Role of hypoxia and cancer stem cells in the resistance to EGFR-TKI in non-small cell lung cancer
Project/Area Number |
24591176
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Respiratory organ internal medicine
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Research Institution | Juntendo University |
Principal Investigator |
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Co-Investigator(Kenkyū-buntansha) |
TAKAHASHI Fumiyuki 順天堂大学, 医学部, 准教授 (70327823)
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Project Period (FY) |
2012-04-01 – 2016-03-31
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Project Status |
Completed (Fiscal Year 2015)
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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)
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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.
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Report
(5 results)
Research Products
(21 results)
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[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.
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Journal Title
Mol Cancer Ther
Volume: in press
Related Report
Peer Reviewed
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[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.
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Journal Title
Biochem Biophys Res Commun
Volume: 455
Issue: 3-4
Pages: 332-338
DOI
Related Report
Peer Reviewed
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[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
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Journal Title
PLoS One
Volume: 9(1)
Issue: 1
Pages: e86459-e86459
DOI
Related Report
Peer Reviewed
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[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
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Journal Title
Nature Communications
Volume: 6;3
Issue: 1
Pages: 883-883
DOI
Related Report
Peer Reviewed
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[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
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[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
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[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
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