Restoration of chemoresistance by modifying epithelial-to-mesenchymal transition.

• Project/Area Number: 26461182
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Chiba University
• Principal Investigator: Takiguchi Yuichi 千葉大学, 大学院医学研究院, 教授 (30272321)
• Co-Investigator(Kenkyū-buntansha): 岩澤 俊一郎 千葉大学, 医学部附属病院, 講師 (00527913) ; 関根 郁夫 筑波大学, 医学医療系, 教授 (10508310)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 上皮間葉移行 / TGF / FGF / EGFR / メトホルミン / ニンテダニブ / ピルフェニドン / pirfenidone / nintedanib / MET / 上記間葉転換 / がん / 化学療法 / PD-1 / metformin / mTOR阻害薬 / 薬剤耐性 / mTOR経路

Outline of Final Research Achievements

Epithelial-to-mesenchymal transition (EMT) is a malignant cancer phenotype. Two human lung adenocarcinoma cell lines with an EGFR mutation, PC-9 and HCC-827, were treated with TGF-b; and FGF-2 to induce EMT. A combination of TGF-beta and FGF-2 efficiently induced EMT in both cell lines: through Smad3 pathway in PC-9, and through Smad3, MEK/Erk, and mTOR pathways in HCC-827. The mTOR inhibitor PP242, metformin, and DMSO reverted EMT to different extents and through different pathways, depending on cell lines. EMT induction reduced the sensitivity to gefitinib in both cell lines and to cisplatin in HCC-827, and it increased PD-L1 expression in both cell lines. EMT reversion using each of the 3 agents partly restored chemosensitivity and suppressed PD-L1 expression. In addition, pirfenidone and nintedanib also reverted EMT. These findings suggest that EMT would be a good candidate for targeting cancer therapy.

Research Products

• [Journal Article] Mefenamic acid enhances anticancer drug sensitivity via inhibition of aldo-keto reductase 1C enzyme activity. (2017)
  • Author(s): Shiiba, M., Yamagami, H., Yamamoto, A., Minakawa, Y., Okamoto, A., Kasamatsu, A., Sakamoto, Y., Uzawa, K., Takiguchi, Y. and Tanzawa, H.
  • Journal Title: Oncol Rep Volume: 37 Issue: 4 Pages: 2025-2032
  • DOI: 10.3892/or.2017.5480
  • Peer Reviewed / Open Access
• [Journal Article] Potential Activity of Amrubicin as a Salvage Therapy for Merkel Cell Carcinoma (2017)
  • Author(s): Sakaida, E., Ebata, T., Iwasawa, S., Kurimoto, R., Yonemori, S., Ota, S., Nakatani, Y., Sekine, I. and Takiguchi, Y.
  • Journal Title: Internal Medicine Volume: 56 Issue: 5 Pages: 567-570
  • DOI: 10.2169/internalmedicine.56.7675
  • NAID: 130005399427
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Megalin Blockade with Cilastatin Suppresses Drug-Induced Nephrotoxicity. (2017)
  • Author(s): Hori Y, Aoki N, Kuwahara S, Hosojima M, Kaseda R, Goto S, Iida T, De S, Kabasawa H, Kaneko R, Aoki H, Tanabe Y, Kagamu H, Narita I, Kikuchi T, Saito A.
  • Journal Title: J Am Soc Nephrol. Volume: January 4 Issue: 2 Pages: 227-234
  • DOI: 10.1007/s10637-017-0436-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Concordance between PIK3CA mutations in endoscopic biopsy and surgically resected specimens of esophageal squamous cell carcinoma. (2017)
  • Author(s): Hatogai, K., Fujii, S., Kojima, T., Daiko, H., Doi, T., Ohtsu, A., Ochiai, A., Takiguchi, Y. and Yoshino, T.
  • Journal Title: BMC Cancer Volume: 17 Issue: 1 Pages: 36-36
  • DOI: 10.1186/s12885-016-3041-3
  • Peer Reviewed / Open Access
• [Journal Article] Pirfenidone may revert the epithelial-to-mesenchymal transition in human lung adenocarcinoma (2017)
  • Author(s): Kurimoto, R., Ebata, T., Iwasawa, S., Ishiwata, T., Tada, Y,, Tatsumi, K and Takiguchi, y.
  • Journal Title: Oncol Rep Volume: 37
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A Dilemma on Re-biopsy in the Era of Precision Cancer Therapy (2016)
  • Author(s): Takiguchi, Y
  • Journal Title: Internal Medicine Volume: 55 Issue: 13 Pages: 1683-1684
  • DOI: 10.2169/internalmedicine.55.6567
  • NAID: 130005161011
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Anamorelin (ONO-7643) in Japanese patients with non-small cell lung cancer and cachexia: results of a randomized phase 2 trial. (2016)
  • Author(s): Takayama, K., Katakami, N., Yokoyama, T., Atagi, S., Yoshimori, K., Kagamu, H., Saito, H., Takiguchi, Y., Aoe, K., Koyama, A., Komura, N. and Eguchi, K
  • Journal Title: Supportive care in cancer Volume: NA Issue: 8 Pages: 1-11
  • DOI: 10.1007/s00520-016-3144-z
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Quality of life and survival survey of cancer cachexia in advanced non-small cell lung cancer patients-Japan nutrition and QOL survey in patients with advanced non-small cell lung cancer study. (2016)
  • Author(s): Takayama, K., Atagi, S., Imamura, F., Tanaka, H., Minato, K., Harada, T., Katakami, N., Yokoyama, T., Yoshimori, K., Takiguchi, Y., Hataji, O., Takeda, Y., Aoe, K., Kim, Y.H., Yokota, S., Tabeta, H., Tomii, K., Ohashi, Y., Eguchi, K. and Watanabe, K.
  • Journal Title: Supportive care in cancer Volume: NA Issue: 8 Pages: 1-8
  • DOI: 10.1007/s00520-016-3156-8
  • Peer Reviewed
• [Journal Article] Safety of a short hydration method for cisplatin administration in comparison with a conventional method―a retrospective study. (2016)
  • Author(s): Sakaida, E., Iwasawa, S., Kurimoto, R., Ebata, T., Imai, C., Oku, T., Sekine, I., Tada, Y., Tatsumi, K. and Takiguchi, Y.
  • Journal Title: Japanese Journal of Clinical Oncology. Volume: 46 Issue: 4 Pages: 370-377
  • DOI: 10.1093/jjco/hyv203
  • Peer Reviewed
• [Journal Article] Drug resistance originating from a TGF-beta/FGF-2-driven epithelial-to-mesenchymal transition and its reversion in human lung adenocarcinoma cell lines harboring an EGFR mutation. (2016)
  • Author(s): Kurimoto, R., Iwasawa, S., Ebata, T., Ishiwata, T., Sekine, I., Tada, Y., Tatsumi, K., Koide, S., Iwama, A. and Takiguchi, Y.
  • Journal Title: International journal of oncology Volume: 48 Issue: 5 Pages: 1825-1836
  • DOI: 10.3892/ijo.2016.3419
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Prophylactic dexamethasone for radiation-induced bone-pain flare. (2016)
  • Author(s): Ishiwata, T., Iwasawa, S., Kurimoto, R., Ebata, T. and Takiguchi, Y.
  • Journal Title: The Lancet. Oncology Volume: 17 Issue: 2 Pages: e39-e40
  • DOI: 10.1016/s1470-2045(15)00622-1
  • Peer Reviewed
• [Journal Article] Retrospective analysis of unknown primary cancers with malignant pleural effusion at initial diagnosis. (2016)
  • Author(s): Ebata, T., Okuma, Y., Nakahara, Y., Yomota, M., Takagi, Y., Hosomi, Y., Asami, E., Omuro, Y., Hishima, T., Okamura, T. and Takiguchi, Y.
  • Journal Title: Thorac Cancer Volume: 7 Issue: 1 Pages: 39-43
  • DOI: 10.1111/1759-7714.12271
  • Peer Reviewed
• [Journal Article] Multicenter Phase II Study of Nedaplatin and Irinotecan for Patients with Squamous Cell Carcinoma of the Lung: Thoracic Oncology Research Group 0910. (2015)
  • Author(s): YAMADA, K., SAITO, H., KONDO, T., MURAKAMI, S., MASUDA, N., YAMAMOTO, M., IGAWA, S., KATONO, K., TAKIGUCHI, Y., IWASAWA, S., KURIMOTO, R., OKAMOTO, H., SHIMOKAWA, T., HOSOMI, Y., TAKAGI, Y., KISHI, K., OHBA, M., OSHITA, F. and WATANABE, K.
  • Journal Title: Anticancer Research Volume: 35 Pages: 6705-6711
  • Peer Reviewed
• [Journal Article] Phase II study of carboplatin, docetaxel and bevacizumab for chemotherapy-naive patients with advanced non-squamous non-small cell lung cancer. (2015)
  • Author(s): Takiguchi, Y., Iwasawa, S., Minato, K., Miura, Y., Gemma, A., Noro, R., Yoshimori, K., Shingyoji, M., Hino, M., Ando, M. and Okamoto, H.
  • Journal Title: Int J Clin Oncol Volume: 20 Issue: 4 Pages: 659-667
  • DOI: 10.1007/s10147-014-0755-6
  • Peer Reviewed
• [Journal Article] Development of medicines for enhancing chemo-sensitivity and radio-sensitivity and uppression of metastasis of cancer cells by drug repositioning method (2015)
  • Author(s): Shiiba, M., Uzawa, K., Kasamatsu, A., Endo-Sakamoto, Y., Takiguchi, Y., Tanzawa, H. and Fujita, S.
  • Journal Title: Journal of The Japanese Stomatological Society Volume: 64 Issue: 3 Pages: 254-261
  • DOI: 10.11277/stomatology.64.254
  • NAID: 130005100733
  • ISSN: 0029-0297, 2185-0461
  • Peer Reviewed
• [Journal Article] Interleukin-1 receptor antagonist (IL1RN) is associated with suppression of early carcinogenic events in human oral malignancies. (2015)
  • Author(s): hiiba, M., Saito, K., Yamagami, H., Nakashima, D., Higo, M., Kasamatsu, A., Sakamoto, Y., Ogawara, K., Uzawa, K., Takiguchi, Y. and Tanzawa, H.
  • Journal Title: International journal of oncology Volume: 46 Issue: 5 Pages: 1978-1984
  • DOI: 10.3892/ijo.2015.2917
  • Peer Reviewed
• [Journal Article] Alveolar Hemorrhage Associated with Pemetrexed Administration (2015)
  • Author(s): Kurimoto, R., Sekine, I., Iwasawa, S., Sakaida, E., Tada, Y., Tatsumi, K., Takahashi, Y., Nakatani, Y., Imai, C. and Takiguchi, Y.
  • Journal Title: Internal Medicine Volume: 54 Issue: 7 Pages: 833-836
  • DOI: 10.2169/internalmedicine.54.3414
  • NAID: 130005063209
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed
• [Journal Article] A randomized phase III trial of oral S-1 plus cisplatin versus docetaxel plus cisplatin in Japanese patients with advanced non-small-cell lung cancer: TCOG0701 CATS trial. (2015)
  • Author(s): Kubota, K., Sakai, H., Katakami, N., Nishio, M., Inoue, A., Okamoto, H., Isobe, H., Kunitoh, H., Takiguchi, Y., Kobayashi, K., Nakamura, Y., Ohmatsu, H., Sugawara, S., Minato, K., Fukuda, M., Yokoyama, A., Takeuchi, M., Michimae, H., Gemma, A. and Kudoh, S.
  • Journal Title: Annals of Oncology Volume: 26 Issue: 7 Pages: 1401-1408
  • DOI: 10.1093/annonc/mdv190
  • Peer Reviewed
• [Journal Article] Decorin in human oral cancer: a promising predictive biomarker of S-1 neoadjuvant chemosensitivity. (2015)
  • Author(s): Kasamatsu, A., Uzawa, K., Minakawa, Y., Ishige, S., Kasama, H., Endo-Sakamoto, Y., Ogawara, K., Shiiba, M., Takiguchi, Y. and Tanzawa, H.
  • Journal Title: Biochemical and biophysical research communications. Volume: 457 Issue: 1 Pages: 71-76
  • DOI: 10.1016/j.bbrc.2014.12.093
  • Peer Reviewed
• [Journal Article] Crizotinib-Induced Abnormal Signal Processing in the Retina. (2015)
  • Author(s): Ishii, T., Iwasawa, S., Kurimoto, R., Maeda, A., Takiguchi, Y. and Kaneda, M.
  • Journal Title: PloS one Volume: 10 Issue: 8 Pages: e0135521-e0135521
  • DOI: 10.1371/journal.pone.0135521
  • Peer Reviewed / Open Access
• [Journal Article] Incidence, risk factors and treatment outcomes of extravasation of cytotoxic agents in an outpatient chemotherapy clinic (2014)
  • Author(s): Sakaida, E. Sekine, I. Iwasawa, S. Kurimoto, R. Uehara, T. Ooka, Y. Akanuma, N. Tada, Y. Imai, C. Oku, T. Takiguchi, Y.
  • Journal Title: Jpn J Clin Oncol Volume: 44 Issue: 2 Pages: 168-171
  • DOI: 10.1093/jjco/hyt186
  • Peer Reviewed
• [Journal Article] Transbronchial biopsy needle rinse solution used for comprehensive biomarker testing in patients with lung cancer. (2014)
  • Author(s): Sakairi Y, Sato K, Itoga S, Saegusa F, Matsushita K, Nakajima T, Yoshida S, Takiguchi Y, Nomura F, Yoshino I.
  • Journal Title: J Thorac Oncol. Volume: 9(1) Issue: 1 Pages: 26-32
  • DOI: 10.1097/jto.0000000000000024
  • Peer Reviewed
• [Journal Article] Detection of chronic obstructive pulmonary disease in community-based annual lung cancer screening: Chiba COPD lung cancer screening study group (2014)
  • Author(s): Sekine Y, Fujisawa T, Suzuki K, Tsutatani S, Kubota K, Ikegami H, Isobe Y, Nakamura M, Takiguchi, Y, Tatsumi K
  • Journal Title: Respirology Volume: 19 Issue: 1 Pages: 98-104
  • DOI: 10.1111/resp.12179
  • Peer Reviewed
• [Journal Article] Controlling distant metastasis and surgical treatment are crucial for improving clinical outcome in uncommon head and neck malignancies, such as non-squamous cell carcinoma (2014)
  • Author(s): Shiiba, M. Unozawa, M. Higo, M. Kouzu, Y. Kasamatsu, A. Sakamoto, Y. Ogawara, K. Uzawa, K. Takiguchi, Y. Tanzawa, H.
  • Journal Title: Mol Clin Oncol Volume: 2 Pages: 609-617
  • Peer Reviewed
• [Journal Article] Current Status of Medical Oncology in Japan―Reality Gleaned from a Questionnaire Sent to Designated Cancer Care Hospitals (2014)
  • Author(s): Takiguchi, Y. Sekine, I. Iwasawa, S. Kurimoto, R. Sakaida, E. Tamura, K.
  • Journal Title: Jpn J Clin Oncol Volume: 44 Issue: 7 Pages: 632-640
  • DOI: 10.1093/jjco/hyu059
  • Peer Reviewed
• [Journal Article] Chronic obstructive pulmonary disease as a risk factor for lung cancer (2014)
  • Author(s): Takiguchi, Y. Sekine, I. Iwasawa, S. Kurimoto, R. Tatsumi, K.
  • Journal Title: World J Clin Oncol Volume: 5 Issue: 4 Pages: 660-666
  • DOI: 10.5306/wjco.v5.i4.660
  • Peer Reviewed
• [Presentation] Alectinib (ALC) versus crizotinib (CRZ) in ALK-inhibitor naive ALK-positive non-small cell lung cancer (ALK+ NSCLC): Primary results from the J-ALEX study. (2016)
  • Author(s): Nokihara, H., Hida, T., Kondo, M., Hak Kim, Y., Azuma, K., Seto, T., Takiguchi, Y., Nishio, M., Yoshioka, H., Imamura, F., Hotta, K., Watanabe, S., Goto, K., Nakagawa, K., Mitsudomi, T., Yamamoto, N., Kuriki, H., Asabe, R., Tanaka, T. and Tamura, T.
  • Organizer: 2016 ASCO.
  • Place of Presentation: Chicago, IL, USA
  • Year and Date: 2016-06-03
  • Int'l Joint Research
• [Presentation] Alteration of drug sensitivity according to the induction and reversion of epithelial-to-mesenchymal transition (EMT) in human lung adenocarcinoma cell lines harboring an EGFR mutation (2016)
  • Author(s): Kurimoto, R., Iwasawa, S., Ebata, T., Ishiwata, T., Sekine, I., Tada, Y., Tatsumi, K., Koide, S., Iwama, A. and Takiguchi, Y.
  • Organizer: 2016 Annual Meeting: American Association for Cancer Research
  • Place of Presentation: New Orleans, LA, USA
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Presentation] Crizotinib disrupt visual processing in the mouse retina. (2015)
  • Author(s): Ishii, T., Iwasawa, S., Kurimoto, R., Maeda, A., Takiguchi, Y. and Kaneda, M.
  • Organizer: Neuroscience 2015
  • Place of Presentation: McCormick Place (Chicago, USA)
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] HSP90 inhibitor produced synergistic cytotoxicity with nutlin-3a on mesothelioma by inhibiting AKT and MDMX activities. (2015)
  • Author(s): Li, Z., Okamoto, S., Morinaga, T., Jiang, Y., Kubo, S., Sekine, I., Takiguchi, Y., Tada, Y., Tatsumi, K., Shimada, H., Hiroshima, K. and Tagawa, M.
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋コングレスセンター（愛知県・名古屋）
  • Year and Date: 2015-10-08
• [Presentation] Phase 2: Docetaxel with or without ramucirumab as therapy for nonsmall cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) activating mutations after prior EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy. (2015)
  • Author(s): Kasahara, K., K, K., Nogami, N., Takayama, K., Takiguchi, Y., Hirashima, T., Aoe, K., Hayashi, H., Saka, H., Takahashi, K., Imamura, F., Oizumi, S., Inoue, A., Satouchi, M., Tatsumi, M., Nakamura, T., Enatsu, S., Tamura, T. and Nakagawa, K.
  • Organizer: The 18th European Cancer Congress 2015
  • Place of Presentation: Messe Wien (Vienna, Austria)
  • Year and Date: 2015-09-25
  • Int'l Joint Research
• [Presentation] NEJ016: Phase II study of carboplatin and weekly paclitaxel plus bevacizumab followed by bevacizumab for highly selected elderly nonsquamous non-small cell lung cancer patients (2015)
  • Author(s): Harada, T., Miura, S., Maemondo, M., Iwashima, A., Sugawara, S., Kobayashi, K., Inoue, A., Nakagawa, T., Takiguchi, Y., Watanabe, H., Seike, M., Ishida, T., Terada, M., Gemma, A. and Yoshizawa, H.
  • Organizer: The 18th European Cancer Congress 2015.
  • Place of Presentation: Messe Wien (Vienna, Austria)
  • Year and Date: 2015-09-25
  • Int'l Joint Research
• [Presentation] Recent challange in the treatment of unresectable locally advanced lung cancer (International Symposium). (2015)
  • Author(s): Takiguchi, Y
  • Organizer: 第55回日本呼吸器学会学術講演会
  • Place of Presentation: 東京国際フォーラム（東京都・千代田区）
  • Year and Date: 2015-04-17
  • Invited
• [Presentation] Current status and controversies in chemoradiotherapy for locally advanced non-small cell lung cancer (JLCS/KASLC Joint-Symposium) (2014)
  • Author(s): Takiguchi, Y.
  • Organizer: 第55回日本肺癌学会学術集会
  • Place of Presentation: 国立京都国際会館（京都府・京都市）
  • Year and Date: 2014-11-14 – 2014-11-16
  • Invited
• [Presentation] Transduced p53 enhances cytotoxic effects achieved with oncolytic adenoviruses on pancreatic carcinoma cells (2014)
  • Author(s): Jiang, Y. Okamoto, S. Li, Z. Kubo, S. Sekine, I. Takiguchi, Y. Tada, Y. Tatsumi, K. Shimada, H. Hiroshima, K. Tagawa, M.
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Combination of nutlin-3a and Hsp90 inhibitors produces p53-dependent synergism on human mesothelioma cells (2014)
  • Author(s): Okamoto, S. Jiang, Y. Li, Z. Kubo, S. Sekine, I. Takiguchi, Y. Tada, Y. Tatsumi, K. Shimada, H. Hiroshima, K. Tagawa, M
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Multicenter phase II study of nedaplatin (NP) and irinotecan (CPT) for patients with advanced squamous cell cancer (SCC) of the Lung thoracic Oncology Research Group (TORG 0910). (2014)
  • Author(s): Saito, H. Yamada, K. Masuda, N. Takiguchi, Y. Hosomi, Y. Okamoto, H. Kishi, K. Oshita, F. Watanabe, K.
  • Organizer: 2014 Annual Meeting of American Society for Clinical Oncology
  • Place of Presentation: McCormick Place（Chicago, the United State of America）
  • Year and Date: 2014-05-30 – 2014-06-03