGF) induced EMT-like morphologic changes and the upregulation of SNAI1 and N-cadherin expression. The downregulation of E-cadherin expression in HepG2 and Huh7 HCC cell lines shows that HGF mediates the EMT in HCC. The knockdown of SNAI1 using siRNA canceled the HGF-mediated morphologic changes and cadherin switching, indicating that SNAI1 is required for the HGF-mediated EMT in HCC. Interestingly, sorafenib and the MEK inhibitor U0126 markedly inhibited the HGF-induced morphologic changes, SNAI1 upregulation, and cadherin switching, whereas the PI3 kinase inhibitor wortmannin did not. Collectively, these findings indicate that sorafenib downregulates SNAI1 expression by inhibiting mitogen-activated protein kinase (MAPK) signaling, thereby inhibiting the EMT in HCC cells. In fact, a wound healing and migration assay revealed that sorafenib completely canceled the HGF-mediated cellular migration in HCC cells. In conclusion, we found that sorafenib exerts a potent inhibitory activity against the EMT by inhibiting MAPK signaling and SNAI1 expression in HCC. Our findings may provide a novel insight into the anti-EMT effect of tyrosine kinase inhibitors in cancer cells. Mol Cancer Ther; 10(1); 169-77. (C)2011 AACR.
• Bortezomib potentially inhibits cellular growth of vascular endothelial cells through suppression of G2/M transition

  Daisuke Tamura; Tokuzo Arao; Kaoru Tanaka; Hiroyasu Kaneda; Kazuko Matsumoto; Kanae Kudo; Keiichi Aomatsu; Yoshihiko Fujita; Takashi Watanabe; Nagahiro Saijo; Yoshikazu Kotani; Yoshihiro Nishimura; Kazuto Nishio

  CANCER SCIENCE 101 6 1403 - 1408 2010年06月 [査読有り]
   

  Bortezomib, a selective 26S proteasome inhibitor, has shown clinical benefits against refractory multiple myeloma. The indirect anti-angiogenic activity of bortezomib has been widely recognized; however, the growth-inhibitory mechanism of bortezomib on vascular endothelial cells remains unclear, especially on the cell cycle. Here, we showed that bortezomib (2 nM of the IC(50) value) potently inhibited the cellular growth of human umbilical vascular endothelial cells (HUVECs) via a vascular endothelial growth factor receptor (VEGFR)-independent mechanism resulting in the induction of apoptosis. Bortezomib significantly increased the vascular permeability of HUVECs, whereas a VEGFR-2 tyrosine kinase inhibitor decreased it. Interestingly, a cell cycle analysis using flow cytometry, the immunostaining of phospho-histone H3, and Giemsa staining revealed that bortezomib suppressed the G2/M transition of HUVECs, whereas the mitotic inhibitor paclitaxel induced M-phase accumulation. A further analysis of cell cycle-related proteins revealed that bortezomib increased the expression levels of cyclin B1, the cdc2/cyclin B complex, and the phosphorylation of all T14, Y15, and T161 residues on cdc2. Bortezomib also increased the ubiquitination of cyclin B1 and wee1, but inhibited the kinase activity of the cdc2/cyclin B complex. These protein modifications support the concept that bortezomib suppresses the G2/M transition, rather than causing M-phase arrest. In conclusion, we demonstrated that bortezomib potently inhibits cell growth by suppressing the G2/M transition, modifying G2/M-phase-related cycle regulators, and increasing the vascular permeability of vascular endothelial cells. Our findings reveal a cell cycle-related mode of action and strongly suggest that bortezomib exerts an additional unique vascular disrupting effect as a vascular targeting drug. (Cancer Sci 2010).
• Overexpression of FOXQ1 is important factor in tumorigenicity and tumor growth

  Kaneda Hiroyasu; Arao Tokuzo; Tanaka Kaoru; Tamura Daisuke; Aomatsu Keiichi; Kudo Kanae; Sakai Kazuko; De Velasco Marco Antonio; Matsumoto Kazuko; Yoshihiko Fujita; Yamada Yasuhide; Tsurutani Junji; Okamoto Isamu; Nakagawa Kazuhiko; Nishio Kazuto; Nagai Tomoyuki; Furuta Kazuyuki

  CANCER RESEARCH 70 2010年04月 [査読有り]
  
• FOXQ1 Is Overexpressed in Colorectal Cancer and Enhances Tumorigenicity and Tumor Growth

  Hiroyasu Kaneda; Tokuzo Arao; Kaoru Tanaka; Daisuke Tamura; Keiichi Aomatsu; Kanae Kudo; Kazuko Sakai; Marco A. De Velasco; Kazuko Matsumoto; Yoshihiko Fujita; Yasuhide Yamada; Junji Tsurutani; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio

  CANCER RESEARCH 70 5 2053 - 2063 2010年03月 [査読有り]
   

  Forkhead box Q1 (FOXQ1) is a member of the forkhead transcription factor family, and it has recently been proposed to participate in gastric acid secretion and mucin gene expression in mice. However, the role of FOXQ1 in humans and especially in cancer cells remains unknown. We found that FOXQ1 mRNA is overexpressed in clinical specimens of colorectal cancer (CRC; 28-fold/colonic mucosa). A microarray analysis revealed that the knockdown of FOXQ1 using small interfering RNA resulted in a decrease in p21(CIP1/WAF1) expression, and a reporter assay and a chromatin immunoprecipitation assay showed that p21 was one of the target genes of FOXQ1. Stable FOXQ1-overexpressing cells (H1299/FOXQ1) exhibited elevated levels of p21 expression and inhibition of apoptosis induced by doxorubicin or camptothecin. Although cellular proliferation was decreased in H1299/FOXQ1 cells in vitro, H1299/FOXQ1 cells significantly increased tumorigenicity [ enhanced green fluorescent protein (EGFP): 2/15, FOXQ1: 7/15] and enhanced tumor growth (437 +/- 301 versus 1735 +/- 769 mm(3), P < 0.001) in vivo. Meanwhile, stable p21 knockdown of H1299/FOXQ1 cells increased tumor growth, suggesting that FOXQ1 promotes tumor growth independent of p21. Microarray analysis of H1299/EGFP and H1299/FOXQ1 revealed that FOXQ1 overexpression upregulated several genes that have positive roles for tumor growth, including VEGFA, WNT3A, RSPO2, and BCL11A. CD31 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining of the tumor specimens showed that FOXQ1 overexpression mediated the angiogenic and antiapoptotic effect in vivo. In conclusion, FOXQ1 is overexpressed in CRC and enhances tumorigenicity and tumor growth presumably through its angiogenic and antiapoptotic effects. Our findings show that FOXQ1 is a new member of the cancer-related FOX family. Cancer Res; 70(5); 2053-63. (C) 2010 AACR.
• De Novo Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in EGFR Mutation-Positive Patients with Non-small Cell Lung Cancer

  Masayuki Takeda; Isamu Okamoto; Yoshihiko Fujita; Tokuzo Arao; Hiroyuki Ito; Masahiro Fukuoka; Kazuto Nishio; Kazuhiko Nakagawa

  JOURNAL OF THORACIC ONCOLOGY 5 3 399 - 400 2010年03月 [査読有り]
   

  Background: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are a predictor of response to treatment with EGFR tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). However, mechanisms of de novo resistance to these drugs in patients harboring EGFR mutations have remained unclear. We examined whether the mutational status of KRAS might be associated with primary resistance to EGFR-TKIs in EGFR mutation-positive patients with NSCLC. Methods: Forty patients with NSCLC with EGFR mutations who were treated with gefitinib or erlotinib and had archival tissue specimens available were enrolled in the study. KRAS mutations were analyzed by direct sequencing. Results: Three (7.5%) of the 40 patients had progressive disease, and two (67%) of these three individuals had both KRAS and EGFR mutations. Conclusions: Our results suggest that KRAS mutation is a negative predictor of response to EGFR-TKIs in EGFR mutation-positive patients with NSCLC.
• mTOR Signal and Hypoxia-Inducible Factor-1 alpha Regulate CD133 Expression in Cancer Cells

  Kazuko Matsumoto; Tokuzo Arao; Kaoru Tanaka; Hiroyasu Kaneda; Kanae Kudo; Yoshihiko Fujita; Daisuke Tamura; Keiichi Aomatsu; Tomohide Tamura; Yasuhide Yamada; Nagahiro Saijo; Kazuto Nishio

  CANCER RESEARCH 69 18 7160 - 7164 2009年09月 [査読有り]
   

  The underlying mechanism regulating the expression of the cancer stem cell/tumor-initiating cell marker CD133/prominin-1 in cancer cells remains largely unclear, although knowledge of this mechanism would likely provide important biological information regarding cancer stem cells. Here, we found that the inhibition of mTOR signaling up-regulated CD133 expression at both the mRNA and protein levels in a CD133-overexpressing cancer cell line. This effect was canceled by a rapamycin-competitor, tacrolimus, and was not modified by conventional cytotoxic drugs. We hypothesized that hypoxia-inducible factor-1 alpha (HIF-1 alpha), a downstream molecule in the mTOR signaling pathway, might regulate CD133 expression; we therefore investigated the relation between CD133 and HIF-1 alpha. Hypoxic conditions up-regulated HIF-1 alpha expression and inversely down-regulated CD133 expression at both the mRNA and protein levels. Similarly, the HIF-1 alpha activator deferoxamine mesylate dose-dependently down-regulated CD133 expression, consistent with the effects of hypoxic conditions. Finally, the correlations between CD133 and the expressions of HIF-1 alpha and HIF-1 beta were examined using clinical gastric cancer samples. A strong inverse correlation (r = -0.68) was observed between CD133 and HIF-1 alpha, but not between CD133 and HIF-1 beta. In conclusion, these results indicate that HIF-1 alpha down-regulates CD133 expression and suggest that mTOR signaling is involved in the expression of CD133 in cancer cells. Our findings provide a novel insight into the regulatory mechanisms of CD133 expression via mTOR signaling and HIF-1 alpha in cancer cells and might lead to insights into the involvement of the mTOR signal and oxygen-sensitive intracellular pathways in the maintenance of stemness in cancer stem cells. [Cancer Res 2009;69(1,8):7 7160-4]
• Bortezomib directly inhibits cellular growth of vascular endothelial cells via VEGF independent pathway

  Tamura Daisuke; Arao Tokuzo; Tanaka Kaoru; Kaneda Yasuhiro; Matsumoto Kazuko; Kudo Kanae; Aomatsu Keiichi; Maegawa Mari; Fujita Yoshihiko; Watanabe Takashi; Kotani Yoshikazu; Nishimura Yoshihiro; Nishio Kazuto

  CANCER RESEARCH 69 2009年05月 [査読有り]
  
• SRPX2 is a novel a chondroitin sulfate proteoglycan

  Tanaka Kaoru; Arao Tokuzo; Maegawa Mari; Matsumoto Kazuko; Tamura Daisuke; Aomatsu Keiichi; Kudo Kanae; Kaneda Hiroyasu; Fujita Yoshihiko; Honda Eiko; Yanagihara Kazuyoshi; Yamada Yasuhide; Okamoto Isamu; Nakagawa Kazuhiko; Nishio Kazuto

  CANCER RESEARCH 69 2009年05月 [査読有り]
  
• Antitumor activity of a novel angiogenesis inhibitor BIBF1120 for hepatocellular carcinoma and a new pharamacodynamic biomarker in blood samples.

  Kudo Kanae; Arao Tokuzo; Tanaka Kaoru; Kaneda Hiroyasu; Maegawa Mari; Matsumoto Kazuko; Tamura Daisuke; Aomatsu Keiichi; Fujita Yoshihiko; Kudo Masatoshi; Nishio Kazuto

  CANCER RESEARCH 69 2009年05月 [査読有り]
  
• Activin-A directly inhibits vascular endothelial cell growth via TGF-\#946; dependent signal pathway.

  Kaneda Hiroyasu; Arao Tokuzo; Tanaka Kaoru; Maegawa Mari; Matsumoto Kazuko; Kudo Kanae; Tamura Daisuke; Aomatsu Keiichi; Fujita Yoshihiko; Yamada Yasuhide; Okamoto Isamu; Nakagawa Kazuhiko; Nishio Kazuto

  CANCER RESEARCH 69 2009年05月 [査読有り]
  
• Antitumor activity and mode of action of pentacyclic oxindole alkaloids from Uncaria tomentosa

  Fujita Yoshihiko; Matsumoto Kazuko; Tanaka Kaoru; Kaneda Hiroyasu; Kudo Kanae; Maegawa Mari; Tamura Daisuke; Aomatsu Keiichi; DeVelasco Marco; Arao Tokuzo; Nishio Kazuto

  CANCER RESEARCH 69 2009年05月 [査読有り]
  
• EGFR Mutation Up-regulates EGR1 Expression through the ERK Pathway

  Mari Maegawa; Tokuzo Arao; Hideyuki Yokote; Kazuko Matsumoto; Kanae Kudo; Kaoru Tanaka; Hiroyasu Kaneda; Yoshihiko Fujita; Fumiaki It; Kazuto Nishio

  ANTICANCER RESEARCH 29 4 1111 - 1117 2009年04月 [査読有り]
   

  Background: DelE746_A750-type EGFR is a constitutively active type of mutation that enhances EGFR signaling. However, the changes in gene expression that occur in mutant EGFR-harboring cells has not been fully studied. Materials and Methods: A gene expression analysis of HEK293 cells transfected with wild-type or mutant EGFR was performed focusing on the significant gene. Results: Early growth response 1 (EGR1), a transcription factor, was the most strongly up-regulated gene in mutant EGFR-transfected cells among the genes examined. An increase in EGR1 expression in the mutant EGFR cells was confirmed using RTPCR or immunoblotting. The expression was up-regulated by EGF stimulation and down-regulated by EGFR-tyrosine kinase inhibitor. In addition, the MEK inhibitor U0126 inhibited EGR1 expression, while the phosphatidylinositol 3-kinase inhibitor LY294002 did not. Conclusion: Mutant EGFR constitutively up-regulates EGR1 through the ERK pathway, and its expression is correlated with EGFR signal activation. Findings provide an insight into a target gene of mutant EGFR and further improve the understanding of the oncogenic properties of EGFR.
• SRPX2 is overexpressed in gastric cancer and promotes cellular migration and adhesion

  Kaoru Tanaka; Tokuzo Arao; Mari Maegawa; Kazuko Matsumoto; Hiroyasu Kaneda; Kanae Kudo; Yoshihiko Fujita; Hideyuki Yokote; Kazuyoshi Yanagihara; Yasuhide Yamada; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio

  INTERNATIONAL JOURNAL OF CANCER 124 5 1072 - 1080 2009年03月 [査読有り]
   

  SRPX2 (Sushi repeat containing protein, X-linked 2) was first identified as a downstream molecule of the E2A-HLF fusion gene in t(17;19)-positive leukemia cells and the biological function of this gene remains unknown. We found that SRPX2 is overexpressed in gastric cancer and the expression and clinical features showed that high mRNA expression levels were observed in patients with unfavorable outcomes using real-time RT-PCR. The cellular distribution of SRPX2 protein showed the secretion of SRPX2 into extracellular regions and its localization in the cytoplasm. The introduction of the SRPX2 gene into HEK293 cells did not modulate the cellular proliferative activity but did enhance the cellular migration activity, as shown using migration and scratch assays. The conditioned-medium obtained from SRPX2-overexpressing cells increased the cellular migration activity of a gastric cancer cell line, SNU-16. In addition, SRPX2 protein remarkably enhanced the cellular adhesion of SNU-16 and HSC-39 and increased the phosphorylation levels of focal adhesion kinase (FAK), as shown using western blotting, suggesting that SRPX2 enhances cellular migration and adhesion through FAK signaling. In conclusion, the overexpression of SRPX2 enhances cellular migration and adhesion in gastric cancer cells. Here, we report that the biological functions of SRPX2 include cellular migration and adhesion to cancer cells. (c) 2008 Wiley-Liss, Inc.
• Epidermal growth factor receptor lacking C-terminal autophosphorylation sites retains signal transduction and high sensitivity to epidermal growth factor receptor tyrosine kinase inhibitor

  Mari Maegawa; Tokuzo Arao; Hideyuki Yokote; Kazuko Matsumoto; Kanae Kudo; Kaoru Tanaka; Hiroyasu Kaneda; Yoshihiko Fujita; Fumiaki Ito; Kazuto Nishio

  CANCER SCIENCE 100 3 552 - 557 2009年03月 [査読有り]
   

  Constitutively active mutations of epidermal growth factor receptor (EGFR) (delE746_A750) activate downstream signals, such as ERK and Akt, through the phosphorylation of tyrosine residues in the C-terminal region of EGFR. These pathways are thought to be important for cellular sensitivity to EGFR tyrosine kinase inhibitors (TKI). To examine the correlation between phosphorylation of the tyrosine residues in the C-terminal region of EGFR and cellular sensitivity to EGFR TKI, we used wild-type (wt) EGFR, as well as the following constructs: delE746_A750 EGFR; delE746_A750 EGFR with substitution of seven tyrosine residues to phenylalanine in the C-terminal region; and delE746_A750 EGFR with a C-terminal truncation at amino acid 980. These constructs were transfected stably into HEK293 cells and designated HEK293/Wt, HEK293/D, HEK293/D7F, and HEK293/D-Tr, respectively. The HEK293/D cells were found to be 100-fold more sensitive to EGFR TKI (AG1478) than HEK293/Wt. Surprisingly, the HEK293/D7F and HEK293/D-Tr cells, transfected with EGFR lacking the C-terminal autophosphorylation sites, retained high sensitivity to EGFR TKI. In these three high-sensitivity cells, the ERK pathway was activated without ligand stimulation, which was inhibited by EGFR TKI. In addition, although EGFR in the HEK293/D7F and HEK293/D-Tr cells lacked significant tyrosine residues for EGFR signal transduction, phosphorylation of Src homology and collagen homology (Shc) was spontaneously activated in these cells. Our results indicate that tyrosine residues in the C-terminal region of EGFR are not required for cellular sensitivity to EGFR TKI, and that an as-yet-unknown signaling pathway of EGFR may exist that is independent of the C-terminal region of EGFR. (Cancer Sci 2009; 100: 552-557).
• Molecular diagnostic methods designed for clinical approach to cancer of unknown origin

  Yoshihiko Fujita; Kazuto Nishio

  Japanese Journal of Cancer and Chemotherapy 36 6 923 - 926 2009年 

  Several studies have shown that patterns of gene expression remain consistent with the tissue of origin in cancer samples. Gene expression profiling may therefore offer a promising new technology to build a "site of origin" classifier with the ultimate aim to determine the origin of cancer of unknown primary (CUP). A single cDNA microarray platform was used to profile 229 tumors of known origin (14 tumor types). This data set was subsequently used for training and validation of a support vector machine (SVM) classifier, demonstrating 89% accuracy to predict a site of origin (13 types). Applying this microarray SVM classifier to 13 cases of CUP, a high confidence prediction was made in 11 of 13 cases. These predictions were supported by comprehensive review of the patients' clinical histories. Thus, data generated using both microarray and quantitative PCR can be used to train and validate a cross-platform SVM model with high prediction accuracy.
• 網羅的体細胞変異解析の動向

  藤田至彦

  Cancer Frontier 11 106 - 111 2009年
• 疾患遺伝子の変異と分子標的薬

  藤田至彦; 西尾和人

  THE LUNG 17 237 - 240 2009年
• Association of epidermal growth factor receptor (EGFR) gene mutations with EGFR amplification in advanced non-small cell lung cancer

  Ryotaro Morinaga; Isamu Okamoto; Yoshihiko Fujita; Tokuzo Arao; Masaru Sekijima; Kazuto Nishio; Hiroyuki Ito; Masahiro Fukuoka; Jun-ichi Kadota; Kazuhiko Nakagawa

  CANCER SCIENCE 99 12 2455 - 2460 2008年12月 [査読有り]
   

  Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the response to EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC). Increased EGFR copy number has also been associated with sensitivity to these drugs. However, given that it is often difficult to obtain sufficient amounts of tumor tissue for genetic analysis from patients with advanced NSCLC, the relationship between these two types of EGFR alterations has remained unclear. We have now evaluated EGFR mutation status both by direct sequencing and with a high-sensitivity assay, the Scorpion-amplification-refractory mutation system, and have determined EGFR copy number by fluorescence in situ hybridization (FISH) analysis in paired tumor specimens obtained from 100 consecutive patients with advanced NSCLC treated with chemotherapy. EGFR mutations or FISH positivity (EGFR amplification or high polysomy) were apparent in 18% (18/100) and 32% (32/100) of patients, respectively. The Scorpion-amplification-refractory mutation system was more sensitive than direct sequencing for the detection of EGFR mutations. Furthermore, EGFR mutations were associated with EGFR amplification (P = 0.009) but not with FISH positivity (P = 0.266). Our results therefore suggest the existence of a significant association between EGFR mutation and EGFR amplification in patients with advanced NSCLC. (Cancer Sci 2008; 99: 2455-2460).
• N-glycan fucosylation of epidermal growth factor receptor modulates receptor activity and sensitivity to epidermal growth factor receptor tyrosine kinase inhibitor

  Kazuko Matsumoto; Hideyuki Yokote; Tokuzo Arao; Mari Maegawa; Kaoru Tanaka; Yoshihiko Fujita; Chikako Shimizu; Toshiaki Hanafusa; Yasuhiro Fujiwara; Kazuto Nishio

  CANCER SCIENCE 99 8 1611 - 1617 2008年08月 [査読有り]
   

  The glycosylation of cell surface proteins is important for cancer biology processes such as cellular proliferation or metastasis. alpha 1,6-Fucosyltransferase (FUT8) transfers a fucose residue to n-linked oligosaccharides on glycoproteins. Herein, we study the effect of fucosylation on epidermal growth factor receptor (EGFR) activity and sensitivity to an EGFR-specific tyrosine kinase inhibitor (EGFR-TKI). The increased fucosylation of EGFR significantly promoted EGF-mediated cellular growth, and the decreased fucosylation by stable FUT8 knockdown weakened the growth response in HEK293 cells. The overexpression of FUT8 cells were more sensitive than the control cells to the EGFR-TKI gefitinib, and FUT8 knockdown decreased the sensitivity to gefitinib. Finally, to examine the effects in a human cancer cell line, we constructed stable FUT8 knockdown A549 cells, and found that these cells also decreased EGF-mediated cellular growth and were less sensitive than the control cells to gefitinib. In conclusion, we demonstrated that the modification of EGFR fucosylation affected EGF-mediated cellular growth and sensitivity to gefitinib. Our results provide a novel insight into how the glycosylation status of a receptor may affect the sensitivity of the cell to molecular target agents. (Cancer Sci 2008; 99: 1611-1617)
• Death-resistant and nonresistant malignant human cell lines under anoxia in vitro

  Megumi Yasuda; Junko Matsubara; Harufumi Yamasaki; Yoshihiko Fujita; Hiroyoshi Konishi; Satoshi Koinuma; Shigeru Taketani; Yoshitaka Horiuchi; Hiroshi Utsumi; Yoshiko Yasuda

  INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 12 6 455 - 462 2007年12月 [査読有り]
   

  Background. Erythropoietin supports the survival of erythroblasts. We previously demonstrated that 24 malignant human cell lines expressed erythropoietin and its receptor and that erythropoietin secretion was enhanced under anoxia. In this study, we examined the viability of 22 of these cell lines excluding two leukemia cell lines under anoxia. Methods. Twenty-two cancer cell lines of various origins were cultured under anoxia or normoxia for 4 days, and their viability was examined at 1-day intervals. The levels of lactate and ATP were measured. The expressions of hypoxia-inducible transcription factor la (HIF-1 alpha.) and Bcl-2 family proteins were examined by western blotting analysis. The cellular and mitochondrial features were examined by microscopy. Results. Eleven of the 22 cancer cell lines examined showed 80% to 100% cell viability after 4 days under anoxia; 2 cell lines showed similar viability for 3 days, 3 cell lines showed similar viability for 2 days, and 6 cell lines showed similar viability for 1 day or less. These 11 death-resistant cell lines, which secrete various amounts of erythropoietin under anoxia, produced significantly more lactate during 2 days under anoxia than under normoxia, with ATP levels about 60% of those before anoxia. ATP returned to the normal level when normoxia was restored after 4 days of anoxia. However, the nonresistant cell lines responded to anoxia by yielding significantly more lactate without a reduction of the ATP level. The expression patterns of Bcl-2 family proteins revealed that apoptosis-inhibiting signals predominated over proapoptotic signals in the death-resistant cells under anoxia. Conclusion. The majority of the cancer cell lines examined survived under anoxia in vitro, through the Pasteur effect, in a dormant state without direct support of erythropoietin.
• Erythropoietin contributes to implantation: Ectopic hemoglobin synthesis in decidual cells of mice

  Yoshiko Yasuda; Tohru Sasaki; Masanori Takagawa; Mitsuyo Maeda; Megumi Yasuda; Tadao Atsumi; Yoshihiko Fujita; Hiroyoshi Fujita

  Congenital Anomalies 47 1 22 - 33 2007年03月 [査読有り]
   

  Erythropoietin, by binding to its receptor, stimulates definitive erythroblasts to accumulate hemoglobin (Hb) by up-regulating erythroid-specific genes and causes differentiation of erythroblasts into erythrocytes. In mouse decidua we have found the expression of transcripts for the erythropoietin receptor, the function of which has not yet been elucidated. Erythropoietin signaling was inhibited by the injection of a soluble form of the erythropoietin receptor capable of binding with erythropoietin into the mouse uterine cavity on day 4 of gestation, and pale and defective decidual bodies appeared three days later. These pale decidual bodies contained defective embryos without extension to the ectoplacental region, while normal reddish decidual bodies contained normal developing embryos and expressed embryonic and adult Hb with characteristic location of the respective hemoglobins in which an ε- or β-globin signal was confirmed. Furthermore, blocking of erythropoietin signaling destroyed Hb-containing cells and resulted in apoptosis that caused embryonic death. Thus, erythropoietin-mediated Hb synthesis is essential for the survival of decidual cells. In addition, although no transcripts for GATA-1 and erythroid heme enzymes could be detected, genes for β-globin, as well as non-specific δ-aminolevulinate synthase, were expressed and regulated in an erythropoietin-dependent manner. This is the first evidence that ectopic Hb synthesis exists and that erythropoietin coregulates erythroid (globin) and nonerythroid (δ-aminolevulinate synthase) genes. © 2007 The Authors.
• Early effects of boron neutron capture therapy on rat glioma models

  Nobuhiro Nakagawa; Fumiharu Akai; Norihito Fukawa; Yoshihiko Fujita; Minoru Suzuki; Koji Ono; Mamoru Taneda

  BRAIN TUMOR PATHOLOGY 24 1 7 - 13 2007年 [査読有り]
   

  Early effects of boron neutron capture therapy (BNCT) on malignant glioma are characterized by reduction of the enhancement area and regression of the peritumoral edema radiologically. The aim of this study was to investigate the early histological changes of tumors and inflammatory cells after BNCT in the rat brain. Rats were treated with BNCT using boronophenylalanine (BPA) 7 days after implantation of C6 glioma cells. The tumors were assessed with magnetic resonance imaging and histopathological examination at 4 days after BNCT. The mean tumor volumes were 39 +/- 2 mm(3) in the BNCT group and 134 18 mm(3) in the control group. In the BNCT group, tumor cells showed a less pleomorphic appearance with atypical nuclei and mitotic figures. The Ki-67 labeling index was 6.5% +/- 4.7% in the BNCT and 35% +/- 3.8% in the control group. The reactions of the inflammatory cells were examined with ED-1 as macrophage marker and OX42 as microglia marker. ED-1- and OX-42-positive cells were reduced both in the core and the marginal area of the tumor in the BNCT group. It is suggested that BNCT reduced tumor progression by suppression of proliferation. Inhibition of the activated macrophages may relate to reduced peritumoral edema in the early phase.
• Erythropoietin regulates tumour growth of human malignancies

  Y Yasuda; Y Fujita; T Matsuo; S Koinuma; S Hara; A Tazaki; M Onozaki; M Hashimoto; T Musha; K Ogawa; H Fujita; Y Nakamura; H Shiozaki; H Utsumi

  CARCINOGENESIS 24 6 1021 - 1029 2003年06月 [査読有り]
   

  In addition to the chief function of erythropoietin (Epo) in promoting erythropoiesis, some other roles have been found in the brain and uterus. We have reported that signalling pathways of Epo and Epo receptor (EpoR) are involved in the tumourigenesis of ovarian and uterine cancers. To determine whether Epo plays a similar role in other malignancies, we studied the expression of Epo in several malignant human cell lines. We found that 24 malignant human cell lines examined express Epo and EpoR regardless of their origins, types, genetic characteristics and biological properties and secrete a very small amount of Epo individually and that most of them respond to hypoxic stimuli by enhanced secretion of Epo. To determine whether the Epo-EpoR pathway operates in tumours of these cell lines, we transplanted several cell lines into nude mice and confirmed the presence of Epo-responsive sites in xenografts in which the phosphorylation of the STAT5 (signal transducer and activator of transcription) is detectable. Furthermore, in nude mice we blocked the Epo signalling in xenografts of two representative cell lines, stomach choriocarcinoma and melanoma, by i.p. injections of EpoR antagonist and found inhibition of angiogenesis and survival of tumour cells leading to destruction of tumour masses and disturbances of phosphorylation of STAT5. In contrast, Epo mimetic peptide promotes angiogenesis and tumour cell survival. These findings suggest that Epo is indispensable for the growth and viability of malignant tumour and also that the deprivation of Epo signalling may be a promising therapy for human malignancy.
• Stat3活性化過程の１分子観察

  藤田至彦

  バイオイメージングでここまで理解る 羊土社 90 - 94 2003年
• Erythropoietin is involved in growth and angiogenesis in malignant tumours of female reproductive organs

  Y Yasuda; Y Fujita; S Masuda; T Musha; K Ueda; H Tanaka; H Fujita; T Matsuo; M Nagao; R Sasaki; Y Nakamura

  CARCINOGENESIS 23 11 1797 - 1805 2002年11月 [査読有り]
   

  The accumulating evidence that erythropoietin and erythropoietin receptor are expressed in various non-haematopoietic organs suggests that erythropoietin signalling might be involved in the growth of tumours, but this possibility has never been examined. We found that mRNAs for erythropoietin and erythropoietin receptor are expressed in malignant tumours of female reproductive organs, where erythropoietin levels are higher than in normal tissues. Furthermore, tumour cells and capillary endothelium showed erythropoietin receptor immunoreactivity. To investigate the role of the erythropoietin/erythropoietin receptor pathway in these tumours, we injected mouse monoclonal antibody against erythropoietin or the soluble form of erythropoietin receptor into blocks of tumour specimens and cultured the blocks. After 12 h of injections, these blocks were examined and compared with control blocks injected with mouse monoclonal antibody, heat denatured soluble form of erythropoietin receptor, mouse serum or saline. Tumour cells and capillaries were markedly decreased in a dose-dependent manner after either injection. A marked increase of the cells containing fragmented DNA and the histopathological characteristics of these cells suggest that the decrease in tumour cells and capillary endothelial cells was due to apoptotic cell death. The co-existence of JAK2 and phosphorylated-JAK2, and STAT5 and phosphorylated STAT5, all of which are involved in the mitogenic signalling of erythropoietin, was found frequently in tumour cells and capillary endothelial cells in the untreated blocks. In contrast, most of the phosphorylated-JAK2- or phosphorylated-STAT5-positive cells had disappeared in the experimental blocks. Moreover, reduced tyrosine phosphorylation of STAT5 in the experimental blocks was confirmed by western blotting analysis. The results strongly indicate that erythropoietin signalling contributes to the growth and/or survival of both transformed cells and capillary endothelial cells in these tumours. Thus, deprivation of erythropoietin signalling may be a useful therapy for erythropoietin-producing malignant tumours.
• Erythropoietin and erythropoietin-receptor producing cells demonstrated by in situ hybridization in mouse visceral yolk sacs

  Yoshiko Yasuda; Masaki Okano; Masaya Nagao; Seiji Masuda; Yoshihiko Fujita; Ryuzo Sasaki

  Anatomical Science International 77 1 58 - 63 2002年03月 [査読有り]
  
• Inhibition of erythropoietin signalling destroys xenografts of ovarian and uterine cancers in nude mice

  Y Yasuda; T Musha; H Tanaka; Y Fujita; H Fujita; H Utsumi; T Matsuo; S Masuda; M Nagao; R Sasaki; Y Nakamura

  BRITISH JOURNAL OF CANCER 84 6 836 - 843 2001年03月 [査読有り]
   

  We have recently shown that malignant tumours from the ovary and uterus expressed erythropoietin (Epo) and its receptor (EpoR), and that deprivation of Epo signal in tumour blocks induced death of malignant cells and capillary endothelial cells in vitro (Yasuda et al, submitted). These in vitro results prompted us to examine the effect of Epo-signal withdrawal on tumours in vivo. RT-PCR analysis demonstrated the expression of mRNAs for Epo and EpoR in the transplants of uterine and ovarian tumours in nude mice. Then we injected locally anti-Epo antibody or soluble form of EpoR into the transplants. At 12 h, 1, 7 or 14 days after the injection, all transplants were resected and examined macro- and microscopically. Tumour size was reduced in Epo signal-deprived transplants. Immunohistochemical examinations revealed destruction of Epo-responding malignant and capillary endothelial cells through apoptotic death. The degree of tumour regression correlated well with the dose and frequency of the injections. Control xenografts with saline injection or needle insertion showed well-developed tumour masses. This Epo response pathway will have profound implications for our understanding of the development and progression of malignant tumours and for the use of Epo-signal deprivation as an effective therapy. (C) 2001 Cancer Research Campaign http://www.bjcancer.com.
• Expression of erythropoietin in human female reproductive organs

  Y Yasuda; Y Fujita; T Musha; H Tanaka; S Shiokawa; K Nakamatsu; S Mori; T Matsuo; Y Nakamura

  MOLECULAR, CELLULAR AND DEVELOPMENTAL BIOLOGY OF REPRODUCTION 8 215 - 222 2001年 [査読有り]
   

  Erythropoietin (Epo) is known to be a lineage specific cytokine which regulates the number of circulating erythrocytes. Most of it is produced in the kidney. Recently, Epo has been reported to be synthesized in the normal brain, placenta, and capillary endothelium. We also have found that uterine endometrium expresses Epo signals in an estrogen-dependent manner, and that Epo contributes to angiogenesis in the endometrium in mice. To clarify the functional activity of Epo in human reproductive organs, we examined Epo signaling in these organs by Southern analysis of RT-PCR products and studied the distribution of substances relevant to Epo signal transduction by immunohistochemistry and Western blotting. Epo mRNA is expressed in the normal human cervix, endometrium and ovary, but it is not always detected in the specimens. Immunohistochemical analysis revealed Epo-receptor (EpoR) protein in: a) the endothelium of vessels, in glandular and surface epithelial cells, in decidual cells of the endometrium, and b) in follicles at various stages including oocytes, granulosa, theca interna cells and lutein cells of the ovary. Moreover, co-expression of JAK2 and phosphotyrosine, which reflects tyrosine phosphorylation via JAK2, and co-expression of EpoR and STAT5, which is a transcriptional factor relevant to mitogenic activity, were seen at these Epo-responsive sites. Western blotting analysis of these organs confirmed the immunohistochemical results. These findings imply that female reproductive organs can produce Epo, and that signal transduction of Epo contributes to the cyclic changes in the female reproductive organs.
• Differential interactions of the C terminus and the cytoplasmic I-II loop of neuronal Ca2+ channels with G-protein alpha and beta gamma subunits - I. Molecular determination

  T Furukawa; T Nukada; Y Mori; M Wakamori; Y Fujita; H Ishida; K Fukuda; S Kato; M Yoshii

  JOURNAL OF BIOLOGICAL CHEMISTRY 273 28 17585 - 17594 1998年07月 [査読有り]
   

  Interactions of G-protein a (G alpha) and beta gamma subunits (G beta gamma) with N- (alpha(1B)) and P/Q-type (alpha(1A)) Ca2+ channels were investigated using the Xenopus oocyte expression system. G(i3)alpha was found to inhibit both N- and P/Q-type channels by receptor agonists, whereas G beta(1)gamma(2) was responsible for prepulse facilitation of N-type channels. L-type channels (alpha(1C)) were not regulated by G alpha or G beta gamma. For N-type, prepulse facilitation mediated via G beta gamma was impaired when the cytoplasmic I-II loop (loop 1) was deleted or replaced with the alpha(1C) loop 1. G alpha-mediated inhibitions were also impaired by substitution of the alpha(1C) loop 1, but only when the C terminus was deleted. For P/Q type, by contrast, deletion of the C terminus alone diminished G alpha-mediated inhibition. Moreover, a chimera of L-type with the alpha(1B) loop 1 gained G beta gamma-dependent ent facilitation, whereas an L type chimera with the Nor P/Q-type C terminus gained G alpha-mediated inhibition. These findings provide evidence that loop 1 of N-type channels is a regulatory site for G beta gamma and the C termini of P/Q- and N-types for G alpha.
• Voltage and pH dependent block of cloned N-type Ca2+ channels by amlodipine

  T Furukawa; T Nukada; K Suzuki; Y Fujita; Y Mori; M Nishimura; M Yamanaka

  BRITISH JOURNAL OF PHARMACOLOGY 121 6 1136 - 1140 1997年07月 [査読有り]
   

  1 Two types of Ca2+ channel alpha(1)-subunits were co-expressed in Xenopus oocytes with the Ca2+ channel alpha(2)- and beta(1)-subunits. The Ba2+ current through the alpha(1C)alpha(2) beta and the alpha(1B)alpha(2) beta channels had electrophysiological and pharmacological properties of L- and N-type Ca2+ channels, respectively. 2 Amlodipine had a strong blocking action on both the L-type and N-type Ca2+ channels expressed in the oocyte. The potency of the amlodipine block on the N-type Ca2+ channel was comparable to that on the L-type Ca2+ channel. At -100 mV holding potential, the IC50 values for amlodipine block on the L-type and N-type Ca2+ channel were 2.4 and 5.8 mu M, respectively. 3 The blocking action of amlodipine on the N-type Ca2+ channel was dependent on holding potential and extracellular pH, as has been observed with amlodipine block on the L-type Ca2+ channel. A depolarized holding potential and high pH enhanced the blocking action of amlodipine, 4 The time course of block development by amlodipine was similar for L-type and N-type Ca2+ channels. However, it was slower than the time course of block development by nifedipine for the L-type Ca2+ channel.
• DISTINCTIVE FUNCTIONAL-PROPERTIES OF THE NEURONAL BII (CLASS-E) CALCIUM-CHANNEL

  M WAKAMORI; T NIIDOME; D FURUTAMA; T FURUICHI; K MIKOSHIBA; Y FUJITA; TANAKA, I; K KATAYAMA; A YATANI; A SCHWARTZ; Y MORI

  RECEPTORS & CHANNELS 2 4 303 - 314 1994年 [査読有り]
   

  Functional diversity of voltage-dependent calcium channels (VDCC) is primarily due to the existence of six distinct genes of the channel-forming subunit alpha(1), which can be further classified into the L-type and neuronal non-L-type subfamilies. We have examined functional properties of the calcium channel BII expressed from the cloned cDNA, in Xenopus oocytes, and compared the results with the other members of the non-L-type subfamily, the BI and BIII channels. The BII channel is a high voltage-activated calcium channel pharmacologically featured by its unique sensitivity to the inorganic blocker Ni2+. The decaying component of the BII current shows high sensitivity to Ni2+ similar to that of the low voltage-activated channels and the R-type channel in cerebellar granule cells, whereas the sustained component is relatively resistant to Ni2+ as are the other high voltage-activated calcium channels. Dihydropyridines, omega-CgTx-GVIA, and omega-Aga-IVA, which have been used to discriminate L-, N-, and P-types, do not affect the BII current. The mode of modulation of the BII channel by auxiliary subunits is strikingly different from that observed in the L-type channels. Both activation and inactivation rates of the BII current are decelerated by coexpression of the beta subunit, and this effect is cancelled by further coexpression of the alpha(2) subunit. In situ tissue distribution studies indicate a higher level of BII mRNA expression in the hippocamus compared to other brain regions, revealing important difference in the relative abundance of BI, BII, and BIII channels in brain tissues. Overall, the results suggest that the BII channel forms a novel functional category of VDCC that is different from T-, L-, N-, and P-type.
• MOLECULAR DIVERSITY OF VOLTAGE-DEPENDENT CALCIUM-CHANNEL

  Y MORI; T NIIDOME; Y FUJITA; M MYNLIEFF; RT DIRKSEN; KG BEAM; N IWABE; T MIYATA; D FURUTAMA; T FURUICHI; K MIKOSHIBA

  Ann N Y Acad Sci . 707 87 - 108 1993年12月 [査読有り]
  
• PRIMARY STRUCTURE AND FUNCTIONAL EXPRESSION OF THE OMEGA-CONOTOXIN-SENSITIVE N-TYPE CALCIUM-CHANNEL FROM RABBIT BRAIN

  Y FUJITA; M MYNLIEFF; RT DIRKSEN; MS KIM; T NIIDOME; J NAKAI; T FRIEDRICH; N IWABE; T MIYATA; T FURUICHI; D FURUTAMA; K MIKOSHIBA; Y MORI; KG BEAM

  NEURON 10 4 585 - 598 1993年04月 [査読有り]
   

  The complete amino acid sequence of a rabbit brain calcium channel (BIII) has been deduced by cloning and sequencing the cDNA. The open reading frame encodes 2339 amino acids, which corresponds to an M(r) of 261,167. A phylogenetic tree representing evolutionary relationships indicates that BIII is grouped together with the other rabbit brain calcium channels, BI and BII, into a subfamily that is distinct from the dihydropyridine-sensitive L-type subfamily. Transient expression in cultured skeletal muscle myotubes derived from muscular dysgenic mice demonstrates that the BIII channel mediates an omega-conotoxin-sensitive calcium current with kinetics and voltage dependence like those previously reported for whole-cell N-type current. Cell-attached patch recordings, with isotonic barium as the charge carrier, revealed distinct single channels with an average slope conductance of 14.3 pS.
• EFFECTS OF SUBSTITUTION OF PUTATIVE TRANSMEMBRANE SEGMENTS ON NICOTINIC ACETYLCHOLINE-RECEPTOR FUNCTION

  T TOBIMATSU; Y FUJITA; K FUKUDA; K TANAKA; Y MORI; T KONNO; M MISHINA; S NUMA

  FEBS LETTERS 222 1 56 - 62 1987年09月 [査読有り]
  
• LOCATION OF A DELTA-SUBUNIT REGION DETERMINING ION-TRANSPORT THROUGH THE ACETYLCHOLINE-RECEPTOR CHANNEL

  K IMOTO; C METHFESSEL; B SAKMANN; M MISHINA; Y MORI; T KONNO; K FUKUDA; M KURASAKI; H BUJO; Y FUJITA; S NUMA

  NATURE 324 6098 670 - 674 1986年12月 [査読有り]
  
• LOCATION OF FUNCTIONAL REGIONS OF ACETYLCHOLINE-RECEPTOR ALPHA-SUBUNIT BY SITE-DIRECTED MUTAGENESIS

  M MISHINA; T TOBIMATSU; K IMOTO; K TANAKA; Y FUJITA; K FUKUDA; M KURASAKI; H TAKAHASHI; Y MORIMOTO; T HIROSE; S INAYAMA; T TAKAHASHI; M KUNO; S NUMA

  NATURE 313 6001 364 - 369 1985年 [査読有り]
  

講演・口頭発表等

• がん疼痛に対するオピオイド選択のための多型バイオマーカーの探索  [通常講演]

  藤田至彦; 松岡弘道; 鶴谷純司; 千葉康敬; 酒井清裕; 吉田健史; 大武陽一; 小山敦子; 西尾和人; 中川和彦

  第27回日本緩和医療学会学術大会 2022年07月 口頭発表（一般）
• クルクミンモノグルクロニドはPten欠損前立腺癌の腫瘍微小環境を調節し抗腫瘍活性を示す

  倉 由吏恵; デベラスコ・マルコ; 坂井 和子; 藤田 至彦; 橋本 士; 森 康範; 南 高文; 藤田 和利; 掛谷 秀昭; 植村 天受; 西尾 和人

  日本癌学会総会記事 2021年09月 (一社)日本癌学会
  
• がん疼痛に対するオピオイド選択のためのバイオマーカーを用いたランダム化比較試験(Relief Study)

  松岡 弘道; 鶴谷 純司; 千葉 康敬; 藤田 至彦; 酒井 清裕; 吉田 健史; 大武 陽一; 名倉 美樹; 小山 敦子; 西尾 和人; 中川 和彦

  Palliative Care Research 2021年06月 (NPO)日本緩和医療学会
  
• バレット腺癌におけるPDZK1の作用

  半田 修; 半田 有紀子; 福嶋 真弥; 大澤 元保; 村尾 高久; 松本 啓志; 藤田 至彦; 西尾 和人; 梅垣 英次; 塩谷 昭子

  日本抗加齢医学会総会プログラム・抄録集 2021年06月 (一社)日本抗加齢医学会
  
• 異種間遺伝子発現解析による免疫プロファイリングへの応用について

  坂野 恵理; 倉 由吏恵; 坂井 和子; 藤田 至彦; 野澤 昌弘; 吉川 和宏; 西尾 和人; デベラスコ・マルコ; 植村 天受

  日本癌学会総会記事 2020年10月 (一社)日本癌学会
  
• 前立腺癌特異的Ptenノックアウトマウスにおけるマイクロバイオームについての検討

  倉 由吏恵; 坂井 和子; 藤田 至彦; 野澤 昌弘; 吉川 和宏; 西尾 和人; デベラスコ・マルコ; 植村 天受

  日本癌学会総会記事 2020年10月 (一社)日本癌学会
  
• Exploration of biomarkers for the choice of chemotherapy in colorectal cancer patients  [通常講演]

  藤田至彦

  第17回日本臨床腫瘍学会学術集会 2019年07月 ポスター発表
• 大腸がん治療法選択のためのバイオマーカーの探索的研究  [通常講演]

  藤田 至彦; 坂井 和子; 山崎 健太郎; 西尾 和人

  第23回日本がん分子標的治療学会学術集会 2019年06月 ポスター発表
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  倉由吏恵; 坂井和子; 野澤昌弘; 藤田至彦; DE VELASCO Marco A.; DE VELASCO Marco A.; 西尾和人; 植村天受

  日本がん分子標的治療学会学術集会プログラム・抄録集 2019年
• 非小細胞肺癌における次世代シークエンサーを用いた融合遺伝子検出法の臨床性能検証に関する研究

  西尾和人; 坂井和子; DE VELASCO Marco; 藤田至彦

  日本がん分子標的治療学会学術集会プログラム・抄録集 2019年
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  坂井和子; 藤田至彦; デベラスコ マルコ; 西尾和人

  日本臨床プロテオゲノミクス研究会要旨集(Web) 2019年
• 分子バーコード法によるctDNA 中の変異プロフィリングと耐性機序の探索

  坂井和子; 藤田至彦; デベラスコ マルコ; 西尾和人

  日本臨床プロテオゲノミクス研究会要旨集(Web) 2019年
• Target molecules for treatment of cancer of unknown primary site  [通常講演]

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  第22回日本がん分子標的治療学会 2018年05月
• Novel target molecules for treatment of cancer of unknown primary  [通常講演]

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  109th AACR Annual Meeting 2018年04月
• 原発不明がんにおける腫瘍微小免疫環境と予後の関連性

  原谷浩司; 林秀敏; 高濱隆幸; 澤田貴宏; 中村靖司; 伊藤彰彦; 千葉康敬; 谷崎潤子; 藤田至彦; 坂井和子; 西尾和人; 中川和彦

  日本臨床腫瘍学会学術集会(CD-ROM) 2018年
• まれなEGFR遺伝子変異L861QおよびS768I陽性非小細胞性肺癌に対する最適なEGFR阻害剤の選択  [通常講演]

  坂野 恵里; 冨樫 庸介; 中村 雄; 千葉 眞人; 小林 祥久; 林 秀敏; 谷崎 潤子; 寺嶋 雅人; デ・ベラスコ・マルコ A; 坂井 和子; 藤田 至彦; 光冨 徹哉; 西尾 和人

  日本癌学会総会記事 2017年09月 日本癌学会
  
• FGFR遺伝子異常を有する肺扁平上皮癌の術後再発生存期間に対する影響とマルチキナーゼ阻害薬に対する感受性  [通常講演]

  西尾 和人; 金田 裕靖; 谷崎 潤子; 坂井 和子; 冨樫 庸介; 寺嶋 雅人; デベラスコ・マルコ; 藤田 至彦; 坂野 恵里; 中村 雄; 武田 真幸; 伊藤 彰彦; 光冨 徹哉; 中川 和彦; 岡本 勇

  肺癌 2017年06月 (NPO)日本肺癌学会
  
• 非小細胞肺がんにおける受容体型チロシンキナーゼ遺伝子変異の機能解析  [通常講演]

  寺嶋 雅人; 冨樫 庸介; 佐藤 克明; 水内 寛; 坂井 和子; 須田 健一; 中村 雄; 坂野 恵里; 林 秀敏; デベラス・マルコ; 藤田 至彦; 冨田 秀太; 光冨 徹哉; 西尾 和人

  近畿大学医学雑誌 2016年12月 近畿大学医学会
  
• DDR2 E655K変異タンパク質はユビキチン-プロテアソーム系による分解を受け機能が喪失する  [通常講演]

  寺嶋 雅人; 冨樫 庸介; 坂井 和子; 中村 雄; 坂野 恵里; デベラスコ・マルコ; 藤田 至彦; 西尾 和人

  日本癌学会総会記事 2016年10月 日本癌学会
  
• 頭頸部または食道扁平上皮癌に対するアファチニブの効果 頭頸部扁平上皮癌における活性型発癌性HER4遺伝子変異  [通常講演]

  中村 雄; 冨樫 庸介; 寺嶋 雅人; デベラスコ・マルコ; 坂井 和子; 藤田 至彦; 桶川 隆嗣; 濱田 傑; 西尾 和人

  日本癌学会総会記事 2016年10月 日本癌学会
  
• PTENノックアウトマウス前立腺癌において選択的スプライシングは頻繁に認められる  [通常講演]

  デベラスコ・マルコ; 倉 由吏恵; 坂井 和子; 藤田 至彦; 冨樫 庸介; 寺嶋 雅人; 吉川 和宏; 西尾 和人; 植村 天受

  日本癌学会総会記事 2016年10月 日本癌学会
  
• PTENノックアウトマウス前立腺癌におけるノンコーディングRNAの検討  [通常講演]

  倉 由吏恵; デベラスコ・マルコ; 坂井 和子; 藤田 至彦; 冨樫 庸介; 寺嶋 雅人; 吉川 和宏; 西尾 和人; 植村 天受

  日本癌学会総会記事 2016年10月 日本癌学会
  
• 腫瘍内クローン数定量化プログラムによる卵巣がんのクローン数と遺伝子変異の関連解析  [通常講演]

  坂井 和子; 浮田 真沙世; 高矢 寿光; 藤田 至彦; 寺嶋 雅人; デベラスコ・マルコ; 万代 昌紀; 西尾 和人

  日本癌学会総会記事 2016年10月 日本癌学会
  
• 患者自身の疼痛改善への期待は、疼痛予後を改善する  [通常講演]

  松岡 弘道; 牧村 ちひろ; 小山 敦子; 酒井 清裕; 和泉 宏昌; 大塚 正友; 藤田 至彦; 鶴谷 純司; 吉田 健史; 西尾 和人; 中川 和彦

  Palliative Care Research 2016年06月 (NPO)日本緩和医療学会
  
• がん疼痛とカルニチン欠乏症との関連性についての探索的研究  [通常講演]

  酒井 清裕; 松岡 弘道; 大武 陽一; 牧村 ちひろ; 和泉 宏昌; 大塚 正友; 藤田 至彦; 鶴谷 純司; 西尾 和人; 中川 和彦; 小山 敦子

  Palliative Care Research 2016年06月 (NPO)日本緩和医療学会
  
• 比較的早期の肺がん患者由来cell free DNAの体細胞遺伝子変異検出率の臨床病理学的規定因子の検討

  坂井和子; 藤田至彦; 西尾和人

  日本がん分子標的治療学会学術集会プログラム・抄録集 2016年
• Exploration of novel target molecules for treatment of cancer of unknown primary  [通常講演]

  Yoshihiko Fujita; Kazuko Sakai; Takayasu Kurata; Masato Terashima; Hidetoshi Hayashi; Kazuhiko Nakagawa; Kazuto Nishio

  第75回日本癌学会学術総会 2016年
• Exploratory analysis of predictive biomarkers of oxaliplatin versus irinotecan in combination with bevacizumab for patients with metastatic colorectal cancer in WJOG4407G study  [通常講演]

  Yoshihiko Fujita; Kentaro Yamazaki; MS Oba; Kei Muro; Y Negoro; Motoki Yoshida; Koichi Suyama; Takuya Kurimoto; Naotoshi Sugimoto; Nobuhiko Seki; Mikio Sato; M Ebi; Hiroshi Tamagawa; Shinya Ueda; Takao Tamura; Narikazu Boku; Ichinosuke Hyodo; Takharu Yamanaka; Junji Tsurutani; Kazuto Nishio

  第３８回欧州臨床腫瘍学会（ＥＳＭＯ） 於オーストリア、ウィーン 2015年09月
• Melanoma transition is frequently accompanied by a loss of cytoglobin, a putative tumor suppressor, in melanocytes  [通常講演]

  Yoshihiko Fujita; Satoshi Koinuma; Marco De Velasco; Bolz Jan; Yosuke Togashi; Masato Terashima; Hidetoshi Hayashi; Takuya Matsuo; Kazuto Nishio

  106th AACR Annual Meeting 2015年04月
• がん疼痛治療におけるバイオマーカー探察  [通常講演]

  松岡 弘道; 牧村 ちひろ; 大塚 正友; 酒井 清裕; 阪本 亮; 小山 敦子; 西尾 和人; 中川 和彦; 藤田 至彦; 鶴谷 純司

  日本内科学会雑誌 2015年02月 (一社)日本内科学会
  
• モルヒネ治療効果を予測する心理的因子,およびバイオマーカー研究  [通常講演]

  牧村ちひろ; 松岡弘道; 酒井清裕; 阪本亮; 大塚正友; 藤田至彦; 西尾和人; 小山敦子; 中川和彦

  日本サイコオンコロジー学会総会プログラム・抄録集 2015年
• 喫煙によるニコチン曝露はEGFR遺伝子変異陽性肺がんにおいてEGFR-TKIの耐性因子である  [通常講演]

  林 秀敏; 冨樫 庸介; 岡本 邦男; 田中 妙; 文田 壮一; 新谷 亮多; 清川 寛文; 坂本 洋一; 寺嶋 雅人; de Velasco Marco A; 坂井 和子; 藤田 至彦; 冨田 秀太; 加藤 元一; 中川 和彦; 西尾 和人

  肺癌 2014年10月 (NPO)日本肺癌学会
  
• 低酸素はALK融合遺伝子を有するH3122肺癌細胞株のALK阻害剤に対する耐性化を誘導する  [通常講演]

  冨樫 庸介; 林 秀敏; 寺嶋 雅人; 坂井 和子; 藤田 至彦; 冨田 秀太; 中川 和彦; 西尾 和人

  肺癌 2014年10月 (NPO)日本肺癌学会
  
• 新規ALK阻害剤であるアレクチニブはMET阻害剤との併用で効果が高まる  [通常講演]

  冨樫 庸介; 林 秀敏; 寺嶋 雅人; 坂井 和子; 藤田 至彦; 冨田 秀太; 中川 和彦; 西尾 和人

  肺癌 2014年10月 (NPO)日本肺癌学会
  
• MEK遺伝子変異を有する胃がんに対するMEK阻害剤の有効性(MEK inhibitor for gastric cancer with MEK1 gene mutations)  [通常講演]

  冨樫 庸介; 加藤 寛章; 林 秀敏; 寺嶋 雅人; デベラスコ・マルコ; 坂井 和子; 藤田 至彦; 冨田 秀太; 安田 卓司; 西尾 和人

  日本癌学会総会記事 2014年09月 日本癌学会
  
• KIAA1199はグリコーゲンホスホリラーゼキナーゼβサブユニットと結合してグリコーゲンの分解さらには細胞生存を亢進する(KIAA1199 interacts with PHKB and promotes glycogen breakdown and cancer cell survival)  [通常講演]

  寺嶋 雅人; 藤田 至彦; 冨樫 庸介; 坂井 和子; 冨田 秀太; 西尾 和人

  日本癌学会総会記事 2014年09月 日本癌学会
  
• メラノサイトからメラノーマへの移行は、しばしばがん抑制因子であるサイトグロビンの発現低下を伴う  [通常講演]

  藤田至彦; 鯉沼聡; デベラスコ マルコ; ボルツ ヤン; 冨樫庸介; 寺嶋雅人; 林秀敏; 松尾拓哉; 西尾和人

  第７３回日本癌学会学術総会 2014年09月
• マイクロアレイをもちいた原発不明がんの診断バイオマーカーの探索  [通常講演]

  藤田至彦; 倉橋一成; 倉田宝保; 洪泰浩; 坂井和子; 中川和彦; 西尾和人

  第１８回日本がん分子標的治療学会学術集会 2014年06月
• A microarray-based gene expression analysis identified diagnostic biomarkers for unknown primary cancer  [通常講演]

  Yoshihiko Fujita; Issei Kurahashi; Takayasu Kurata; Yasuhiro Koh; Kazuko Sakai; Kazuhiko Nakagawa; Kazuto Nishio

  105th AACR Annual Meeting 2014年04月
• MEK1遺伝子変異を有する胃がん細胞株に対するMEK阻害剤の有効性と臨床サンプルの検討

  冨樫庸介; 曽我部俊介; 加藤寛章; 寺嶋雅人; 林秀敏; 林秀敏; 坂井和子; 藤田至彦; 冨田秀太; 安田卓志; 西尾和人

  日本臨床腫瘍学会学術集会(CD-ROM) 2014年
• NGSによる極微量検体を用いたmultiplex mutation analysisの最適化(Optimization of multiplex mutation analysis based on minimum amount of lung cancer specimen)  [通常講演]

  冨田 秀太; 坂井 和子; 藤田 至彦; 寺嶋 雅人; 富樫 庸介; デベラスコ・マルコ; 光冨 徹哉; 中川 和彦; 西尾 和人

  日本癌学会総会記事 2013年10月 日本癌学会
  
• 肺癌生物像に基づいた、新しい肺癌治療の戦略 EGFR遺伝子変異を有する肺癌においてβカテニンを阻害することでEGFR-TKIの効果が増強する  [通常講演]

  冨樫 庸介; 林 秀敏; 寺嶋 雅人; 藤田 至彦; 坂井 和子; 冨田 秀太; 中川 和彦; 西尾 和人

  肺癌 2013年10月 (NPO)日本肺癌学会
  
• 食道扁平上皮癌で高頻度に増幅しているORAOV1遺伝子は腫瘍増大と低分化な組織型に関与している

  冨樫庸介; 荒尾徳三; 加藤寛章; 松本和子; 寺嶋雅人; 林秀敏; 藤田至彦; 安田卓司; 塩崎均; 西尾和人

  日本臨床腫瘍学会学術集会(CD-ROM) 2013年
• A Microarray-Based Gene Expression Analysis Identified Diagnostic Biomarkers for Unknown Primary Cancer  [通常講演]

  Yoshihiko Fujita; Issei Kurahashi; Takayasu Kurata; Yasuhiro Koh; Kazuko Sakai; Kazuhiko Nakagawa; Kazuto Nishio

  第３８回欧州臨床腫瘍学会（ＥＳＭＯ） 於オランダ、アムステルダム 2013年
• 食道扁平上皮癌におけるEGFR、HER2、FGFR2、METの遺伝子増幅(Gene amplification of EGFR, HER2, FGFR2, and MET in esophageal squamous cell carcinoma)  [通常講演]

  加藤 寛章; 荒尾 徳三; 林 秀敏; 吉田 修平; 永井 知行; 松本 和子; 藤田 至彦; 木村 英晴; 安田 卓司; 奥野 清隆; 塩崎 均; 西尾 和人

  日本癌学会総会記事 2012年08月 日本癌学会
  
• 大腸がんにおけるHS6ST2発現とその臨床的意義(Characteristics of HS6ST2 expression in colorectal cancer)  [通常講演]

  木村 英晴; 波多邉 繁; 荒尾 徳三; 林 秀敏; 永井 知行; 松本 和子; 藤田 至彦; 伊藤 彰彦; 奥野 清隆; 西尾 和人

  日本癌学会総会記事 2012年08月 日本癌学会
  
• OCT4偽遺伝子であるPOU5F1Bの増殖は胃がんにおいて予後不良因子である(Amplification of OCT4-pseudogene POU5F1B is a poor prognostic factor in gastric cancer)  [通常講演]

  林 秀敏; 荒尾 徳三; 松本 和子; 永井 知行; 木村 英晴; デベラスコ・マルコ; 藤田 至彦; 山田 康秀; 中川 和彦; 西尾 和人

  日本癌学会総会記事 2012年08月 日本癌学会
  
• 肺癌における微量EGFR-TKI耐性遺伝子変異の検出  [通常講演]

  藤田 至彦; 須田 健一; 木村 英晴; 松本 和子; 荒尾 徳三; 西條 長宏; 谷田部 恭; 光冨 徹哉; 西尾 和人

  第１６回日本がん分子標的治療学会 2012年06月
• Detection of EGFR T790M mutation in nonsmall-cell lung cancer patients using colony hybridization assay.  [通常講演]

  Yoshihiko Fujita; Kenichi Suda; Hideharu Kimura; Kazuko Matsumoto; Tokuzo Arao; Tomoyuki Nagai; Hidetoshi Hayashi; Kazuyuki Furuta; Hiroaki Kato; Nagahiro Saijo; Yasushi Yatabe; Tetsuya Mitsudomi; kazuto Nishio

  103th AACR Annual Meeting 2012年04月
• Snailに誘導される上皮間葉移行とチュブリン作用系抗癌剤の感受性

  吉田修平; 田村大介; 荒尾徳三; 松本和子; 木村英晴; 藤田至彦; 林秀敏; 林秀敏; 永井知行; 金田裕靖; 西尾和人

  日本臨床腫瘍学会学術集会プログラム・抄録集 2012年
• ソラフェニブの上皮間葉移行阻害効果

  永井知行; 永井知行; 木村英晴; 荒尾徳三; 松本和子; 藤田至彦; 吉田修平; 林秀敏; 工藤正俊; 西尾和人

  日本臨床腫瘍学会学術集会プログラム・抄録集 2012年
• 食道扁平上皮癌におけるEGFR-familyの遺伝子増幅とEGFRの遺伝子変異

  加藤寛章; 荒尾徳三; 松本和子; 藤田至彦; 木村英晴; 安田卓司; 奥野清隆; 塩崎均; 西尾和人

  日本臨床腫瘍学会学術集会プログラム・抄録集 2012年
• FGFR阻害薬によるCD133の発現制御機構の解析

  松本和子; 荒尾徳三; 吉田修平; 林秀敏; 藤田至彦; 加藤寛章; 永井知行; 木村英晴; 西尾和人

  日本臨床腫瘍学会学術集会プログラム・抄録集 2012年
• "Gene amplification of EGFR, HER2, HER3 and HER4 in esophageal squamous cell carcinoma. "

  Tokuzo Arao; Kazuko Matsumoto; Yoshihiko Fujita; Hideharu; Kimura; Kouhei Nishiki; Osamu Shiraishi; Atsushi Yasuda; Ying-Feng Peng; Masayuki Shinkai; Motohiro Imano; Haruhiko Imamoto; Takushi Yasuda; Kiyotaka Okuno; Hitoshi; Shiozaki; Kazuto Nishio

  103th AACR Annual Meeting 2012年
• " Amplification of OCT4-pseudogene POU5F1B is a poor prognostic factor in gastric cancer. "

  Hidetoshi Hayashi; Tokuzo Arao; Kazuko Matsumoto; Tomoyuki Nagai; Hideharu Kimura; Marco A. De Velasco; Yoshihiko Fujita; Yasuhide Yamada; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio

  103th AACR Annual Meeting 2012年
• Impact of TJP-1 and TWIST expression on post-operative prognosis in hepatocellular Carcinoma.

  Tomoyuki Nagai; Tokuzo Arao; Kazuko Matsumoto; Kazuko Sakai; Kanae Kudo; Hiroyasu Kaneda; Daisuke Tamura; Keiichi Aomatsu; Hideharu Kimura; Yoshihiko Fujita; Satoru Hagiwara; Toshiharu Sakurai; Kazuomi Ueshima; Seiji Haji; Masatoshi Kudo; Kazuto Nishi

  103th AACR Annual Meeting 2012年
• "Characteristics of HS6ST2 expression in colorectal cancer. "

  Hideharu Kimura; Shigeru Hatabe; Tokuzo Arao; Hidetoshi Hayashi; Tomoyuki Nagai; Kazuko Matsumoto; Yoshihiko Fujita; Masao Fukushima; Akihiko Ito; Kiyotaka; Okuno; Kazuto Nishio

  103th AACR Annual Meeting 2012年
• 非小細胞肺がん患者におけるEGFR T790M変異の新規検出法  [通常講演]

  藤田 至彦; 須田 健一; 木村 英晴; 松本 和子; 荒尾 徳三; 西條 長宏; 谷田部 恭; 光冨 徹哉; 西尾 和人

  第７0回日本癌学会学術総会 2011年10月
• 肝細胞癌におけるTJP-1とTwist発現の肝癌切除後の予後への影響(Impact of TJP-1 and TWIST expression on post-operative prognosis in hepatocellular carcinoma)  [通常講演]

  永井 知行; 荒尾 徳三; 松本 和子; 工藤 可苗; 木村 英晴; 藤田 至彦; 萩原 智; 櫻井 俊治; 上嶋 一臣; 土師 誠二; 工藤 正俊; 西尾 和人

  日本癌学会総会記事 2011年09月 日本癌学会
  
• 大腸がんにおけるHS6ST2発現とその臨床的特徴(Characteristics of HS6ST2 Expression in Colorectal Cancer)  [通常講演]

  木村 英晴; 波多邉 繁; 荒尾 徳三; 林 秀敏; 永井 知行; 松本 和子; 工藤 可苗; 藤田 至彦; 伊藤 彰彦; 奥野 清隆; 西尾 和人

  日本癌学会総会記事 2011年09月 日本癌学会
  
• レスベラトロールのアザ誘導体はマクロファージ遊走阻止因子（MIF）の阻害作用をもつ  [通常講演]

  藤田至彦; 田村大介; 青松圭一; 金田裕靖; 古田一行; 工藤可苗; 坂井和子; 永井知行; 松本和子; 木村英晴; 荒尾徳三; 大川原正; 西尾和人

  第１５回日本がん分子標的治療学会学術集会 2011年06月
• "Aza-derivatives of resveratrol are potent inhibitors of macrophage migration inhibitory factor (MIF).  [通常講演]

  Yoshihiko Fujita; Rafiqul Islam Islam; Hideharu Kimura; Kazuko Matsumoto; Kazuyuki Furuta; Tomoyuki Nagai; Kanae Kudo; Hiroyasu Kaneda; Daisuke Tamura; Kazuko Sakai; Keiichi Aomatsu; Tokuzo Arao; Tadashi Okawara; Kazuto Nishio

  102th AACR Annual Meeting 2011年04月
• "Short Poly A sequence in HGF promoter region is involved in overexpression of HGF in cancer cells. "

  Kazuko Sakai; Tokuzo Arao; Kazuko Matsumoto; Hideharu Kimura; Yoshihiko Fujita; Hiroyasu Kaneda; Daisuke Tamura; Keiichi Aomatsu; Kanae Kudo; Tomoyuki Nagai; Marco A. De; Velasco; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio

  102th AACR Annual Meeting 2011年
• "Critical roles of FOXQ1 in tumor angiogenesis of colorectal cancer. "

  Hiroyasu Kaneda; Tokuzo Arao, Kazuko; Matsumoto; Kanae Kudo; Daisuke Tamura; Keiichi Aomatsu; Tomoyuki Nagai; Kazuko Sakai; Hideharu Kimura, Kazuyuki; Furuta; Yoshihiko Fujita; Marco A. De Velasco; Nagahiro Saijo; Yasuhide Yamada; Isamu Okamoto, Kazuhiko; Nakagawa; Kazuto Nishio

  102th AACR Annual Meeting 2011年
• "Slug-mediated epithelial mesenchymal transition in lung cancer cells. "

  Tamura Daisuke; Tokuzo Arao; Tomoyuki Nagai; Kazuyuki Furuta; Kazuko Sakai; Kanae Kudo; Hiroyasu Kaneda, Keiichi; Aomatsu; Yoshihiko Fujita; Kazuko Matsumoto; Yoshikazu Kotani; Yoshihiro Nishimura; Nagahiro Saijo; Kazuto Nishio

  102th AACR Annual Meeting 2011年
• "FGFR inhibitor regulates CD133 expression in FGFR2- amplified gastric cancer cells. "

  Kazuko Matsumoto; Tokuzo Arao; Kazuyuki Furuta; Tomoyuki Nagai; Kanae Kudo; Hiroyasu Kaneda; Daisuke Tamura; Keiichi Aomatsu; Kazuko Sakai; Yoshihiko Fujita; Hideharu Kimura; Yasuhide Yamada; Kazuto Nishio

  102th AACR Annual Meeting 2011年
• 転写因子snail、slugは角膜上皮細胞においてEMTを誘導しTP63発現レベルを減少させる(Snail and Slug transcription factors induce EMT and down-regulate TP63 mRNA expression in corneal epithelial cells)  [通常講演]

  青松 圭一; 荒尾 徳三; 古田 一行; 松本 和子; 金田 裕靖; 工藤 可苗; 田村 大介; 永井 知行; 坂井 和子; 木村 英晴; 藤田 至彦; 下村 嘉一; 西尾 和人

  日本癌学会総会記事 2010年08月 日本癌学会
  
• SNAI2に惹起されるEMTは肺癌においてチュブリン作用薬に対する感受性を亢進する(SNAI2-mediated epithelial mesenchymal transition increases the drug sensitivity to tubulin binding agents in lung cancer)  [通常講演]

  田村 大介; 荒尾 徳三; 永井 知行; 古田 一行; 坂井 和子; 工藤 可苗; 金田 裕靖; 青松 圭一; 藤田 至彦; 松本 和子; 西村 善博; 西條 長宏; 西尾 和人

  日本癌学会総会記事 2010年08月 日本癌学会
  
• 分子標的治療 ソラフェニブは肝細胞癌株において、HGF起因の上皮間葉移行(Epithelial mesenchymal transition)を阻害する(Molecular target therapy Sorafenib inhibits the hepatocyte growth factor-mediated epithelial mesenchymal transition in hepatocellular carcinoma)  [通常講演]

  永井 知行; 荒尾 徳三; 坂井 和子; 工藤 可苗; 金田 裕靖; 田村 大介; 青松 圭一; 木村 英春; 藤田 至彦; 松本 和子; 西條 長宏; 工藤 雅俊; 西尾 和人

  日本癌学会総会記事 2010年08月 日本癌学会
  
• 血管内皮細胞におけるVEGFR2チロシンキナーゼ阻害薬の耐性機構(Drug resistance to vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor in vascular endothelial cells)  [通常講演]

  松本 和子; 荒尾 徳三; 工藤 可苗; 古田 一行; 坂井 和子; 永井 知行; 金田 裕靖; 田村 大介; 青松 圭一; 藤田 至彦; 木村 英晴; 西尾 和人

  日本癌学会総会記事 2010年08月 日本癌学会
  
• Gefitinib耐性株を用いた耐性機序の探索(Expression levels of EGFR-ligands are up-regnlated in EGFR tyrosine kinase inhibitor-resistant cell line)  [通常講演]

  坂井 和子; 荒尾 徳三; 古田 一行; 永井 知行; 工藤 可苗; 金田 裕靖; 田村 大介; 青松 圭一; 藤田 至彦; 松本 和子; 小泉 史明; 西尾 和人

  日本癌学会総会記事 2010年08月 日本癌学会
  
• 腫瘍細胞増殖におけるMIF-CD74シグナル経路の関与  [通常講演]

  藤田至彦; 古田一行; 工藤可苗; 坂井和子; 永井知行; 金田裕靖; 田村大介; 青松圭一; 木村英晴; 松本和子; 荒尾徳三; 西尾和人

  第69回日本癌学会学術総会 2010年
• "Characterization of human umbilical vein endothelial cell clones resistant to VEGFR2 tyrosine kinase inhibitor. "

  Kazuko Matsumoto; Tokuzo Arao, Kazuyuki; Furuta; Kazuko Sakai; Tomoyuki Nagai; Kanae Kudo; Hiroyasu Kaneda; Daisuke Tamura; Keiichi Aomatsu; Yoshihiko Fujita; Kazuto Nishio

  101th AACR Annual Meeting 2010年
• "Integration of whole genome exon array and array CGH analysis in gastric and colorectal cancer cell lines. "

  Kazuyuki Furuta; Tokuzo Arao; Kazuko Sakai; Tomoyuki Nagai; Daisuke Tamura; Keiichi Aomatsu; Kanae Kudo; Hiroyasu; Kaneda; Yoshihiko Fujita; Kazuko Matsumoto; Yasuhide Yamada; Kazuyoshi Yanagihara; Masaru Sekijima; Kazuto Nishio

  101th AACR Annual Meeting 2010年
• "Sorafenib inhibits hepatocyte growth factorinduced epithelial mesenchymal transition in hepatocellular carcinoma. "

  Nagai Tomoyuki; Tokuzo Arao; Kazuyuki Furuta; Kazuko Sakai; Kanae Kudo; Hiroyasu; Kaneda; Daisuke Tamura; Keiichi Aomatsu; Yoshihiko Fujita; Kazuko Matsumoto; Nagahiro Saijo; Masatoshi Kudo; Kazuto Nishio

  101th AACR Annual Meeting 2010年
• "Snail and slug-mediated epithelial mesenchymal transition in lung cancer cells. "

  Tamura Daisuke; Tokuzo Arao Arao; Tomoyuki Nagai Nagai; Keiichi Aomatsu; Kazuko Sakai; Kanae Kudo; Hiroyasu Kaneda, Kazuko; Matsumoto; Kazuyuki Furuta; Yoshihiko Fujita; Yoshikazu Kotani; Yoshihiro Nishimura; Nagahiro Saijo; Kazuto Nishio

  101th AACR Annual Meeting 2010年
• "Overexpression of FOXQ1 is important factor in tumorigenicity and tumor growth. "

  Hiroyasu Kaneda; Tokuzo Arao; Kaoru Tanaka; Daisuke Tamura, Keiichi; Aomatsu; Kanae Kudo; Kazuko Sakai; Marco A. De Velasco; Kazuko Matsumoto; Fujita Yoshihiko; Yasuhide; Yamada, Junji Tsurutani; Isamu Okamoto, Kazuhiko; Nakagawa; Kazuto Nishio; Tomoyuki Nagai; Kazuyuki Furuta

  101th AACR Annual Meeting 2010年
• Expression levels of EGFR-ligands are upregulated in EGFR tyrosine kinase inhibitor-resistant cell line.

  Kazuko Sakai; Tokuzo Arao; Kazuyuki Furuta; Tomoyuki Nagai; Kanae Kudo; Hiroyasu Kaneda; Daisuke Tamura; Keiichi Aomatsu; Yoshihiko Fujita, Kazuko; Matsumoto; Fumiaki Koizumi; Kazuto Nishio

  101th AACR Annual Meeting 2010年
• 血液標本における新規薬物動態バイオマーカーの血管新生阻害剤BIBF1120の抗腫瘍活性(Antitumor activity of a novel angiogenesis inhibitor BIBF1120 a new pharamacodynamic biomarker in blood samples)  [通常講演]

  工藤 可苗; 荒尾 徳三; 坂井 和子; 永井 知行; 田村 大介; 青松 圭一; デベラスコ・マルコ; 金田 裕靖; 藤田 至彦; 松本 和子; 工藤 正俊; 西尾 和人

  日本癌学会総会記事 2009年08月 日本癌学会
  
• TGF-βはヒト角膜上皮細胞の増殖とEMT関連遺伝子発現を調節する(TGF-beta regulates proliferation and EMT-related gene expression of human corneal epithelial cell)  [通常講演]

  青松 圭一; 荒尾 徳三; 坂井 和子; 永井 知行; 田村 大介; 工藤 可苗; 金田 裕靖; 藤田 至彦; 松本 和子; 下村 嘉一; 西尾 和人

  日本癌学会総会記事 2009年08月 日本癌学会
  
• mTORシグナルとHIF-1 alphaは癌細胞のCD133の発現を制御する(mTOR signal and HIF-1 alpha regulate CD133 expression in cancer cells)  [通常講演]

  松本 和子; 荒尾 徳三; 坂井 和子; 永井 知行; 田村 大介; 青松 圭一; 工藤 可苗; デベラスコ・マルコ; 金田 裕靖; 藤田 至彦; 山田 康秀; 西尾 和人

  日本癌学会総会記事 2009年08月 日本癌学会
  
• 胃癌高発現遺伝子SRPX2は胃癌細胞の遊走・接着を誘導する(SRPX2 is overexpressed in gastric cancer and promotes cellular migration and adhesion)  [通常講演]

  荒尾 徳三; 田中 薫; 青松 圭一; 田村 大介; 工藤 可苗; 金田 裕靖; 藤田 至彦; 松本 和子; 柳原 五吉; 山田 康秀; 岡本 勇; 中川 和彦; 西尾 和人

  日本癌学会総会記事 2009年08月 日本癌学会
  
• エクソンアレイとSNPアレイによるがん細胞株のエクソン異常の探索(Whole genome exon array and SNP array detected alternative splicing in gastrointestinal cancer cell lines)  [通常講演]

  古田 一行; 荒尾 徳三; 坂井 和子; 永井 知行; 田村 大介; 青松 圭一; 工藤 可苗; デベラスコ・マルコ; 金田 裕靖; 藤田 至彦; 松本 和子; 関島 勝; 西尾 和人

  日本癌学会総会記事 2009年08月 日本癌学会
  
• アクチビン-AはTGFβ依存性シグナルを介して血管内皮細胞の増殖を直接抑制する(Activin-A directly inhibits vascular endothelial cell growth via TGF-beta dependent signal pathway)  [通常講演]

  金田 裕靖; 荒尾 徳三; 田中 薫; 永井 智行; 工藤 可苗; 田村 大介; 青松 圭一; 松本 和子; 藤田 至彦; 山田 康秀; 岡本 勇; 中川 和彦; 西尾 和人

  日本癌学会総会記事 2009年08月 日本癌学会
  
• Antitumor activity and mode of action of pentacyclic oxindole alkaloids from Uncaria tomentosa  [通常講演]

  Yoshihiko Fujita; Kazuko Matsumoto; Kaoru Tanaka; Hiroyasu Kaneda; Kanae Kudo; Mari Maegawa; Daisuke Tamura; Keiichi Aomatsu; Marco DeVelasco; Tokuzo Arao; Kazuto Nishio

  100th AACR Annual Meeting 2009年 2009年04月 AMER ASSOC CANCER RESEARCH
  
• エポックメイキングな薬学を目指して 基礎と臨床の架橋となる生命科学 超分子[2]Rotaxaneによる抗腫瘍効果と特徴ある作用様式  [通常講演]

  牧尾 圭悟; 原 一樹; 木村 公彦; 牛島 逸子; 新矢 時寛; 高田 十志和; 藤田 至彦; 西尾 和人; 小野 信文

  日本薬学会年会要旨集 2009年03月 (公社)日本薬学会
  
• 抗がん活性を持つロタキサンの合成

  高田十志和; 小山靖人; 中薗和子; 小野信文; 西尾和人; 藤田至彦

  日本化学会講演予稿集 2009年
• "Antitumor activity of a novel angiogenesis inhibitor BIBF1120 for hepatocellular carcinoma and a new pharamacodynamic biomarker in blood samples.

  Kanae Kudo; Tokuzo Arao; Kaoru Tanaka; Hiroyasu Kaneda, Mari; Maegawa; Kazuko Matsumoto; Daisuke Tamura, Keiichi; Aomatsu; Yoshihiko Fujita; Masatoshi Kudo; Kazuto Nishio

  100th AACR Annual Meeting 2009年
• CD133 expression is affected by rapamycin in cancer cells.

  Kazuko Matsumoto; Tokuzo Arao; Kaoru Tanaka; Hiroyasu; Kaneda; Kanae Kudo; Mari Maegawa; Daisuke Tamura, Keiichi; Aomatsu; Yoshihiko Fujita; Yasuhide Yamada; Kazuto Nishio

  100th AACR Annual Meeting 2009年
• SRPX2 is a novel a chondroitin sulfate proteoglycan.

  Kaoru Tanaka; Tokuzo Arao; Mari Maegawa; Kazuko Matsumoto; Daisuke Tamura; Keiichi Aomatsu; Kanae Kudo; Hiroyasu Kaneda; Yoshihiko Fujita, Eiko; Honda; Kazuyoshi Yanagihara; Yasuhide Yamada; Isamu; Okamoto; Kazuhiko Nakagawa; Kazuto Nishio

  100th AACR Annual Meeting 2009年
• Activin-A directly inhibits vascular endothelial cell growth via TGF-b dependent signal pathway.

  Hiroyasu Kaneda; Tokuzo Arao; Kaoru Tanaka; Mari Maegawa; Kazuko Matsumoto; Kanae Kudo; Daisuke Tamura, Keiichi; Aomatsu; Yoshihiko Fujita; Yasuhide Yamada; Isamu; Okamoto; Kazuhiko Nakagawa; Kazuto Nishio

  100th AACR Annual Meeting 2009年
• Bortezomib directly inhibits cellular growth of vascular endothelial cells via VEGF independent pathway.

  Daisuke Tamura; Tokuzo Arao; Kaoru Tanaka; Yasuhiro Kaneda; Kazuko Matsumoto; Kanae Kudo; Keiichi Aomatsu; Mari; Maegawa; Yoshihiko Fujita; Takashi Watanabe; Yoshikazu Kotani; Yoshihiro Nishimura; Kazuto Nishio

  100th AACR Annual Meeting 2009年
• ユニークなインターロック分子・ロタキサンの抗がん物質としての有用性  [通常講演]

  藤田至彦; 小野信文; 高田十志和; パトラ・ラジャシュリー; デベラスコ・マルコ; 横手秀行; 荒尾徳三; 松本和子; 前川麻里; 田中薫; 金田裕靖; 工藤可苗; 西尾和人

  第67回日本癌学会学術総会 2008年10月
• 胃癌細胞におけるIMP-3遺伝子の機能解析(IMP-3 overexpression promotes cellular proliferation activity in gastric cancer)  [通常講演]

  田中 薫; 荒尾 徳三; 前川 麻里; 松本 和子; 工藤 可苗; 金田 裕靖; 藤田 至彦; 柳原 五吉; 山田 康秀; 岡本 勇; 中川 和彦; 西尾 和人

  日本癌学会総会記事 2008年09月 日本癌学会
  
• VEGFR2チロシンキナーゼ阻害剤のフローサイトメトリーによるチロシンリン酸化阻害剤の検討(Inhibition of phospho-tyrosine in VEGFR2+CD45dim population as a biomarker for VEGFR2 tyrosine kinase inhibitors)  [通常講演]

  工藤 可苗; 荒尾 徳三; 松本 和子; 田中 薫; 前川 麻里; 金田 裕靖; 藤田 至彦; 工藤 正俊; 西尾 和人

  日本癌学会総会記事 2008年09月 日本癌学会
  
• トラスツズマブ療法における新規バイオマーカーの探索的研究(Identification of predictive biomarkers for response to Trastuzumab using glycobiological analysis)  [通常講演]

  松本 和子; 荒尾 徳三; 前川 麻里; 田中 薫; 金田 裕靖; 工藤 可苗; 藤田 至彦; 小泉 史明; 清水 千佳子; 田村 研治; 藤原 康弘; 西尾 和人

  日本癌学会総会記事 2008年09月 日本癌学会
  
• 新規癌関連遺伝子FOXQ1は大腸癌細胞株において細胞周期制御因子p21waf1/Cip1を制御する(FOXQ1 is a novel p21 regulator in colorectal cancer cells)  [通常講演]

  金田 裕靖; 荒 徳三; 田中 薫; 前川 麻里; 松本 和子; 工藤 可苗; 藤田 至彦; 山田 康秀; 岡本 勇; 中川 和彦; 西尾 和人

  日本癌学会総会記事 2008年09月 日本癌学会
  
• 野生型と15塩基欠失型EGFRに対するマイクロアレイ発現解析(Microarray analysis for wild type and delE746_A750 type of EGFR introduced cells)  [通常講演]

  前川 麻里; 荒尾 徳三; 松本 和子; 工藤 可苗; 田中 薫; 金田 裕靖; 藤田 至彦; 伊藤 文昭; 西尾 和人

  日本癌学会総会記事 2008年09月 日本癌学会
  
• 新規連結分子ロタキサンの抗腫瘍効果  [通常講演]

  藤田至彦; 小野信文; 高田十志和; パトラ・ラジャシュリー; デベラスコ・マルコ; 荒尾徳三; 横手秀行; 松本和子; 前川麻里; 田中薫; 金田裕靖; 工藤可苗; 西尾和人

  第１２回日本がん分子標的治療研究会総会 2008年06月
• Antitumor activity and mode of action of a unique interlocked molecule rotaxane.  [通常講演]

  Yoshihiko Fujita; Nobufumi Ono; Toshikazu Takata; Rajashree Patra; Marco DeVelasco; HideyukiYokote; Tokuzo Arao; Kazuko Matsumoto; Mari Maegawa; Kaoru Tanaka; Hiroyasu Kaneda; Kanae Kudo; Yuzuru Abe; Kazuto Nishio

  99th AACR Annual Meeting 2008年04月
• FOXQ1 is a novel p21 regulator in colorectal cancer cells.

  Hiroyasu Kaneda; Tokuzo Arao; Kaoru Tanaka; Mari Maegawa; Kazuko Matsumoto; Kanae Kudo; Yoshihiko Fujita; Isamu; Okamoto; Kazuhiko Nakagawa; Kazuto Nishio

  99th AACR Annual Meeting 2008年
• Cells expressing EGFR lacing C-terminal are still hypersensitive to EGFR tyrosine kinase inhibitor.

  Mari Maegawa; Takuzo Arao; Kazuko Matsumoto; Kanae Kudo; Kaoru Tanaka; Hiroyasu Kaneda; Yoshihiko Fujita; Fumiaki Ito; Kazuto Nishio

  99th AACR Annual Meeting 2008年
• Microarray analysis for EGFR tyrosine kinase inhibitor resistant cell line.

  Tokuzo Arao; Fumiaki Koizumi; Hiroyasu; Kaneda; Kaoru Tanaka; Mari Maegawa; Kazuko Matsumoto; Kanae Kudo; Yoshihiko Fujita; Kazuto Nishio

  99th AACR Annual Meeting 2008年
• IMP-3 promotes cellular proliferation activity in gastric cancer.

  Kaoru Tanaka; Tokuzo Arao; Mari Maegawa; Kazuko; Matsumoto; Kanae Kudo; Hiroyasu Kaneda; Yoshihiko Fujita; Kazuyoshi Yanagihara; Yasuhide Yamada; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio

  99th AACR Annual Meeting 2008年
• Suppression of CD133 expression by siRNA modulated the expression of the genes associated with differentiation in cancer cells.

  Kazuko Matsumoto; Tokuzo Arao; Kaoru Tanaka; Yasuhiro Kaneda; Kanae Kudo; Mari Maegawa; Yoshihiko Fujita; Yasuhide Yamada; Kazuto Nishio

  99th AACR Annual Meeting 2008年
• フコシル化によるEGFレセプター活性化の制御とEGFR-TKIの感受性の検討(Regulation of EGFR activity through N-glycan fucosylation and effect on the sensitivity of EGFR-TKI)  [通常講演]

  松本 和子; 横手 秀行; 前川 麻里; 田中 薫; 金田 裕靖; デベラスコ・マルコ; 藤田 至彦; 荒尾 徳三; 西尾 和人

  日本癌学会総会記事 2007年08月 日本癌学会
  
• 変異型EGFRのシグナル伝達経路(A novel signaling pathway of deletional mutant EGFR)  [通常講演]

  前川 麻里; 横手 秀行; 松本 和子; 田中 薫; 金田 裕靖; 藤田 至彦; デベラスコ・マルコ; 荒尾 徳三; 小泉 史明; 伊藤 文昭; 西尾 和人

  日本癌学会総会記事 2007年08月 日本癌学会
  
• SPRX2 mRNA発現の抑制は胃癌細胞の増殖と接着を阻害する(Suppression of SRPX2 mRIMA expression inhibits cellular growth and adhesion in gastric cancer cells)  [通常講演]

  田中 薫; 荒尾 徳三; 前川 麻里; 松本 和子; 金田 裕靖; 阿部 譲; 藤田 至彦; 横手 秀行; 柳原 五吉; 山田 康秀; 岡本 勇; 中川 和彦; 西尾 和人

  日本癌学会総会記事 2007年08月 日本癌学会
  
• 新規連結分子ロタキサンの抗腫瘍活性と作用様式  [通常講演]

  藤田至彦; 小野信文; 高田十志和; デベラスコ・マルコ; 横手秀行; 荒尾徳三; 松本和子; 前川麻里; 田中薫; 金田裕靖; 阿倍譲; 西尾和人

  第67回日本癌学会学術総会 2007年
• KIAA1199 is a novel therapeutic target for gastric cancer.

  Tokuzo Arao; Yasuhide Yamada; Kaoru Tanaka; Kazuko; Matsumoto; Mari Maegawa; Yoshihiko Fujita; Hideyuki Yokote; Kazuto Nishio

  98th AACR Annual Meeting 2007年
• SRPX2 is a novel therapeutic target in gastric cancer.

  Kaoru Tanaka; Tokuzo Arao; Mari Maegawa; Kazuko Matsumoto; Yoshihiko Fujita; Hideyuki Yokote; Kazuyoshi Yanagihara; Yasuhide; Yamada; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio

  98th AACR Annual Meeting 2007年
• EphA4-RYK interaction stimulates Wnt signaling and promotes glioma cell proliferation and migration.

  Mari Maegawa; Hideyuki Yokote; Kazuko Matsumoto; Kaoru Tanaka; Tokuzo Arao; Yoshihiko Fujita; Kazuya Fukuoka; Kazuto Nishio

  98th AACR Annual Meeting 2007年
• Regulation of EGFR activity through N-glycan fucosylation and effect on the sensitivity of EGFR-TKI.

  Kazuko Matsumoto; Hideyuki Yokote; Kaoru Tanaka; Mari Maegawa; Tokuzo Arao; Yoshihiko Fujita; Kazuto Nishio

  98th AACR Annual Meeting 2007年
• 子宮と卵巣におけるサイトグロビンの発現とその意義  [通常講演]

  藤田至彦; 鯉沼聡; 松尾拓哉; 島岡昌生; 塩田充; 竹谷茂; 安田佳子

  第110回日本解剖学会総会 2005年
• ラット精巣におけるグロビンタンパクの局在とその意義

  松尾拓哉; 鯉沼聡; 藤田至彦; 安田佳子

  第110回日本解剖学会総会 2005年
• A novel role of erythropoietine: ectopic hemoglobin synthesis in female reproductive organs

  Yoshiko Yasuda; Yoshihiko Fujita; Hiroyoshi Fujita; Terunaga Musha; Takuya Matsuo; Satoshi Koinuma; Yukio Nakamura

  第16回国際解剖学会議・第109回日本解剖学会総会 2004年
• Spermatogenesis is suppressed in Testis of rats exposed prenatally to bisphenol A

  Takuya Matsuo; Yoshihiko Fujita; Satoshi Koinuma; Yoshiko Yasuda

  第16回国際解剖学会議・第109回日本解剖学会総会 2004年
• １分子蛍光法によるインターロイキン6刺激後のStat3の追跡：２量体化と核膜上への移行について  [通常講演]

  藤田至彦; 伊藤裕恵; 飯野亮太; 吉村昭彦; 楠見明弘

  第４１回日本生物物理学会年会 2003年
• 胎生期マウス胚体と脳原基におけるエリスロポエチン量とその意義

  松尾拓哉; 鯉沼聡; 藤田至彦; 安田佳子

  第７９回解剖学会近畿支部学術集会 2003年
• インターロイキン6刺激によるStat3の２量体化と核膜上への移行の機構：１分子蛍光法による解析  [通常講演]

  藤田至彦; 伊藤裕恵; 飯野亮太; 田賀哲也; 吉村昭彦; 楠見明弘

  第５５回日本細胞生物学会大会 2002年
• １分子蛍光法によるインターロイキン６刺激後のgp130信号複合体形成機構の解析―― アクチン線維との相互作用  [通常講演]

  藤田至彦; 伊藤裕恵; 中西華代; 飯野亮太; 田賀哲也; 楠見明弘

  第39回日本生物物理学会年会 2001年
• インターロイキン6刺激によるgp130信号複合体とアクチン線維との相互作用：１分子蛍光法による解析  [通常講演]

  藤田至彦; 伊藤裕恵; 飯野亮太; 田賀哲也; 楠見明弘

  第５４回日本細胞生物学会大会 2001年
• 大腸菌アミノ酸感覚受容体の二次元結晶化  [通常講演]

  藤田至彦; 川岸郁朗; 岩間智徳; 藤吉好則

  日本生物物理学会第３６回年会 1998年
• マウス胚体の胎児型および成人型赤血球産生能

  安田佳子; 藤田至彦; 永尾雅哉; 増田誠司; 佐々木隆造

  日本発生生物学会第３１回大会 1998年
• Ｇ蛋白質によるN型カルシウムチャンネルの調節機構

  古川泰司; 額田敏秀; 森泰生; 藤田至彦; 吉井光信

  第６８回日本生化学会大会 1995年
• ウサギＮ型カルシウムチャンネルの構造と機能の解析  [通常講演]

  藤田至彦; 森泰生; 金萬石; 新留徹広; Michelle Mynlieff

  第666回日本生化学会大会 1993年
• 新規脳Ca2+チャンネルの一次構造とcDNAの機能的発現

  新留徹広; 金萬石; 古玉大介; 古市貞一; 御子柴克彦; 藤田至彦; 金萬石; Thomas Friedrich; 田中勲; 片山幸一; Arnold Schwartz; 八谷アツ子; 森泰生

  第66回日本生化学会大会 1993年
• "ニコチン性アセチルコリン受容体サブユニットの推定膜貫通領域の置換  [通常講演]

  飛松孝正; 藤田至彦; 福田和彦; 田中健一; 森泰生; 今野卓; 三品昌美

  第６１回日本生化学会大会 1988年
• ニコチン性アセチルコリン受容体チャンネルのイオン透過速度決定部位

  井本敬二; C. Methfessel; B. Sakmann; 三品昌美; 森泰生; 今野卓; 福田和彦; 蔵崎正明; 武城英明; 藤田至彦; 沼正作

  第６０回日本生化学会大会 1987年
• アセチルコリン受容体サブユニットのイオンチャンネル形成部位

  三品昌美; 飛松孝正; 井本敬二; 田中健一; 藤田至彦; 福田和彦; 蔵崎正明; 高橋英雄; 森本裕紀; 高橋智幸; 久野宗; 沼正作

  第５８回日本生化学会大会 1985年
• アセチルコリン受容体のアセチルコリン結合部位

  三品昌美; 飛松孝正; 井本敬二; 田中健一; 藤田至彦; 福田和彦; 蔵崎正明; 高橋英雄; 森本裕紀; 広瀬忠明; 稲山誠一; 高橋智幸; 久野宗; 沼正作

  第５８回日本生化学会大会 1985年
• 軸配位子を共有結合で結合させたヘムの合成および性質  [通常講演]

  吉田善一; 藤田至彦; 川瀬徳造

  日本化学会第４９春季年会 1984年
• オキシゲナーゼの酵素モデルとしてのヘムを用いた酸素化反応  [通常講演]

  吉田善一; 藤田至彦; 川瀬徳造

  第１７回酸化反応討論会(日本化学会) 1983年

MISC

• COMT遺伝子型バイオマーカーを用いたがん性疼痛に対するモルヒネとオキシコドンの比較 無作為化臨床試験

  阪本亮; 阪本亮; 松岡弘道; 鶴谷純司; 千葉康敬; 藤田至彦; 酒井清裕; 吉田健史; 吉田健史; 名倉美樹; 大武陽一; 小山敦子; 小山敦子; 西尾和人; 中川和彦 日本心身医学会総会ならびに学術講演会抄録集 64th 2023年
• がん疼痛に対するオピオイド選択のためのバイオマーカーを用いたランダム化比較試験(Relief Study)

  松岡弘道; 松岡弘道; 松岡弘道; 鶴谷純司; 鶴谷純司; 千葉康敬; 藤田至彦; 酒井清裕; 酒井清裕; 酒井清裕; 吉田健史; 吉田健史; 大武陽一; 大武陽一; 大武陽一; 小山敦子; 小山敦子; 西尾和人; 中川和彦 日本臨床腫瘍学会学術集会(CD-ROM) 19th 2022年
• 分子バーコード法によるctDNA 中の変異プロフィリングと耐性機序の探索

  坂井和子; 藤田至彦; デベラスコ マルコ; 西尾和人 日本臨床プロテオゲノミクス研究会要旨集(Web) 2019 2019年
• 非小細胞肺癌における次世代シークエンサーを用いた融合遺伝子検出法の 臨床性能検証に関する研究

  坂井和子; 藤田至彦; デベラスコ マルコ; 西尾和人 日本臨床プロテオゲノミクス研究会要旨集(Web) 2019 2019年
• 大腸がん治療法選択のためのバイオマーカーの探索的研究

  藤田至彦; 坂井和子; 山崎健太郎; 西尾和人 日本がん分子標的治療学会学術集会プログラム・抄録集 23rd 2019年
• 非小細胞肺癌における次世代シークエンサーを用いた融合遺伝子検出法の臨床性能検証に関する研究

  西尾和人; 坂井和子; DE VELASCO Marco; 藤田至彦 日本がん分子標的治療学会学術集会プログラム・抄録集 23rd 2019年
• Pimキナーゼ阻害薬は去勢抵抗性前立腺癌マウスモデルにおいて腫瘍増殖を抑制し生存期間を延長する

  倉由吏恵; 坂井和子; 野澤昌弘; 藤田至彦; DE VELASCO Marco A.; DE VELASCO Marco A.; 西尾和人; 植村天受 日本がん分子標的治療学会学術集会プログラム・抄録集 23rd 2019年
• 原発不明がんにおける腫瘍微小免疫環境と予後の関連性

  原谷浩司; 林秀敏; 高濱隆幸; 澤田貴宏; 中村靖司; 伊藤彰彦; 千葉康敬; 谷崎潤子; 藤田至彦; 坂井和子; 西尾和人; 中川和彦 日本臨床腫瘍学会学術集会(CD-ROM) 16th 2018年
• Gene expression and mutation profiling for cancer of unknown primary

  Hidetoshi Hayashi; Shuta Tomida; Yoshihiko Fujita; Yosuke Togashi; Kazuko Sakai; Kazuto Nishio; Kazuhiko Nakagawa ANNALS OF ONCOLOGY 28 2017年10月
• まれなEGFR遺伝子変異L861QおよびS768I陽性非小細胞性肺癌に対する最適なEGFR阻害剤の選択

  坂野 恵里; 冨樫 庸介; 中村 雄; 千葉 眞人; 小林 祥久; 林 秀敏; 谷崎 潤子; 寺嶋 雅人; デ・ベラスコ・マルコ A; 坂井 和子; 藤田 至彦; 光冨 徹哉; 西尾 和人 日本癌学会総会記事 76回 YSA -4 2017年09月
• FGFR遺伝子異常を有する肺扁平上皮癌の術後再発生存期間に対する影響とマルチキナーゼ阻害薬に対する感受性

  西尾 和人; 金田 裕靖; 谷崎 潤子; 坂井 和子; 冨樫 庸介; 寺嶋 雅人; デベラスコ・マルコ; 藤田 至彦; 坂野 恵里; 中村 雄; 武田 真幸; 伊藤 彰彦; 光冨 徹哉; 中川 和彦; 岡本 勇 肺癌 57 (3) 253 -253 2017年06月
• FGFR遺伝子異常を有する肺扁平上皮癌の術後再発生存期間に対する影響とマルチキナーゼ阻害薬に対する感受性

  西尾和人; 金田裕靖; 谷崎潤子; 坂井和子; 冨樫庸介; 寺嶋雅人; デベラスコ マルコ; 藤田至彦; 坂野恵里; 中村雄; 武田真幸; 伊藤彰彦; 光冨徹哉; 中川和彦; 岡本勇 肺癌(Web) 57 (3) 2017年
• 非小細胞肺がんにおける受容体型チロシンキナーゼ遺伝子変異の機能解析

  寺嶋 雅人; 冨樫 庸介; 佐藤 克明; 水内 寛; 坂井 和子; 須田 健一; 中村 雄; 坂野 恵里; 林 秀敏; デベラス・マルコ; 藤田 至彦; 冨田 秀太; 光冨 徹哉; 西尾 和人 近畿大学医学雑誌 41 (3-4) 20A -20A 2016年12月
• 非小細胞肺がんにおける受容体型チロシンキナーゼ遺伝子変異の機能解析

  寺嶋 雅人; 冨樫 庸介; 佐藤 克明; 水内 寛; 坂井 和子; 須田 健一; 中村 雄; 坂野 恵里; 林 秀敏; デベラス・マルコ; 藤田 至彦; 冨田 秀太; 光冨 徹哉; 西尾 和人 近畿大学医学雑誌 41 (3-4) 20A -20A 2016年12月
• Molecular biomarkers of high risk for cancer in Barrett's esophagus

  Kyosuke Goda; Akiko Shiotani; Takahisa Murao; Minoru Fujita; Hiroshi Matsumoto; Ken Haruma; Yoshihiko Fujita; Kazuto Nishio; Timothy M. Wallace; Michael B. Wallace JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 31 25 -25 2016年11月
• 腫瘍内クローン数定量化プログラムによる卵巣がんのクローン数と遺伝子変異の関連解析

  坂井 和子; 浮田 真沙世; 高矢 寿光; 藤田 至彦; 寺嶋 雅人; デベラスコ・マルコ; 万代 昌紀; 西尾 和人 日本癌学会総会記事 75回 P -3191 2016年10月
• PTENノックアウトマウス前立腺癌におけるノンコーディングRNAの検討

  倉 由吏恵; デベラスコ・マルコ; 坂井 和子; 藤田 至彦; 冨樫 庸介; 寺嶋 雅人; 吉川 和宏; 西尾 和人; 植村 天受 日本癌学会総会記事 75回 E -1029 2016年10月
• PTENノックアウトマウス前立腺癌において選択的スプライシングは頻繁に認められる

  デベラスコ・マルコ; 倉 由吏恵; 坂井 和子; 藤田 至彦; 冨樫 庸介; 寺嶋 雅人; 吉川 和宏; 西尾 和人; 植村 天受 日本癌学会総会記事 75回 E -1073 2016年10月
• 頭頸部または食道扁平上皮癌に対するアファチニブの効果 頭頸部扁平上皮癌における活性型発癌性HER4遺伝子変異

  中村 雄; 冨樫 庸介; 寺嶋 雅人; デベラスコ・マルコ; 坂井 和子; 藤田 至彦; 桶川 隆嗣; 濱田 傑; 西尾 和人 日本癌学会総会記事 75回 P -2296 2016年10月
• DDR2 E655K変異タンパク質はユビキチン-プロテアソーム系による分解を受け機能が喪失する

  寺嶋 雅人; 冨樫 庸介; 坂井 和子; 中村 雄; 坂野 恵里; デベラスコ・マルコ; 藤田 至彦; 西尾 和人 日本癌学会総会記事 75回 P -3047 2016年10月
• 原発不明癌の治療のための標的分子の探索

  藤田 至彦; 坂井 和子; 倉田 宝保; 寺嶋 雅人; 林 秀敏; 中川 和彦; 西尾 和人 日本癌学会総会記事 75回 P -2111 2016年10月
• PTENノックアウトマウス前立腺癌におけるノンコーディングRNAの検討

  倉 由吏恵; デベラスコ・マルコ; 坂井 和子; 藤田 至彦; 冨樫 庸介; 寺嶋 雅人; 吉川 和宏; 西尾 和人; 植村 天受 日本癌学会総会記事 75回 E -1029 2016年10月
• PTENノックアウトマウス前立腺癌において選択的スプライシングは頻繁に認められる

  デベラスコ・マルコ; 倉 由吏恵; 坂井 和子; 藤田 至彦; 冨樫 庸介; 寺嶋 雅人; 吉川 和宏; 西尾 和人; 植村 天受 日本癌学会総会記事 75回 E -1073 2016年10月
• 頭頸部または食道扁平上皮癌に対するアファチニブの効果 頭頸部扁平上皮癌における活性型発癌性HER4遺伝子変異

  中村 雄; 冨樫 庸介; 寺嶋 雅人; デベラスコ・マルコ; 坂井 和子; 藤田 至彦; 桶川 隆嗣; 濱田 傑; 西尾 和人 日本癌学会総会記事 75回 P -2296 2016年10月
• DDR2 E655K変異タンパク質はユビキチン-プロテアソーム系による分解を受け機能が喪失する

  寺嶋 雅人; 冨樫 庸介; 坂井 和子; 中村 雄; 坂野 恵里; デベラスコ・マルコ; 藤田 至彦; 西尾 和人 日本癌学会総会記事 75回 P -3047 2016年10月
• 腫瘍内クローン数定量化プログラムによる卵巣がんのクローン数と遺伝子変異の関連解析

  坂井 和子; 浮田 真沙世; 高矢 寿光; 藤田 至彦; 寺嶋 雅人; デベラスコ・マルコ; 万代 昌紀; 西尾 和人 日本癌学会総会記事 75回 P -3191 2016年10月
• 原発不明癌の治療のための標的分子の探索

  藤田 至彦; 坂井 和子; 倉田 宝保; 寺嶋 雅人; 林 秀敏; 中川 和彦; 西尾 和人 日本癌学会総会記事 75回 P -2111 2016年10月
• がん疼痛とカルニチン欠乏症との関連性についての探索的研究

  酒井 清裕; 松岡 弘道; 大武 陽一; 牧村 ちひろ; 和泉 宏昌; 大塚 正友; 藤田 至彦; 鶴谷 純司; 西尾 和人; 中川 和彦; 小山 敦子 Palliative Care Research 11 (Suppl.) S311 -S311 2016年06月
• 患者自身の疼痛改善への期待は、疼痛予後を改善する

  松岡 弘道; 牧村 ちひろ; 小山 敦子; 酒井 清裕; 和泉 宏昌; 大塚 正友; 藤田 至彦; 鶴谷 純司; 吉田 健史; 西尾 和人; 中川 和彦 Palliative Care Research 11 (Suppl.) S355 -S355 2016年06月
• Molecular Biomarkers of High Risk for Cancer in Barrett's Esophagus

  Takahisa Murao; Akiko Shiotani; Minoru Fujita; Noriaki Manabe; Ken Haruma; Yoshihiko Fujita; Kazuto Nishio; Timothy M. Wallace; Rene E. Gomez; Manuel Berzosa; Herbert C. Wolfsen; Michael B. Wallace GASTROENTEROLOGY 150 (4) S852 -S852 2016年04月
• 比較的早期の肺がん患者由来cell free DNAの体細胞遺伝子変異検出率の臨床病理学的規定因子の検討

  坂井和子; 藤田至彦; 西尾和人 日本がん分子標的治療学会学術集会プログラム・抄録集 20th 2016年
• Afatinib activity against head-and-neck or esophageal squamous cell carcinoma: Significance of activating oncogenic HER4 mutations in head-and-neck squamous cell carcinoma

  Y. Togashi; Y. Nakamura; S. Tomida; H. Hayashi; M. A. de Velasco; K. Sakai; Y. Fujita; S. Hamada; K. Nishio ANNALS OF ONCOLOGY 26 97 -97 2015年12月
• Integrative algorithm to determine the metastatic carcinoma tissue of origin using next generation sequencing (NGS)

  Hidetoshi Hayashi; Shuta Tomida; Yosuke Togashi; Kazuko Sakai; Yoshihiko Fujita; Junji Tsurutani; Issei Kurahashi; Takayasu Kurata; Kazuhiko Nakagawa; Kazuto Nishio ANNALS OF ONCOLOGY 26 86 -86 2015年11月
• 非小細胞肺がんにおけるDDR2変異の機能解析

  寺嶋 雅人; 冨樫 庸介; 坂井 和子; 佐藤 克明; 須田 健一; 水上 拓郎; 坂野 恵里; 中村 雄; De Velasco Marco; 藤田 至彦; 冨田 秀太; 光冨 徹哉; 西尾 和人 日本癌学会総会記事 74回 P -2223 2015年10月
• 非小細胞肺がんにおけるDDR2変異の機能解析

  寺嶋 雅人; 冨樫 庸介; 坂井 和子; 佐藤 克明; 須田 健一; 水上 拓郎; 坂野 恵里; 中村 雄; De Velasco Marco; 藤田 至彦; 冨田 秀太; 光冨 徹哉; 西尾 和人 日本癌学会総会記事 74回 P -2223 2015年10月
• Exploratory analysis of predictive biomarkers of oxaliplatin versus irinotecan in combination with bevacizumab for patients with metastatic colorectal cancer in WJOG4407G study

  Y. Fujita; K. Yamazaki; M. S. Oba; K. Muro; Y. Negoro; M. Yoshida; K. Suyama; T. Kurimoto; N. Sugimoto; N. Seki; M. Sato; M. Ebi; H. Tamagawa; S. Ueda; T. Tamura; N. Boku; I. Hyodo; T. Yamanaka; J. Tsurutani; K. Nishio EUROPEAN JOURNAL OF CANCER 51 S384 -S384 2015年09月
• Fibroblast growth factor 9 gene amplification can induce resistance to anti-EGFR therapy in colorectal cancer

  T. Mizukami; Y. Togashi; E. Banno; M. Terashima; M. A. De Velasco; K. Sakai; H. Hayashi; Y. Fujita; S. Tomida; T. Eguchi Nakajima; N. Boku; A. Ito; K. Nakagawa; K. Nishio EUROPEAN JOURNAL OF CANCER 51 S46 -S46 2015年09月
• Clinicopathological and genetic differences between low-grade and high-grade colorectal mucinous adenocarcinoma

  Y. Togashi; Y. Yoshioka; T. Chikugo; M. Terashima; T. Mizukami; H. Hayashi; K. Sakai; M. De Velasco; S. Tomida; Y. Fujita; K. Okuno; K. Nishio EUROPEAN JOURNAL OF CANCER 51 S390 -S390 2015年09月
• Activin signal promotes cancer progression and is involved in cachexia in a subset of pancreatic cancer

  Yosuke Togashi; Akihiro Kogita; Hiroki Sakamoto; Hidetoshi Hayashi; Masato Terashima; Marco A. de Velasco; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Masayuki Kitano; Masatoshi Kudo; Kazuto Nishio CANCER RESEARCH 75 2015年08月
• Melanoma transition is frequently accompanied by a loss of cytoglobin, a putative tumor suppressor, in melanocytes

  Yoshihiko Fujita; Satoshi Koinuma; Marco De Velasco; Bolz Jan; Yosuke Togashi; Masato Terashima; Hidetoshi Hayashi; Takuya Matsuo; Kazuto Nishio CANCER RESEARCH 75 2015年08月
• FGF9 gene amplification can induce resistance to anti-EGFR therapy in colorectal cancer

  Takuro Mizukami; Yosuke Togashi; Eri Banno; Masato Terashima; Marco A. de Velasco; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Takako Eguchi Nakajima; Narikazu Boku; Kazuto Nishio CANCER RESEARCH 75 2015年08月
• がん疼痛治療におけるバイオマーカー探察

  松岡 弘道; 牧村 ちひろ; 大塚 正友; 酒井 清裕; 阪本 亮; 小山 敦子; 西尾 和人; 中川 和彦; 藤田 至彦; 鶴谷 純司 日本内科学会雑誌 104 (Suppl.) 237 -237 2015年02月
• モルヒネ治療効果を予測する心理的因子,およびバイオマーカー研究

  牧村ちひろ; 松岡弘道; 酒井清裕; 阪本亮; 大塚正友; 藤田至彦; 西尾和人; 小山敦子; 中川和彦 日本サイコオンコロジー学会総会プログラム・抄録集 28th 78 2015年
• MEK INHIBITORS ARE EFFECTIVE AGAINST GASTRIC CANCER CELL LINES WITH ONCOGENIC MEK1 GENE MUTATIONS

  Yosuke Togashi; Shunsuke Sogabe; Hiroaki Kato; Masato Terashima; Hidetoshi Hayashi; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Takushi Yasuda; Kazuto Nishio ANNALS OF ONCOLOGY 25 2014年10月
• CHRONIC NICOTINE EXPOSURE MEDIATES RESISTANCE TO EGFR-TKI IN EGFR-MUTATED LUNG CANCER VIA EGFR SIGNAL

  Hidetoshi Hayashi; Yosuke Togashi; Kunio Okamoto; Soichi Fumita; Masato Terashima; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Kazuhiko Nakagawa; Kazuto Nishio ANNALS OF ONCOLOGY 25 2014年10月
• Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic cancer

  Yosuke Togashi; Hiroki Sakamoto; Hidetoshi Hayashi; Masato Terashima; Marco A. de Velasco; Yoshihiko Fujita; Yasuo Kodera; Kazuko Sakai; Shuta Tomida; Masayuki Kitano; Masatoshi Kudo; Kazuto Nishio CANCER RESEARCH 74 (19) 2014年10月
• A microarray-based gene expression analysis identified diagnostic biomarkers for unknown primary cancer

  Yoshihiko Fujita; Issei Kurahashi; Takayasu Kurata; Yasuhiro Koh; Kazuko Sakai; Kazuhiko Nakagawa; Kazuto Nishio CANCER RESEARCH 74 (19) 2014年10月
• 新規ALK阻害剤であるアレクチニブはMET阻害剤との併用で効果が高まる

  冨樫 庸介; 林 秀敏; 寺嶋 雅人; 坂井 和子; 藤田 至彦; 冨田 秀太; 中川 和彦; 西尾 和人 肺癌 54 (5) 403 -403 2014年10月
• 低酸素はALK融合遺伝子を有するH3122肺癌細胞株のALK阻害剤に対する耐性化を誘導する

  冨樫 庸介; 林 秀敏; 寺嶋 雅人; 坂井 和子; 藤田 至彦; 冨田 秀太; 中川 和彦; 西尾 和人 肺癌 54 (5) 470 -470 2014年10月
• 喫煙によるニコチン曝露はEGFR遺伝子変異陽性肺がんにおいてEGFR-TKIの耐性因子である

  林 秀敏; 冨樫 庸介; 岡本 邦男; 田中 妙; 文田 壮一; 新谷 亮多; 清川 寛文; 坂本 洋一; 寺嶋 雅人; de Velasco Marco A; 坂井 和子; 藤田 至彦; 冨田 秀太; 加藤 元一; 中川 和彦; 西尾 和人 肺癌 54 (5) 626 -626 2014年10月
• メラノサイトからメラノーマへの移行は、しばしばがん抑制因子であるサイトグロビンの発現低下を伴う(Cytoglobin, a putative tumor suppressor, is frequently lost in melanocyte during melanoma transition)

  藤田 至彦; 鯉沼 聡; デベラスコ・マルコ; ボルツ・ヤン; 富樫 庸介; 寺嶋 雅人; 林 秀敏; 松尾 拓哉; 西尾 和人 日本癌学会総会記事 73回 P -3066 2014年09月
• KIAA1199はグリコーゲンホスホリラーゼキナーゼβサブユニットと結合してグリコーゲンの分解さらには細胞生存を亢進する(KIAA1199 interacts with PHKB and promotes glycogen breakdown and cancer cell survival)

  寺嶋 雅人; 藤田 至彦; 冨樫 庸介; 坂井 和子; 冨田 秀太; 西尾 和人 日本癌学会総会記事 73回 P -2211 2014年09月
• MEK遺伝子変異を有する胃がんに対するMEK阻害剤の有効性(MEK inhibitor for gastric cancer with MEK1 gene mutations)

  冨樫 庸介; 加藤 寛章; 林 秀敏; 寺嶋 雅人; デベラスコ・マルコ; 坂井 和子; 藤田 至彦; 冨田 秀太; 安田 卓司; 西尾 和人 日本癌学会総会記事 73回 P -2349 2014年09月
• Novel Single Nucleotide Polymorphism Markers for Low Dose Aspirin-Associated Small Bowel Bleeding: A DMET Microarray Profiling Study

  Akiko Shiotani; Takahisa Murao; Yoshihiko Fujita; Yoshinori Fujimura; Takashi Sakakibara; Tomoari Kamada; Kazuto Nishio; Ken Haruma GASTROENTEROLOGY 146 (5) S126 -S126 2014年05月
• マイクロアレイをもちいた原発不明がんの診断バイオマーカーの探索

  藤田至彦; 倉田宝保; 坂井和子; 中川和彦; 西尾和人 日本がん分子標的治療学会学術集会プログラム・抄録集 18th 2014年
• MEK1遺伝子変異を有する胃がん細胞株に対するMEK阻害剤の有効性と臨床サンプルの検討

  冨樫庸介; 曽我部俊介; 加藤寛章; 寺嶋雅人; 林秀敏; 林秀敏; 坂井和子; 藤田至彦; 冨田秀太; 安田卓志; 西尾和人 日本臨床腫瘍学会学術集会(CD-ROM) 12th 2014年
• ORAOV1 IS AMPLIFIED IN ESOPHAGEAL SQUAMOUS CELL CANCER AND RELATED TO TUMOR GROWTH AND POORLY DIFFERENTIATED TUMOR

  Y. Togashi; T. Arao; H. Kato; K. Matsumoto; M. Terashima; H. Hayashi; Y. Fujita; T. Yasuda; H. Shiozaki; K. Nishio ANNALS OF ONCOLOGY 24 2013年11月
• CONSTRUCTION OF A 3D CULTURE ASSAY SYSTEM FOR ANTI-CANCER DRUG TESTING

  M. Terashima; K. Sakai; Y. Fujita; M. A. De Velasco; K. Nishio ANNALS OF ONCOLOGY 24 2013年11月
• 肺癌生物像に基づいた、新しい肺癌治療の戦略 EGFR遺伝子変異を有する肺癌においてβカテニンを阻害することでEGFR-TKIの効果が増強する

  冨樫 庸介; 林 秀敏; 寺嶋 雅人; 藤田 至彦; 坂井 和子; 冨田 秀太; 中川 和彦; 西尾 和人 肺癌 53 (5) 397 -397 2013年10月
• NGSによる極微量検体を用いたmultiplex mutation analysisの最適化(Optimization of multiplex mutation analysis based on minimum amount of lung cancer specimen)

  冨田 秀太; 坂井 和子; 藤田 至彦; 寺嶋 雅人; 富樫 庸介; デベラスコ・マルコ; 光冨 徹哉; 中川 和彦; 西尾 和人 日本癌学会総会記事 72回 458 -458 2013年10月
• A microarray-based gene expression analysis identified diagnostic biomarkers for unknown primary cancer

  Y. Fujita; I. Kurahashi; T. Arao; T. Kurata; Y. Koh; K. Sakai; K. Nakagawa; K. Nishio EUROPEAN JOURNAL OF CANCER 49 S197 -S197 2013年09月
• Over Expression of Cd55 and Loss of Dsc2 From Barrett's Columnar-Lined Esophagus Are Associated With Esophageal Adenocarcinoma Risk

  Takahisa Murao; Akiko Shiotani; Yoshiki Kimura; Hiroshi Matsumoto; Tomoari Kamada; Noriaki Manabe; Yoshihiko Fujita; Tokuzo Arao; Kazuto Nishio; Jiro Hata; Ken Haruma GASTROENTEROLOGY 144 (5) S517 -S517 2013年05月
• 食道扁平上皮癌で高頻度に増幅しているORAOV1遺伝子は腫瘍増大と低分化な組織型に関与している

  冨樫庸介; 荒尾徳三; 加藤寛章; 松本和子; 寺嶋雅人; 林秀敏; 藤田至彦; 安田卓司; 塩崎均; 西尾和人 日本臨床腫瘍学会学術集会(CD-ROM) 11th 2013年
• 上皮成長因子受容体遺伝子異常と肺発癌

  藤田至彦 日本臨床最新肺癌学増刊号 西尾和人編 135 -139 2013年 [招待有り]
  
• AMPLIFICATION OF OCT4-PSEUDOGENE POU5F1B IS A POOR PROGNOSTIC FACTOR IN GASTRIC CANCER

  H. Hayashi; T. Arao; K. Matsumoto; T. Nagai; H. Kimura; M. A. De Velasco; Y. Fujita; Y. Yamada; K. Nakagawa; K. Nishio ANNALS OF ONCOLOGY 23 112 -112 2012年10月
• OVEREXPRESSION OF FOXQ1 IS IMPORTANT FACTOR IN TUMORIGENECITY AND TUMOR GROWTH

  H. Kaneda; T. Arao; K. Tanaka; K. Matsumoto; H. Kimura; T. Nagai; K. Sakai; Y. Fujita; M. A. De Velasco; Y. Yamada; J. Tsurutani; I. Okamoto; K. Nakagawa; K. Nishio ANNALS OF ONCOLOGY 23 112 -112 2012年10月
• CHARACTERISTICS OF HS6ST2 EXPRESSION IN COLORECTAL CANCER

  H. Kimura; S. Hatabe; T. Arao; H. Hayashi; K. Matsumoto; T. Nagai; Y. Fujita; H. Kato; K. Okuno; K. Nishio ANNALS OF ONCOLOGY 23 160 -160 2012年10月
• A NOVEL MASS SPECTROMETRY-BASED ASSAY FOR DIAGNOSIS OF EML4-ALK-POSITIVE NON-SMALL-CELL LUNG CANCER

  K. Sakai; I. Okamoto; K. Takezawa; T. Hirashima; H. Kaneda; M. Takeda; K. Matsumoto; H. Kimura; Y. Fujita; K. Nakagawa; T. Arao; K. Nishio ANNALS OF ONCOLOGY 23 103 -103 2012年10月
• ACTIVIN-A DIRECTLY INHIBITS VASCULAR ENDOTHELIAL CELL GROWTH VIA TGF-beta-DEPENDENT SIGNAL PATHWAY

  H. Kaneda; T. Arao; K. Tanaka; K. Matsumoto; H. Kimura; T. Nagai; Y. Fujita; M. A. De Velasco; Y. Yamada; I. Okamoto; K. Nakagawa; K. Nishio ANNALS OF ONCOLOGY 23 134 -134 2012年10月
• OCT4偽遺伝子であるPOU5F1Bの増殖は胃がんにおいて予後不良因子である(Amplification of OCT4-pseudogene POU5F1B is a poor prognostic factor in gastric cancer)

  林 秀敏; 荒尾 徳三; 松本 和子; 永井 知行; 木村 英晴; デベラスコ・マルコ; 藤田 至彦; 山田 康秀; 中川 和彦; 西尾 和人 日本癌学会総会記事 71回 186 -186 2012年08月
• 大腸がんにおけるHS6ST2発現とその臨床的意義(Characteristics of HS6ST2 expression in colorectal cancer)

  木村 英晴; 波多邉 繁; 荒尾 徳三; 林 秀敏; 永井 知行; 松本 和子; 藤田 至彦; 伊藤 彰彦; 奥野 清隆; 西尾 和人 日本癌学会総会記事 71回 348 -348 2012年08月
• 食道扁平上皮癌におけるEGFR、HER2、FGFR2、METの遺伝子増幅(Gene amplification of EGFR, HER2, FGFR2, and MET in esophageal squamous cell carcinoma)

  加藤 寛章; 荒尾 徳三; 林 秀敏; 吉田 修平; 永井 知行; 松本 和子; 藤田 至彦; 木村 英晴; 安田 卓司; 奥野 清隆; 塩崎 均; 西尾 和人 日本癌学会総会記事 71回 369 -369 2012年08月
• Gene amplification of EGFR, HER2, HER3 and HER4 in esophageal squamous cell carcinoma

  Hiroaki Kato; Tokuzo Arao; Kazuko Matsumoto; Yoshihiko Fujita; Hideharu Kimura; Kouhei Nishiki; Osamu Shiraishi; Atsushi Yasuda; Ying-Feng Peng; Masayuki Shinkai; Motohiro Imano; Haruhiko Imamoto; Takushi Yasuda; Kiyotaka Okuno; Hitoshi Shiozaki; Kazuto Nishio CANCER RESEARCH 72 2012年04月
• Detection of EGFR T790M mutation in non-small-cell lung cancer patients using colony hybridization assay

  Yoshihiko Fujita; Kenichi Suda; Hideharu Kimura; Kazuko Matsumoto; Tokuzo Arao; Tomoyuki Nagai; Hidetoshi Hayashi; Kazuyuki Furuta; Hiroaki Kato; Nagahiro Saijo; Yasushi Yatabe; Tetsuya Mitsudomi; Kazuto Nishio CANCER RESEARCH 72 2012年04月
• Impact of TJP-1 and TWIST expression on post-operative prognosis in hepatocellular carcinoma

  Tomoyuki Nagai; Tokuzo Arao; Kazuko Matsumoto; Kazuko Sakai; Kanae Kudo; Hiroyasu Kaneda; Daisuke Tamura; Keiichi Aomatsu; Hideharu Kimura; Yoshihiko Fujita; Satoru Hagiwara; Toshiharu Sakurai; Kazuomi Ueshima; Seiji Haji; Masatoshi Kudo; Kazuto Nishio CANCER RESEARCH 72 2012年04月
• Amplification of OCT4-pseudogene POU5F1B is a poor prognostic factor in gastric cancer

  Hidetoshi Hayashi; Tokuzo Arao; Kazuko Matsumoto; Tomoyuki Nagai; Hideharu Kimura; Marco A. De Velasco; Yoshihiko Fujita; Yasuhide Yamada; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio CANCER RESEARCH 72 2012年04月
• Characteristics of HS6ST2 expression in colorectal cancer

  Hideharu Kimura; Shigeru Hatabe; Tokuzo Arao; Hidetoshi Hayashi; Tomoyuki Nagai; Kazuko Matsumoto; Yoshihiko Fujita; Masao Fukushima; Akihiko Ito; Kiyotaka Okuno; Kazuto Nishio CANCER RESEARCH 72 2012年04月
• FGFR阻害薬によるCD133の発現制御機構の解析

  松本和子; 荒尾徳三; 吉田修平; 林秀敏; 藤田至彦; 加藤寛章; 永井知行; 木村英晴; 西尾和人 日本臨床腫瘍学会学術集会プログラム・抄録集 10th 2012年
• 食道扁平上皮癌におけるEGFR-familyの遺伝子増幅とEGFRの遺伝子変異

  加藤寛章; 荒尾徳三; 松本和子; 藤田至彦; 木村英晴; 安田卓司; 奥野清隆; 塩崎均; 西尾和人 日本臨床腫瘍学会学術集会プログラム・抄録集 10th 2012年
• ソラフェニブの上皮間葉移行阻害効果

  永井知行; 永井知行; 木村英晴; 荒尾徳三; 松本和子; 藤田至彦; 吉田修平; 林秀敏; 工藤正俊; 西尾和人 日本臨床腫瘍学会学術集会プログラム・抄録集 10th 2012年
• Snailに誘導される上皮間葉移行とチュブリン作用系抗癌剤の感受性

  吉田修平; 田村大介; 荒尾徳三; 松本和子; 木村英晴; 藤田至彦; 林秀敏; 林秀敏; 永井知行; 金田裕靖; 西尾和人 日本臨床腫瘍学会学術集会プログラム・抄録集 10th 2012年
• 大腸がんにおけるHS6ST2発現とその臨床的特徴(Characteristics of HS6ST2 Expression in Colorectal Cancer)

  木村 英晴; 波多邉 繁; 荒尾 徳三; 林 秀敏; 永井 知行; 松本 和子; 工藤 可苗; 藤田 至彦; 伊藤 彰彦; 奥野 清隆; 西尾 和人 日本癌学会総会記事 70回 235 -235 2011年09月
• 肝細胞癌におけるTJP-1とTwist発現の肝癌切除後の予後への影響(Impact of TJP-1 and TWIST expression on post-operative prognosis in hepatocellular carcinoma)

  永井 知行; 荒尾 徳三; 松本 和子; 工藤 可苗; 木村 英晴; 藤田 至彦; 萩原 智; 櫻井 俊治; 上嶋 一臣; 土師 誠二; 工藤 正俊; 西尾 和人 日本癌学会総会記事 70回 368 -368 2011年09月
• 非小細胞肺がん患者におけるEGFR T790変異の新規検出法(Sensitive detection of EGFR T790M mutation in non-small-cell lung cancer patients)

  藤田 至彦; 須田 健一; 木村 英晴; 松本 和子; 荒尾 徳三; 西條 長宏; 谷田部 恭; 光冨 徹哉; 西尾 和人 日本癌学会総会記事 70回 374 -374 2011年09月
• Slug-mediated epithelial mesenchymal transition in lung cancer cells

  Tamura Daisuke; Tokuzo Arao; Tomoyuki Nagai; Kazuyuki Furuta; Kazuko Sakai; Kanae Kudo; Hiroyasu Kaneda; Keiichi Aomatsu; Yoshihiko Fujita; Kazuko Matsumoto; Yoshikazu Kotani; Yoshihiro Nishimura; Nagahiro Saijo; Kazuto Nishio CANCER RESEARCH 71 2011年04月
• FGFR inhibitor regulates CD133 expression in FGFR2-amplified gastric cancer cells

  Kazuko Matsumoto; Tokuzo Arao; Kazuyuki Furuta; Tomoyuki Nagai; Kanae Kudo; Hiroyasu Kaneda; Daisuke Tamura; Keiichi Aomatsu; Kazuko Sakai; Yoshihiko Fujita; Hideharu Kimura; Yasuhide Yamada; Kazuto Nishio CANCER RESEARCH 71 2011年04月
• Aza-derivatives of resveratrol are potent inhibitors of macrophage migration inhibitory factor (MIF)

  Yoshihiko Fujita; Rafiqul Islam Islam; Hideharu Kimura; Kazuko Matsumoto; Kazuyuki Furuta; Tomoyuki Nagai; Kanae Kudo; Hiroyasu Kaneda; Daisuke Tamura; Kazuko Sakai; Keiichi Aomatsu; Tokuzo Arao; Tadashi Okawara; Kazuto Nishio CANCER RESEARCH 71 2011年04月
• Short Poly A sequence in HGF promoter region is involved in overexpression of HGF in cancer cells

  Kazuko Sakai; Tokuzo Arao; Kazuko Matsumoto; Hideharu Kimura; Yoshihiko Fujita; Hiroyasu Kaneda; Daisuke Tamura; Keiichi Aomatsu; Kanae Kudo; Tomoyuki Nagai; Marco A. De Velasco; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio CANCER RESEARCH 71 2011年04月
• Gefitinib耐性株を用いた耐性機序の探索(Expression levels of EGFR-ligands are up-regnlated in EGFR tyrosine kinase inhibitor-resistant cell line)

  坂井 和子; 荒尾 徳三; 古田 一行; 永井 知行; 工藤 可苗; 金田 裕靖; 田村 大介; 青松 圭一; 藤田 至彦; 松本 和子; 小泉 史明; 西尾 和人 日本癌学会総会記事 69回 195 -195 2010年08月
• 血管内皮細胞におけるVEGFR2チロシンキナーゼ阻害薬の耐性機構(Drug resistance to vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor in vascular endothelial cells)

  松本 和子; 荒尾 徳三; 工藤 可苗; 古田 一行; 坂井 和子; 永井 知行; 金田 裕靖; 田村 大介; 青松 圭一; 藤田 至彦; 木村 英晴; 西尾 和人 日本癌学会総会記事 69回 272 -272 2010年08月
• 分子標的治療 ソラフェニブは肝細胞癌株において、HGF起因の上皮間葉移行(Epithelial mesenchymal transition)を阻害する(Molecular target therapy Sorafenib inhibits the hepatocyte growth factor-mediated epithelial mesenchymal transition in hepatocellular carcinoma)

  永井 知行; 荒尾 徳三; 坂井 和子; 工藤 可苗; 金田 裕靖; 田村 大介; 青松 圭一; 木村 英春; 藤田 至彦; 松本 和子; 西條 長宏; 工藤 雅俊; 西尾 和人 日本癌学会総会記事 69回 273 -273 2010年08月
• SNAI2に惹起されるEMTは肺癌においてチュブリン作用薬に対する感受性を亢進する(SNAI2-mediated epithelial mesenchymal transition increases the drug sensitivity to tubulin binding agents in lung cancer)

  田村 大介; 荒尾 徳三; 永井 知行; 古田 一行; 坂井 和子; 工藤 可苗; 金田 裕靖; 青松 圭一; 藤田 至彦; 松本 和子; 西村 善博; 西條 長宏; 西尾 和人 日本癌学会総会記事 69回 280 -280 2010年08月
• 転写因子snail、slugは角膜上皮細胞においてEMTを誘導しTP63発現レベルを減少させる(Snail and Slug transcription factors induce EMT and down-regulate TP63 mRNA expression in corneal epithelial cells)

  青松 圭一; 荒尾 徳三; 古田 一行; 松本 和子; 金田 裕靖; 工藤 可苗; 田村 大介; 永井 知行; 坂井 和子; 木村 英晴; 藤田 至彦; 下村 嘉一; 西尾 和人 日本癌学会総会記事 69回 318 -318 2010年08月
• 腫瘍細胞増殖におけるMIF-CD74シグナル経路の関与(Implication of MIF-CD74 signal pathway in tumorigenesis)

  藤田 至彦; 古田 一行; 工藤 可苗; 坂井 和子; 永井 知行; 金田 裕靖; 田村 大介; 青松 圭一; 木村 英晴; 松本 和子; 荒尾 徳三; 西尾 和人 日本癌学会総会記事 69回 527 -527 2010年08月
• Integration of whole genome exon array and array CGH analysis in gastric and colorectal cancer cell lines

  Kazuyuki Furuta; Tokuzo Arao; Kazuko Sakai; Tomoyuki Nagai; Daisuke Tamura; Keiichi Aomatsu; Kanae Kudo; Hiroyasu Kaneda; Yoshihiko Fujita; Kazuko Matsumoto; Yasuhide Yamada; Kazuyoshi Yanagihara; Masaru Sekijima; Kazuto Nishio CANCER RESEARCH 70 2010年04月
• Expression levels of EGFR-Iigands are up-regulated in EGFR tyrosine kinase inhibitor-resistant cell line

  Kazuko Sakai; Tokuzo Arao; Kazuyuki Furuta; Tomoyuki Nagai; Kanae Kudo; Hiroyasu Kaneda; Daisuke Tamura; Keiichi Aomatsu; Yoshihiko Fujita; Kazuko Matsumoto; Fumiaki Koizumi; Kazuto Nishio CANCER RESEARCH 70 2010年04月
• アクチビン-AはTGFβ依存性シグナルを介して血管内皮細胞の増殖を直接抑制する(Activin-A directly inhibits vascular endothelial cell growth via TGF-beta dependent signal pathway)

  金田 裕靖; 荒尾 徳三; 田中 薫; 永井 智行; 工藤 可苗; 田村 大介; 青松 圭一; 松本 和子; 藤田 至彦; 山田 康秀; 岡本 勇; 中川 和彦; 西尾 和人 日本癌学会総会記事 68回 49 -49 2009年08月
• エクソンアレイとSNPアレイによるがん細胞株のエクソン異常の探索(Whole genome exon array and SNP array detected alternative splicing in gastrointestinal cancer cell lines)

  古田 一行; 荒尾 徳三; 坂井 和子; 永井 知行; 田村 大介; 青松 圭一; 工藤 可苗; デベラスコ・マルコ; 金田 裕靖; 藤田 至彦; 松本 和子; 関島 勝; 西尾 和人 日本癌学会総会記事 68回 165 -165 2009年08月
• 胃癌高発現遺伝子SRPX2は胃癌細胞の遊走・接着を誘導する(SRPX2 is overexpressed in gastric cancer and promotes cellular migration and adhesion)

  荒尾 徳三; 田中 薫; 青松 圭一; 田村 大介; 工藤 可苗; 金田 裕靖; 藤田 至彦; 松本 和子; 柳原 五吉; 山田 康秀; 岡本 勇; 中川 和彦; 西尾 和人 日本癌学会総会記事 68回 252 -252 2009年08月
• mTORシグナルとHIF-1 alphaは癌細胞のCD133の発現を制御する(mTOR signal and HIF-1 alpha regulate CD133 expression in cancer cells)

  松本 和子; 荒尾 徳三; 坂井 和子; 永井 知行; 田村 大介; 青松 圭一; 工藤 可苗; デベラスコ・マルコ; 金田 裕靖; 藤田 至彦; 山田 康秀; 西尾 和人 日本癌学会総会記事 68回 276 -276 2009年08月
• TGF-βはヒト角膜上皮細胞の増殖とEMT関連遺伝子発現を調節する(TGF-beta regulates proliferation and EMT-related gene expression of human corneal epithelial cell)

  青松 圭一; 荒尾 徳三; 坂井 和子; 永井 知行; 田村 大介; 工藤 可苗; 金田 裕靖; 藤田 至彦; 松本 和子; 下村 嘉一; 西尾 和人 日本癌学会総会記事 68回 446 -446 2009年08月
• 血液標本における新規薬物動態バイオマーカーの血管新生阻害剤BIBF1120の抗腫瘍活性(Antitumor activity of a novel angiogenesis inhibitor BIBF1120 a new pharamacodynamic biomarker in blood samples)

  工藤 可苗; 荒尾 徳三; 坂井 和子; 永井 知行; 田村 大介; 青松 圭一; デベラスコ・マルコ; 金田 裕靖; 藤田 至彦; 松本 和子; 工藤 正俊; 西尾 和人 日本癌学会総会記事 68回 484 -484 2009年08月
• エポックメイキングな薬学を目指して 基礎と臨床の架橋となる生命科学 超分子[2]Rotaxaneによる抗腫瘍効果と特徴ある作用様式

  牧尾 圭悟; 原 一樹; 木村 公彦; 牛島 逸子; 新矢 時寛; 高田 十志和; 藤田 至彦; 西尾 和人; 小野 信文 日本薬学会年会要旨集 129年会 (1) 261 -261 2009年03月
• 抗がん活性を持つロタキサンの合成

  高田十志和; 小山靖人; 中薗和子; 小野信文; 西尾和人; 藤田至彦 日本化学会講演予稿集 89th (2) 2009年
• 原発不明癌の分子診断の現状と課題

  藤田至彦; 西尾和人 癌と化学療法 36 923 -926 2009年 [招待有り]
  
• 野生型と15塩基欠失型EGFRに対するマイクロアレイ発現解析(Microarray analysis for wild type and delE746_A750 type of EGFR introduced cells)

  前川 麻里; 荒尾 徳三; 松本 和子; 工藤 可苗; 田中 薫; 金田 裕靖; 藤田 至彦; 伊藤 文昭; 西尾 和人 日本癌学会総会記事 67回 195 -195 2008年09月
• 新規癌関連遺伝子FOXQ1は大腸癌細胞株において細胞周期制御因子p21waf1/Cip1を制御する(FOXQ1 is a novel p21 regulator in colorectal cancer cells)

  金田 裕靖; 荒 徳三; 田中 薫; 前川 麻里; 松本 和子; 工藤 可苗; 藤田 至彦; 山田 康秀; 岡本 勇; 中川 和彦; 西尾 和人 日本癌学会総会記事 67回 299 -300 2008年09月
• トラスツズマブ療法における新規バイオマーカーの探索的研究(Identification of predictive biomarkers for response to Trastuzumab using glycobiological analysis)

  松本 和子; 荒尾 徳三; 前川 麻里; 田中 薫; 金田 裕靖; 工藤 可苗; 藤田 至彦; 小泉 史明; 清水 千佳子; 田村 研治; 藤原 康弘; 西尾 和人 日本癌学会総会記事 67回 336 -336 2008年09月
• VEGFR2チロシンキナーゼ阻害剤のフローサイトメトリーによるチロシンリン酸化阻害剤の検討(Inhibition of phospho-tyrosine in VEGFR2+CD45dim population as a biomarker for VEGFR2 tyrosine kinase inhibitors)

  工藤 可苗; 荒尾 徳三; 松本 和子; 田中 薫; 前川 麻里; 金田 裕靖; 藤田 至彦; 工藤 正俊; 西尾 和人 日本癌学会総会記事 67回 365 -365 2008年09月
• ユニークなインターロック分子 ロタキサンの抗がん物質としての有用性(Rotaxane, a unique interlocked molecule, as a potential antitumor agent)

  藤田 至彦; 小野 信文; 高田 十志和; パトラ・ラジャシュリー; デベラスコ・マルコ; 横手 秀行; 荒尾 徳三; 松本 和子; 前川 麻里; 田中 薫; 金田 裕靖; 工藤 可苗; 西尾 和人 日本癌学会総会記事 67回 391 -391 2008年09月
• 胃癌細胞におけるIMP-3遺伝子の機能解析(IMP-3 overexpression promotes cellular proliferation activity in gastric cancer)

  田中 薫; 荒尾 徳三; 前川 麻里; 松本 和子; 工藤 可苗; 金田 裕靖; 藤田 至彦; 柳原 五吉; 山田 康秀; 岡本 勇; 中川 和彦; 西尾 和人 日本癌学会総会記事 67回 404 -404 2008年09月
• 新規連結分子ロタキサンの抗腫瘍活性と作用様式(Antitumor activitiy and mode of action of a unique interlocked molecule rotaxane)

  藤田 至彦; 小野 信文; 高田 十志和; デベラスコ・マルコ; 横手 秀行; 荒尾 徳三; 松本 和子; 前川 麻里; 田中 薫; 金田 裕靖; 阿部 譲; 西尾 和人 日本癌学会総会記事 66回 205 -205 2007年08月
• SPRX2 mRNA発現の抑制は胃癌細胞の増殖と接着を阻害する(Suppression of SRPX2 mRIMA expression inhibits cellular growth and adhesion in gastric cancer cells)

  田中 薫; 荒尾 徳三; 前川 麻里; 松本 和子; 金田 裕靖; 阿部 譲; 藤田 至彦; 横手 秀行; 柳原 五吉; 山田 康秀; 岡本 勇; 中川 和彦; 西尾 和人 日本癌学会総会記事 66回 475 -475 2007年08月
• 変異型EGFRのシグナル伝達経路(A novel signaling pathway of deletional mutant EGFR)

  前川 麻里; 横手 秀行; 松本 和子; 田中 薫; 金田 裕靖; 藤田 至彦; デベラスコ・マルコ; 荒尾 徳三; 小泉 史明; 伊藤 文昭; 西尾 和人 日本癌学会総会記事 66回 501 -501 2007年08月
• フコシル化によるEGFレセプター活性化の制御とEGFR-TKIの感受性の検討(Regulation of EGFR activity through N-glycan fucosylation and effect on the sensitivity of EGFR-TKI)

  松本 和子; 横手 秀行; 前川 麻里; 田中 薫; 金田 裕靖; デベラスコ・マルコ; 藤田 至彦; 荒尾 徳三; 西尾 和人 日本癌学会総会記事 66回 501 -501 2007年08月
• Erythropoietin regulates tumour growth of human malignancies (vol 24, pg 1021, 2003)

  Y Yasuda; Y Fujita; T Matsuo; S Koinuma; S Hara; A Tazaki; M Onozaki; M Hashimoto; T Musha; K Ogawa; H Fujita; Y Nakamura; H Shiozaki; H Utsumi CARCINOGENESIS 24 (9) 1567 -1567 2003年09月
• Stat3活性化過程の１分子観察（総説）

  藤田至彦; 分担執筆; 楠見明弘; 小林剛; 吉村昭彦; 徳永万喜洋 バイオイメージングでここまで理解る（羊土社） 90 -94 2003年
• Vascular endothelial growth factor in edematous mouse embryos induced by retinoic acid in utero

  Yasuda Yoshiko; Fujita Yoshihiko; Ueda Koichi; Matsuo Takuya; Onozaki Mie; Sakamoto Michiko K; Konishi Hiroyoshi Congenital anomalies 41 (2) 95 -105 2001年06月

産業財産権

• 特願2015-187300:治療法の選択方法およびそれを示すバイオマーカー  2016年09月24日

  西尾和人, 藤田至彦

受賞

• 2022年07月 日本緩和医療学会 最優秀演題賞
   がん疼痛に対するオピオイド選択のための多型バイオマーカーの探索 

  受賞者: 藤田至彦;松岡弘道;鶴谷純司;千葉康敬;酒井清裕;吉田健史;大武陽一;小山敦子;西尾和人;中川和彦
• 2012年 日本がん分子標的治療学会 優秀ポスター賞
   

  受賞者: 藤田至彦
• 1995年 フンボルト財団 研究奨学金助成
   

  受賞者: 藤田至彦
• 1994年 長寿科学振興財団研究者支援事業 研究奨学金助成
   

  受賞者: 藤田至彦
• 1994年 キャノンヨーロッパ財団 欧州長期特別奨学金
   

  受賞者: 藤田至彦

共同研究・競争的資金等の研究課題

• 転移性大腸がんに対するベバシズマブ併用療法選択のためのバイオマーカーの探索的研究

  日本学術振興会：科学研究費助成事業

  研究期間 : 2017年04月 -2020年03月 

  代表者 : 藤田至彦
• がん疼痛へのオピオイド使用に対するバイオマーカーを用いたランダム化比較試験

  日本医療研究開発機構：AMED研究費（分担）

  研究期間 : 2014年04月 -2017年03月 

  代表者 : 中川和彦
• 未治療原発不明癌に対する次世代シークエンスを用いた原発巣推定に基づく治療効果の意義を問う第ＩＩ相試験

  日本医療研究開発機構：AMED研究費（分担）

  研究期間 : 2014年04月 -2017年03月 

  代表者 : 中川和彦
• レスベラトロールのアザ誘導体化合物による細胞増殖抑制機構の解明

  日本学術振興会：科学研究費助成事業

  研究期間 : 2013年04月 -2016年03月 

  代表者 : 藤田至彦
• 電位依存性カルシウムチャンネルの関与する神経機能調節機構の分子生物学的研究

  日本学術振興会：科学研究費助成事業

  研究期間 : 1993年 -1993年 

  代表者 : 藤田 至彦

   

  電位依存性カルシウムチャンネルは多様な細胞機能の調節に重要な役割を果たしている。我々が行ってきたcDNAクローニングによるカルシウムチャンネルの構造決定及びcDNA発現による機能的同定により、カルシウムチャンネルは6種の遺伝子によりコードされており、さらにL型及び非L型サブファミリーに分類されることが明らかになった。今回、BI(P型)、及びBIII(N型)チャンネルと共に非L型サブファミリーに属するBIIチャンネルの発現実験をゼノパス卵母細胞を用いて行った。BIIチャンネルによる内向きバリウム電流は-20mV以上の試験電位で出現し、+13.7±9.3mVで最大になった。BIIチャンネルは活性化速度においてはBIやBIIIチャンネルと類似していたが、不活性化速度はBI及びBIIIチャンネルよりも有意に速く、+10mVにおいて半減期は82.4+33.9msであった。最大電流の50%に不活性化される電位はBI(-8.2mV)及びBIII(-27.9mV)よりも深く、-33.9mVである。BIIチャンネルはDHP、ω-コノトキシン、ω-アガトキシンの全てに非感受性であった。低閾値チャネルを阻害する100μMニッケルイオンはBIIチャンネルを50%以上阻害した。更には単一チャンネル電流の解析をしたところ、110mMBa^<2+>をチャージキャリアとするとスロープコンダクタンスは12.1pSとなり、これはBIの16pS及びBIIIの14pSより若干低い。 以上の実験によりBIIチャンネルは全くどの型にもあてはまらない新しい型であることが明らかになった。さらにBI、BII及びBIIIの3種の非L型チャンネルは共に神経伝達物質放出に関与すると考えられる。また機能的性質の異なる3種のチャンネルの相対的発現量を変化させることにより放出する伝達物質を変えたり、放出量を調節したりというシナプス可塑性の基礎を非L型チャネルの分子的多様性がなすと考えられる。
• カルシウム情報伝達の分子機構に関する研究

  日本学術振興会：科学研究費助成事業

  研究期間 : 1993年 -1993年 

  代表者 : 井本 敬二; 中井 淳一; STUHMER Walt; BEAM Kurt G.; 森 泰生; 藤田 至彦

   

  1) 電位依存性カルシウムチャンネルは,4つの相同性を有する繰り返し単位(リピート)からなり,それぞれのリピートには6つの膜貫通領域があると推定されている.これまでの研究で,お互いに類似の心筋カルシウムチャンネルと骨格筋カルシウムチャンネルの活性化速度の違いは,リピートIのアミノ酸配列の違いによることが明らかにされていた.活性化速度の差異がリピートIのどの部分に由来するかをさらに詳細に検討するために,リピートIのある部分が心筋カルシウムチャンネルに由来し,リピートIの残りの部分が骨格筋カルシウムチャンネルに由来するキメラカルシウムチャンネルを系統的に作製した.キメラcDNAをmuscular dysgenesisマウス由来の培養骨格筋細胞に注入して発現させ,電気生理学的にキメラチャンネルの活性化速度を求めた. その結果リピートIの第3推定膜貫通領域(S3)とS3とS4を結ぶ部分(S3-S4linker)が活性化速度の差異にかかわることが明らかとなった.S4は電位センサーと想定されていることを考えあわせると,膜電位の変化に伴うS4の変化が,本研究で明らかにされたS3及びその周辺に伝えられ,最終的にチャンネルの開口につながるものと考えられる. カルシウムチャンネルは主要部分を形作るαサブユニットと,その他の小サブユニットより構成されている.小サブユニットをαサブユニットに合わせて発現されると,カルシウムチャンネルの活性が増大することが知られているが,その機序は知られていない.このため,心筋カルシウムチャンネルを,単独あるいは小サブユニットと同時にCHO細胞に発現させ,RNAブロッティング,蛋白ゲル,ジヒドロピリジン結合能,電気生理学的解析を行って,小サブユニットの働きを検討した.その結果,小サブユニットはαサブユニットのRNA量・蛋白量に変化を与えることはなかった.小サブユニットはカルシウムチャンネルとして機能するために必要なコンフォーメションをとるために必要であると結論した. 興奮収縮連関に関与するリピートIIとリピートIIIを結ぶ部分については,さらに詳細に検討中である. ナトリウムチャンネル・カルシウムチャンネルのイオン選択機構に関しては,さらに多くの実験データを得,現在それらを解析検討中である.とくにナトリウムチャンネルには不活性化を抑制する変異を同時に導入することにより,実験の精度を向上させることが可能であった.2) ウサギ脳を材料として用い,新たなカルシウムチャンネルαサブユニットのcDNAクローニングを行い,その塩基配列を決定することにより,本チャンネルの全一次構造を明らかにした.この脳カルシウムチャンネル(BIIIと命名)は2,339個のアミノ酸残基よりなり,計算による分子量は261kDaであった.本カルシウムチャンネルは他のカルシウムチャンネルと相同性を有している.とくに脳カルシウムチャンネルであるBI,BIIとの相同性が高く,これら3つのカルシウムチャンネルで,ジヒドロピリジン感受性Lタイプカルシウムチャンネルとは異なったサブグループを形成すると考えられた. cDANより,発現プラスミドを作製し,muscular dysgenesisのマウス由来の培養骨格筋細胞に注入することにより,BIIIカルシウムチャンネルを発現させた.発現したカルシウムチャンネルはω-コノトキシンに感受性であり,従来Nタイプとして報告されて来たカルシウムチャンネルと類似の開閉と電位依存性を示した.また単一チャンネルコンダクタンスは14.3pSであった.Nタイプのカルシウムチャンネルは神経伝達物質放出に大きくかかわっていると考えられており,NタイプカルシウムチャンネルのcDNAクローニングは,今後の脳科学の発展に大きく寄与すると考えられる.
• 神経伝達物質受容体およびイオンチャンネルの構造と機能に関する研究

  日本学術振興会：科学研究費助成事業

  研究期間 : 1988年 -1991年 

  代表者 : 沼 正作; 藤田 至彦; 福田 和彦; 竹島 浩; 田辺 勉; 井本 敬二; 久保 泰; 野田 昌晴

   

  (ア)変異を導入したニコチン性アセチルコリン受容体(nAChR)の機能解析から、チャンネルの内壁、狭小部を構成する部位、イオン選択性に関わる部位を同定した。(イ)変異Na^+チャンネルの機能解析より、活性化の電位感受機構に直接関与する部位、不活性化に関与する部位を同定した。またチャンネル外側開口部あるいは内壁を形成すると推測される部位を同定した。(ウ)cDNAクロ-ニングより心筋Ca^<2+>ジハイドロピリジン(DHP)受容体の全一次構造を決定し、cDNAよりL型C^<2+>チャンネルを発現させた。cDNAクロ-ニングより脳Ca^<2+>チャンネルの一つの全一次構造を解明し、本チャンネルが小脳に多く、活性化閾値の高いニフェジピンやωコノトキシンに非感受性のチャンネルであることを示した。骨格筋DHP受容体が興奮収縮連関(EーC coupling)に必須の成分(おそらくvoltage sensor)およびslow Ca^<2+>チャンネルとして二重の機能を果たし、charge movementの成因に深く関与していることを示した。DHP受容体のEーC couplingのタイプ(骨格筋型あるいは心筋型)を決定する領域、活性化の速度を決定する領域を同定した。cDNAクロ-ニングにより骨格筋および心筋のリアノジン受容体の全一次構造を明らかにし、cDNAから機能を有するCa^<2+>放出チャンネルを発現させた。(エ)ムスカリン性アセチルコリン受容体(mAChR)サブタイプの特性を検討した。mACHRサブタイプが異なるeffector systemと選択的に共役することを明らかにした。キメラmAChRの機能解析からeffector systemとの選択的共役およびアゴニストの結合に関与する部位を示した。NG108ー15 neuroblastomaーglioma雑種細胞の2種のK^+チャンネルおよび網膜光受容細胞cGMPーgatedチャンネルのcDNAクロ-ニングと発現を行った。(オ)CHO細胞または培養昆虫細胞にイオンチャンネル蛋白を発現させ、精製した蛋白を用いて、結晶化条件(界面活性剤、pH、温度、沈澱剤など)の検討を行った。

その他のリンク

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