Molecular biological analysis of radiation induced epithelial-mesenchymal transition on cancer stem cell of rectal cancer

• Project/Area Number: 22591484
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Mie University
• Principal Investigator: TANAKA Koji 三重大学, 医学部附属病院, 講師 (10345986)
• Co-Investigator(Kenkyū-buntansha): INOUE Yasuhiro 三重大学, 医学部付属病院, 講師 (20324535) ; MIKI Chikao 三重大学, 大学院・医学系研究科, 准教授 (50242962) ; KUSUNOKI Masato 三重大学, 大学院・医学系研究科, 教授 (50192026)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2012: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000); Fiscal Year 2011: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2010: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
• Keywords: 小腸大腸肛門外科学 / 直腸癌 / 化学放射線療法 / 癌幹細胞 / 上皮間葉移行 / 大腸癌 / 二光子レーザー顕微鏡

Research Abstract

We hypothesized that residual cancer cells after chemoradiotherapy (CRT) for rectal cancer have the treatment (CRT)-resistant property and contain putative CSCs, compared with pre-CRT cancer specimens. Furthermore, residual cancer cells which survived CRT may acquire metastatic potential induced by EMT. The expression of CD133, leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), glucose transporter 1 (GLUT1), and hypoxia inducible factor-1α (HIF-1α) on residual cancer cells after CRT was associated with cancer recurrence and patient prognosis. The expression of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) on residual cancer cells after CRT was also associated with cancer recurrence. The expression of CXCR4 and its ligand CXCL12, fibroblast activation protein-α (FAP-α), and stromal cell-derived factor-1 (SDF-1) on the cancer stroma after CRT was also associated with cancer recurrence and patient prognosis. In vitro study, radiation induced EMT in colorectal cancer cells, resulting in the acquisition of invasive and metastatic properties. Neurotrophic receptor tropomyosin related kinase (TrkB) also induced EMT in colorectal cancer cells. TrkB was inversely correlated with E-cadherin, and associated with poor prognosis of colorectal cancer patients. CD133 was increased in a radiation dose-dependent manner, despite of the decreased number of clonogenic radiation-surviving cells.

Research Products

• [Journal Article] Leucine-rich repeat-containing G protein-coupled receptor 5 expression in ductular reactions after chemotherapy for metastatic colorectal cancer (2013)
  • Author(s): Saigusa S, Tanaka K, Toiyama Y, Matsushita K, Kawamura M, Okugawa Y, Uchida K, Inoue Y, Mohri Y, Kusunoki M.
  • Journal Title: Hepatol Res Volume: 43 Pages: 84-90
  • NAID: 10031183461
  • Peer Reviewed
• [Journal Article] Significant correlation between LKB1 and LGR5 gene expression and the association with poor recurrence-free survival in rectal cancer after preoperative chemoradiotherapy (2013)
  • Author(s): Saigusa S, Inoue Y, Tanaka K, Toiyama Y, Kawamura M, Okugawa Y, Okigami M, Hiro J, Uchida K, Mohri Y, Kusunoki M
  • Journal Title: JCancer Res Clin Oncol Volume: 139 Pages: 131-8
  • Peer Reviewed
• [Journal Article] Leucine-rich repeat-containing G protein-coupled receptor 5 expression in ductular reactions after chemotherapy for metastatic colorectal cancer. (2013)
  • Author(s): Saigusa S, Tanaka K, et al
  • Journal Title: Hepatol Res. Volume: 43 Issue: 1 Pages: 84-90
  • DOI: 10.1111/j.1872-034x.2012.01048.x
  • NAID: 10031183461
  • Peer Reviewed
• [Journal Article] Clinical significance of LGR5 and CD44 expression in locally advanced rectal cancer after preoperative chemoradiotherapy (2012)
  • Author(s): Saigusa S, Inoue Y, Tanaka K, Toiyama Y, Matsushita K, Kawamura M, Okugawa Y, Hiro J, Uchida K, Mohri Y, Kusunoki M.
  • Journal Title: Int J Oncol Volume: 41 Pages: 1643-52
  • Peer Reviewed
• [Journal Article] In vivo real-time imaging of chemotherapy response on the liver metastatic tumor microenvironment using multiphoton microscopy (2012)
  • Author(s): Tanaka K, Okigami M, Toiyama Y, Morimoto Y, Matsushita K, Kawamura M, Hashimoto K, Saigusa S, Okugawa Y, Inoue Y, Uchida K, Araki T, Mohri Y, Mizoguchi A, Kusunoki M
  • Journal Title: Oncol Rep Volume: 28 Pages: 1822-30
  • Peer Reviewed
• [Journal Article] Intravital imaging of gastrointestinal diseases in preclinical models using two-photon laser scanning microscopy (2012)
  • Author(s): Tanaka K, Toiyama Y, Inoue Y, Uchida K, Araki T, Mohri Y, Mizoguchi A, Kusunoki M
  • Journal Title: Surg Today Volume: 43 Pages: 123-9
  • NAID: 10031167976
  • Peer Reviewed
• [Journal Article] Gene expression profiles of tumor regression grade in locally advanced rectal cancer after neoadjuvant chemoradiotherapy (2012)
  • Author(s): Saigusa S, Tanaka K, Toiyama Y, Matsushita K, Kawamura M, Okugawa Y, Hiro J, Inoue Y, Uchida K, Mohri Y, Kusunoki M
  • Journal Title: Oncol Rep Volume: 28 Pages: 855-61
  • Peer Reviewed
• [Journal Article] Correlation of MACC1 and MET expression in rectal cancer after neoadjuvant chemoradiotherapy (2012)
  • Author(s): Kawamura M, Saigusa S, Toiyama Y, Tanaka K, Okugawa Y, Hiro J, Uchida K, Mohri Y, Inoue Y, Kusunoki M
  • Journal Title: Anticancer Res Volume: 32 Pages: 1527-31
  • Peer Reviewed
• [Journal Article] High TrkB expression levels are associated with poor prognosis and EMT induction in colorectal cancer cells. (2012)
  • Author(s): Fujikawa H, Tanaka K, Toiyama Y, Saigusa S, Inoue Y, Uchida K, Kusunoki M
  • Journal Title: J Gastroenterol Volume: 47 Pages: 775-84
  • NAID: 10030962144
  • Peer Reviewed
• [Journal Article] CXCL5, a promoter of cell proliferation, migration and invasion, is a novel serum prognostic marker in patientswith colorectal cancer (2012)
  • Author(s): Kawamura M, Toiyama Y, Tanaka K, Saigusa S, Okugawa Y, Hiro J, Uchida K, Mohri Y, Inoue Y, Kusunoki M
  • Journal Title: Eur J Cancer Volume: 48 Pages: 2244-51
  • Peer Reviewed
• [Journal Article] In vivo time-course imaging of tumor angiogenesis in colorectal liver metastases in the same living mice using two-photon laser scanning microscopy (2012)
  • Author(s): Tanaka K, Morimoto Y, Toiyama Y, Matsushita K, Kawamura M, Koike Y, Okugawa Y, Inoue Y, Uchida K, Araki T, Mizoguchi A, Kusunoki M
  • Journal Title: J Oncol Volume: 2012 Pages: 265487-265487
  • NAID: 120003596966
  • Peer Reviewed
• [Journal Article] Prognostic significance of glucosetransporter-1 (GLUT1) gene expression in rectal cancer after preoperative chemoradiotherapy (2012)
  • Author(s): Saigusa S, Toiyama Y, Tanaka K, Okugawa Y, Fujikawa H, Matsushita K, Uchida K, Inoue Y, Kusunoki M.
  • Journal Title: Surg Today Volume: 42 Pages: 460-9
  • Peer Reviewed
• [Journal Article] TS and DPD mRNA levels on formalin-fixed paraffin-embedded specimens as predictors for distant recurrence of rectal cancer treated with preoperative chemoradiotherapy (2012)
  • Author(s): Tanaka K, Saigusa S, Toiyama Y, Koike Y, Okugawa Y, Yokoe T, Inoue Y, Kobayashi M, Miki C, Kusunoki M
  • Journal Title: J Surg Oncol Volume: 105 Pages: 529-34
  • Peer Reviewed
• [Journal Article] Radiation induces epithelial-mesenchymal transition in colorectal cancer cells (2012)
  • Author(s): Kawamoto A, Yokoe T, Tanaka K, Saigusa S, Toiyama Y, Yasuda H, Inoue Y, Miki C, Kusunoki M.
  • Journal Title: Oncol Rep Volume: 27 Pages: 51-7
  • Peer Reviewed
• [Journal Article] Inhibition of HGF/cMET expression prevents distant recurrence of rectal cancer after preoperative chemoradiotherapy (2012)
  • Author(s): Saigusa S, Toiyama Y, Tanaka K, Yokoe T, Fujikawa H, Matsushita K, Okugawa Y, Inoue Y, Uchida K, Mohri Y, Kusunoki M
  • Journal Title: Int J Oncol Volume: 40 Pages: 583-91
  • Peer Reviewed
• [Journal Article] Intravital dual-colored visualization of colorectal liver metastasis in living mice using two photon laser scanning microscopy (2012)
  • Author(s): Tanaka K, Morimoto Y, Toiyama Y, Okugawa Y, Inoue Y, Uchida K, Kimura K, Mizoguchi A, Kusunoki M
  • Journal Title: Microsc Res Tech Volume: 75 Pages: 307-1
  • Peer Reviewed
• [Journal Article] Gene expression profiles of tumor regression grade in locally advanced rectal cancer after neoadjuvant chemoradiotherapy. (2012)
  • Author(s): Saigusa S, Tanaka K, et al
  • Journal Title: Oncol Rep. Volume: 28 Issue: 3 Pages: 855-861
  • DOI: 10.3892/or.2012.1863
  • Peer Reviewed
• [Journal Article] High TrkB expression levels are associated with poor prognosis and EMT induction in colorectal cancer cells. (2012)
  • Author(s): Fujikawa H, Tanaka K, et al
  • Journal Title: J Gastroenterol. Volume: 47 Issue: 7 Pages: 775-784
  • DOI: 10.1007/s00535-012-0532-0
  • NAID: 10030962144
  • Peer Reviewed
• [Journal Article] Clinical significance of radiation-induced CD133 expression in residual rectal cancer cells after chemoradiotherapy (2012)
  • Author(s): AYA KAWAMOTO, KOJI TANAKA, SUSUMU SAIGUSA, YUJI TOIYAMA, YUHKI MORIMOTO, HIROYUKI FUJIKAWA, TAKASHI IWATA, KOHEI MATSUSHITA, TAKESHI YOKOE, HIROMI YASUDA, YASUHIRO INOUE, CHIKAO MIKI, MASATO KUSUNOKI
  • Journal Title: Experimental and Therapeutic Medicine
  • Peer Reviewed
• [Journal Article] Intravital three-dimensional dynamic pathology of experimental colitis in living mice using two-photon laser scanning microscopy (2011)
  • Author(s): Morimoto Y, Tanaka K, Toiyama Y, Inoue Y, Araki T, Uchida K, Kimura K, Mizoguchi A, Kusunoki M
  • Journal Title: J Gastrointest Surg Volume: 15 Pages: 1842-50
  • Peer Reviewed
• [Journal Article] In vivo real-time two-photon microscopic imaging of platelet aggregation induced by selective laser irradiation to the endothelium created in the beta-actin-green fluorescent protein transgenic mice (2011)
  • Author(s): Koike Y, Tanaka K, Okugawa Y, Morimoto Y, Toiyama Y, Uchida K, Miki C, Mizoguchi A, Kusunoki M
  • Journal Title: J Thromb Thrombolysis Volume: 32 Pages: 138-45
  • Peer Reviewed
• [Journal Article] Cancer-associated fibroblasts correlate with poor prognosis in rectal cancer after chemoradiotherapy (2011)
  • Author(s): Saigusa S, Toiyama Y, Tanaka K, Yokoe T, Okugawa Y, Fujikawa H, Matsusita K, Kawamura M, Inoue Y, Miki C, Kusunoki M.
  • Journal Title: Int J Oncol Volume: 38 Pages: 655-63
  • Peer Reviewed
• [Journal Article] Clinical significance of CD133 and hypoxia inducible factor-1α gene expression in rectal cancer after preoperative chemoradiotherapy (2011)
  • Author(s): Saigusa S, Tanaka K, Toiyama Y, Yokoe T, Okugawa Y, Koike Y, Fujikawa H, Inoue Y, Miki C, Kusunoki M
  • Journal Title: Clin Oncol (R Coll Radiol) Volume: 23 Pages: 323-32
  • Peer Reviewed
• [Journal Article] TS and DPD mRNA levels on formalin-fixed paraffin-embedded specimens as predictors for distant recurrence of rectal cancer treated with preoperative chemoradiotherapy (2011)
  • Author(s): Tanaka K, Saigusa S, Toiyama Y, Koike Y, Okugawa Y, Yokoe T, Inoue Y, Kobayashi M, Miki C, Kusunoki M
  • Journal Title: J Sure Oncol
  • Peer Reviewed
• [Journal Article] Immunohistochemical features of CD133 expression: association with resistance to chemoradiotherapy in rectal cancer (2010)
  • Author(s): Saigusa S, Tanaka K, Toiyama Y, Yokoe T, Okugawa Y, Kawamoto A, Yasuda H,Morimoto Y, Fujikawa H, Inoue Y, Miki C, Kusunoki M
  • Journal Title: Oncol Rep Volume: 24 Pages: 345-50
  • Peer Reviewed
• [Journal Article] Stromal CXCR4 and CXCL12 expression is associated with distant recurrence and poor prognosis in rectal cancer after chemoradiotherapy (2010)
  • Author(s): Saigusa S, Toiyama Y, Tanaka K, Yokoe T, Okugawa Y, Kawamoto A, Yasuda H, Inoue Y, Miki C, Kusunoki M
  • Journal Title: Ann Surg Oncol Volume: 17 Pages: 2051-8
  • Peer Reviewed
• [Journal Article] Intravital imaging of DSS-induced cecal mucosal damage in GFP-transgenic mice using two-photon microscopy (2010)
  • Author(s): Toiyama Y, Mizoguchi A, Okugawa Y, Koike Y, Morimoto Y, Araki T, Uchida K, Tanaka K, Nakashima H, Hibi M, Kimura K, Inoue Y, Miki C, Kusunoki M
  • Journal Title: J Gastroenterol Volume: 45 Pages: 544-53
  • NAID: 120002777869
  • Peer Reviewed
• [Journal Article] Stromal CXCR4 and CXCL12 expression is associated with distant recurrence and poor prognosis in rectal cancer after chemoradiotherapy. (2010)
  • Author(s): Saigusa S, Toiyama Y, Tanaka K, Yokoe T, Okugawa Y, Kawamoto A, Yasuda H, Inoue Y, Miki C, Kusunoki M.
  • Journal Title: Ann Surg Oncol. Volume: 17 Pages: 2051-2058
  • Peer Reviewed
• [Journal Article] The Role of Cytoreduction as a Multidisciplinary Treatment Modality for Metastatic Colorectal Cancer. Colorectal Cancer : Risk, Diagnosis and Treatments. Ed : Julianne E.Jenkins. (2010)
  • Author(s): Koji Tanaka, Yasuhiro Inoue, Masato Kusunoki
  • Journal Title: Nova Publishers, New York Volume: Chapter 5, 4th quarter Pages: 161-176
  • Peer Reviewed
• [Journal Article] Intravital imaging of DSS-induced cecal mucosal damage in GFP-transgenic mice using two-photon microscopy. (2010)
  • Author(s): Toiyama Y, Mizoguchi A, Okugawa Y, Koike Y, Morimoto Y, Araki T, Uchida K, Tanaka K, Nakashima H, Hibi M, Kimura K, Inoue Y, Miki C, Kusunoki M.
  • Journal Title: J Gastroenterol. Volume: 45 Pages: 544-553
  • NAID: 120002777869
  • Peer Reviewed
• [Presentation] Koji Tanaka, Masato Okigami, Yuji Toiyama, Yuhki Morimoto, Kohei Matsushita, Mikio Kawamura, Kiyoshi Hashimoto, Susumu Saigusa, Yoshinaga Okugawa, Junichiro Hiro, Yasuhiro Inoue, Keiichi Uchida, Toshimitsu Araki, Yasuhiko Mohri, Akira Mizoguchi, Masato Kusunoki (2012)
  • Author(s): In vivo real-time imaging of tumor microcirculatory alterations in colorectal liver metastatic xenografts by chemotherapy using multiphoton microscopy.J Clin Oncol 30, 2012 (suppl; abstr e21053)
  • Organizer: 2012 ASCO Annual Meeting
  • Place of Presentation: Chicago, Illinois
  • Year and Date: 2012-06-05
• [Presentation] K. Tanaka, Y. Morimoto, Y. Toiyama, S. Saigusa, Y. Okugawa, Y. Inoue, K. Uchida, K. Matsushita, M. Kawamura, A. Mizoguchi, M. Kusunoki (2012)
  • Author(s): Intravital evaluation of time-course efficacy of anticancer drugs on colorectal liver metastases in the same living mice using two-photon laser scanning microscopy.J Clin Oncol 29: 2011 (suppl; abstr 10621)
  • Organizer: 2011 ASCO Annual Meeting
  • Place of Presentation: Chicago, Illinois
  • Year and Date: 2012-06-05
• [Presentation] Time-series assessment of 5-fluorouracil efficacy on murine colorectal liver metastasis model using intravital multiphoton microscopy (2432) (2012)
  • Author(s): Koji Tanaka, Masato Okigami, Yuhki Morimoto, Kohei Matsushita, Mikio Kawamura, Kiyoshi Hashimoto, Yuji Toiyama, Susumu Saigusa, Yoshinaga Okugawa, Yuhki Koike, Yasuhiro Inoue,Toshimitsu Araki, Keiichi Uchida, Yasuhiko Mohri, Akira Mizoguchi, Masato Kusunoki
  • Organizer: AACR 103rdAnnual Meeting 2012
  • Place of Presentation: Chicago, Illinois
  • Year and Date: 2012-04-04
• [Presentation] 化学放射線療法後の遺残食道癌細胞における抗癌剤感受性遺伝子発現 (2012)
  • Author(s): 田中光司
  • Organizer: 第66回日本食道学会学術集会
  • Place of Presentation: 軽井沢
  • Invited
• [Presentation] Intravital dual-colored visualization of colorectal liver metastasis formation in the living mice using two photon laser scanning microscopy (5278) (2011)
  • Author(s): Koji Tanaka, Yuhki Morimoto, Kohei Matsushita, Mikio Kawamura, Yuji Toiyama, Susumu Saigusa, Yoshinaga Okugawa, Yuhki Koike, Yasuhiro Inoue, Chikao Miki, Akira Mizoguchi, Masato Kusunoki.
  • Organizer: AACR 102ndAnnual Meeting 2011
  • Place of Presentation: Orlando, Florida
  • Year and Date: 2011-04-06
• [Presentation] Intravital evaluation of time-course efficacy of anti-cancer drugs on colorectal liver metastases in the same living mice using two-photon laser scanning microscopy (2011)
  • Author(s): Koji Tanaka, Yuhki Morimoto, Yuji Toiyama, Susumu Saigusa, Yoshinaga Okugawa, Yasuhiro Inoue, Keiichi Uchida, Kohei Matsushita, Mikio Kawamura, Akira Mizoguchi, Masato Kusunoki
  • Organizer: The 2011 ASCO Annual Meeting
  • Place of Presentation: Chicago, IL
• [Presentation] The role of cytoreduction for metastatic and recurrent colorectal cancer in the era of multidisciplinary treatments.J Clin Oncol 28, 2010 (suppl; abstre14091) (2010)
  • Author(s): K. Tanaka, Y. Inoue, Y. Toiyama, J. Hiro, T. Iwata, S. Saigusa, M. Ohi, C. Miki, S. Kageyama, M. Kusunoki
  • Organizer: 2010 ASCO Annual Meeting
  • Place of Presentation: Chicago, Illinois
  • Year and Date: 2010-06-08
• [Presentation] Koji Tanaka, Yuhki Morimoto, Yuji Toiyama, Hiromi Yasuda, Susumu Saigusa, Takeshi Yokoe, Toshimitsu Araki, Yasuhiro Inoue, Chikao Miki, Masato Kusunoki. (2010)
  • Author(s): cell transcription factors on colorectal carcinoma and adenoma in familial adenomatous polyposis (3358)
  • Organizer: AACR 101stAnnual Meeting 2010
  • Place of Presentation: Washington, D.C
  • Year and Date: 2010-04-21
• [Presentation] The role of cytoreduction for metastatic and recurrent colorectal cancer in the era of multidisciplinary treatments (2010)
  • Author(s): Koji Tanaka, Yasuhiro Inoue, Yuji Toiyama, Junichiro Hiro, Takashi Iwata, Susumu Saigusa, Masaki Ohi, Chikao Miki, Shinichi Kageyama, Masato Kusunoki
  • Organizer: 2010 ASCO Annual Meeting
  • Place of Presentation: CHICAGO, IL
• [Book] 消化器疾患最新の治療 (2013)
  • Author(s): 菅野健太郎III-C-12. 大腸ポリープ・ポリポーシス田中光司、楠 正人
  • Publisher: 編集 上西紀夫/編集井廻道夫/編集南江堂
• [Book] Clinical Significance of Putative Cancer Stem Cells in Residual Cancer Cells After Chemoradiotherapy for Rectal Cancer. (2011)
  • Author(s): Koji Tanaka, Yasuhiro Inoue, Yuji Toiyama, Keiichi Uchida, Chikao Mikiand Masato Kusunoki.
  • Publisher: ISBN 978-953-307-580-8
• [Book] The Role of Cytoreduction as a Multidisciplinary Treatment Modality for Metastatic Colorectal Cancer (2011)
  • Author(s): Koji Tanaka, Yasuhiro Inoue, Masato Kusunoki
  • Publisher: Koji Tanaka, Yasuhiro Inoue, Masato Kusunoki
• [Book] Clinical Significance of Putative Cancer Stem Cells in Residual Cancer Cells After Chemoradiotherapy for Rectal Cancer (2011)
  • Author(s): Tanaka K, Inoue Y, Toiyama Y, Uchida K, Miki C, Kusunoki M
  • Publisher: InTech
• [Book] 特集:進行癌の治療戦略 6.進行直腸癌の治療戦略 (2010)
  • Author(s): 田中光司、井上靖浩、問山裕二、三木誓雄、楠正人
  • Publisher: 南江堂