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Role of hypoxia and cancer stem cells in the resistance to EGFR-TKI in non-small cell lung cancer

Research Project

Project/Area Number 24591176
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Respiratory organ internal medicine
Research InstitutionJuntendo University

Principal Investigator

Takahashi Kazuhisa  順天堂大学, 医学部, 教授 (80245711)

Co-Investigator(Kenkyū-buntansha) TAKAHASHI Fumiyuki  順天堂大学, 医学部, 准教授 (70327823)
Project Period (FY) 2012-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords非小細胞肺癌 / 癌幹細胞 / EGFR-TKI 耐性 / EGFR-TKI / 低酸素 / EMT / 耐性 / 肺癌 / Gefitinib / 幹細胞 / ZEB1 / microRNA
Outline of Final Research Achievements

Our aim here was to elucidate the role of hypoxia and cancer stem cells (CSCs) in the resistance to EGFR-TKI in non-small cell lung cancer (NSCLC). PC9 and HCC827 were exposed to high concentration of gefitinib under normoxic or hypoxic conditions. Seven days after gefitinib exposure, a small fraction of viable cells were detected, and these were referred to as “gefitinib-resistant persisters” (GRPs). Stem cell genes, such as CD133 and Oct4, were highly expressed, and GRPs exhibited a high potential for tumorigenicity in vivo and self-renewal capability. Importantly, hypoxic exposure significantly increased phosphorylation of IGF1R, and the population of CD133- and Oct4-positive GRPs. Transfection of Oct4 significantly increased CD133-positive GRPs and sphere formation under the treatment of gefitinib. Interestingly, gefitinib resistance induced by high Oct4 expression was more evident under the hypoxia.

Report

(5 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Research-status Report
  • 2013 Research-status Report
  • 2012 Research-status Report
  • Research Products

    (21 results)

All 2016 2015 2014 2013 2012

All Journal Article (10 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 10 results,  Open Access: 1 results,  Acknowledgement Compliant: 1 results) Presentation (11 results)

  • [Journal Article] Oct4 plays a crucial role in the maintenance of gefitinib-resistant lung cancer stem cells.2016

    • Author(s)
      Kobayashi I, Takahashi F, Nurwidya F, Nara T, Hashimoto M, Murakami A,
    • Journal Title

      Biochem Biophys Res Commun

      Volume: in press Issue: 1 Pages: 125-132

    • DOI

      10.1016/j.bbrc.2016.03.064

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cerebral infarction in advanced non-small cell lung cancer.2016

    • Author(s)
      Kato M, Takahashi F, Takahashi K, et al.
    • Journal Title

      BMC Cancer

      Volume: 10 Issue: 1 Pages: 203-203

    • DOI

      10.1186/s12885-016-2233-1

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Chemotherapy induced microRNA-125/HER2 pathway as a novel therapeutic target for trastuzumab-mediated cellular cytotoxicity in small-cell lung cancer.2015

    • Author(s)
      Yagishita S, Takahashi F, Takahashi K, et al.
    • Journal Title

      Mol Cancer Ther

      Volume: 14 Issue: 6 Pages: 1414-23

    • DOI

      10.1158/1535-7163.mct-14-0625

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Chemotherapy induced microRNA-125/HER2 pathway as a novel therapeutic target for trastuzumab-mediated cellular cytotoxicity in small-cell lung cancer.2015

    • Author(s)
      Yagishita S, Fujita Y, Kitazono S, Nakadate Y, Sawada T, Kitamura Y, Shimoyama T, Takahashi F, Takahashi K, Tamura T, Koizumi F.
    • Journal Title

      Mol Cancer Ther

      Volume: in press

    • Related Report
      2014 Research-status Report
    • Peer Reviewed
  • [Journal Article] Treatment with insulin-like growth factor 1 receptor inhibitor reverses hypoxia-induced epithelial-mesenchymal transition in non-small cell lung cancer2014

    • Author(s)
      Nurwidya F, Takahashi F, Kobayashi I, Murakami A, Kato M, Minakata K, Nara T, Hashimoto M, Yagishita S, Baskoro H, Hidayat M, Shimada N, Takahashi K.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 455 Issue: 3-4 Pages: 332-338

    • DOI

      10.1016/j.bbrc.2014.11.014

    • Related Report
      2014 Research-status Report
    • Peer Reviewed
  • [Journal Article] Tocilizumab, a proposed therapy for the cachexia of interleukin 6-expressing lung cancer2014

    • Author(s)
      Ando K, Takahashi F, Kato M, Kaneko N, Doi T, Ohe Y, Koizumi F, Nishio K, Takahashi K.
    • Journal Title

      PLoS One

      Volume: 9 Issue: 7 Pages: e102436-e102436

    • DOI

      10.1371/journal.pone.0102436

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Acquired resistance of non-small cell lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors.2014

    • Author(s)
      Nurwidya F, Takahashi F, Takahashi K. et al.
    • Journal Title

      Respir Investig

      Volume: 52 Issue: 2 Pages: 82-91

    • DOI

      10.1016/j.resinv.2013.07.007

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Hypoxia increases gefitinib-resistant lung cancer stem cells through the activation of insulin-like growth factor 1 receptor2013

    • Author(s)
      Murakami A, Takahashi F, Nurwidya F, Kobayashi I, Minakata K, Hashimoto M, Nara T, Kato M, Tajima K, Shimada N, Iwakami S, Moriyama M, Moriyama H, Koizumi F, Takahashi K
    • Journal Title

      PLoS One

      Volume: 9(1) Issue: 1 Pages: e86459-e86459

    • DOI

      10.1371/journal.pone.0086459

    • Related Report
      2014 Research-status Report 2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Hypoxia induces gefitinib resistance in non-small-cell lung cancer with both mutant and wild-type epidermal growth factor receptors2012

    • Author(s)
      Minakata K, et al. (他12名)
    • Journal Title

      Cancer Sci

      Volume: 103 Issue: 11 Pages: 1946-1954

    • DOI

      10.1111/j.1349-7006.2012.02408.x

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell.2012

    • Author(s)
      Yae T, Tsuchihashi K, Ishimoto T, Motohara T, Yoshikawa M, Yoshida GJ, Wada T, Masuko T,Mogushi K, Tanaka H, Osawa T, Kanki Y, et al
    • Journal Title

      Nature Communications

      Volume: 6;3 Issue: 1 Pages: 883-883

    • DOI

      10.1038/ncomms1892

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Presentation] Cerebral infarction in advanced non-small cell lung cancer2015

    • Author(s)
      Kato M, Takahashi F, Takahashi K, et al.
    • Organizer
      Asian Pacific Society of Respirology
    • Place of Presentation
      Kuala Lumpur
    • Year and Date
      2015-12-03
    • Related Report
      2015 Annual Research Report
  • [Presentation] Role of POU5F1 in gefitinib resistance in EGFR-mutant non-small cell lung cancer (NSCLC)2015

    • Author(s)
      Kobayashi I, Takahashi F, Takahashi K, et al.
    • Organizer
      日本呼吸器学会総会(英語ポスター発表)
    • Place of Presentation
      東京
    • Year and Date
      2015-04-17
    • Related Report
      2015 Annual Research Report
  • [Presentation] Translational Evidence of Zinc finger E-box binding homeoprotein 1 Involvement in Acquired Resistance to Gefitinib in Non-small Cell Lung Cancer2014

    • Author(s)
      Nurwidya F, Takahashi F, Kobayashi I, Shimada N, Murakami A, Baskoro H, Suina K, Kanemaru R, Yagishita S, Asao T, Ohashi R, Muraki K, Yoshioka Y, Takahashi M, Sasaki S, Takahashi K.
    • Organizer
      Congress of the Asian Pacific Society of Respirology (APSR)
    • Place of Presentation
      Bali, Indonesia
    • Year and Date
      2014-11-13 – 2014-11-16
    • Related Report
      2014 Research-status Report
  • [Presentation] Oct4 plays a key role in the persistence of gefitinib-resistant lung cancer stem cells.2014

    • Author(s)
      Kobayashi I, Takahashi F, Nurwidya F, Murakami A, Kato M, Shimada N, Suina K, Kanemaru R, Yagishita S, Ko R, Asao T, Ohashi R, Muraki K, Yoshioka Y, Takahashi M, Takahashi K.
    • Organizer
      Congress of the Asian Pacific Society of Respirology (APSR)
    • Place of Presentation
      Bali, Indonesia
    • Year and Date
      2014-11-13 – 2014-11-16
    • Related Report
      2014 Research-status Report
  • [Presentation] Epithelial-mesenchymal transition-driven gefitinib resistance in non-small cell lung cancer is mediated by zinc-finger E-box protein 1.2014

    • Author(s)
      Nurwidya F, Takahashi F, Murakami A, Kobayashi I, Kato M, Minakata K, Yagishita S, Koyama R, Muraki K, Takahashi M, Shimada N, Takahashi K.
    • Organizer
      Congress of American Thoracic Society (ATS)
    • Place of Presentation
      San Diego, USA
    • Year and Date
      2014-05-16 – 2014-05-21
    • Related Report
      2014 Research-status Report
  • [Presentation] Hypoxia increases gefitinib-resistant lung cancer stem cells through the activation of insulin-like growth factor 1 receptor.2013

    • Author(s)
      Murakami A, Takahashi F, Takahashi K. et al.
    • Organizer
      Asian Pacific Society of Respirology
    • Place of Presentation
      横浜
    • Related Report
      2013 Research-status Report
  • [Presentation] Knockdown of zinc-finger E-box-binding homeobox 1 (ZEB1) reduces stem cells characteristic of gefitinib-resistant-persisters of PC9 cells.2013

    • Author(s)
      Nurwidya F, Takahashi F, Takahashi K. et al.
    • Organizer
      Asian Pacific Society of Respirology
    • Place of Presentation
      横浜
    • Related Report
      2013 Research-status Report
  • [Presentation] ZEB1 is Involved in Hypoxia-induced Gefitinib Resistance in Non-Small Cell Lung Cancer with Sensitive EGFR Mutation (English poster session).2013

    • Author(s)
      Nurwidya F, Takahashi F, Takahashi K. et al.
    • Organizer
      日本呼吸器学会
    • Place of Presentation
      東京
    • Related Report
      2013 Research-status Report
  • [Presentation] Role of ZEB1 in hypoxia-induced epithelial mesenchymal transisition and stem cell features in NSCLC. (English poster session).2013

    • Author(s)
      Nurwidya F, Takahashi F, Takahashi K. et al.
    • Organizer
      日本肺癌学会
    • Place of Presentation
      東京
    • Related Report
      2013 Research-status Report
  • [Presentation] ZEB1 is Involved in Hypoxia-induced Gefitinib Resistance in Non-Small Cell Lung Cancer with Sensitive EGFR Mutation2013

    • Author(s)
      Fariz Nurwidya, Fumiyuki Takahashi, Akiko Murakami, Isao Kobayashi, Kunihiko Minakata, Yoshito Hoshika, Ryo Ko, Shigehiro Yagishita, Naoko Shimada, Kazuhisa Takahashi
    • Organizer
      日本呼吸器学会
    • Place of Presentation
      東京
    • Related Report
      2012 Research-status Report
  • [Presentation] 非小細胞肺癌の低酸素誘導性EGFR-TKI耐性機序におけるZEB1の関与2012

    • Author(s)
      村上朗子、高橋史行、南方邦彦、Fariz Nurwidya、田島健、加藤元康、村木慶子、宿谷威仁、八戸すず、八戸敏史、大橋里奈、小山良、石渡俊次、平間未知大、森貴紀、高橋元美、瀬山邦明、高橋和久
    • Organizer
      日本呼吸器学会
    • Place of Presentation
      神戸
    • Related Report
      2012 Research-status Report

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Published: 2013-05-31   Modified: 2019-07-29  

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