Investigation in the microenvironment of lung cancer and malignant pleural mesothelioma for the development of biomarker for the resistance to bevacizumab

• Project/Area Number: 26461191
• 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: The University of Tokushima
• Principal Investigator: GOTO Hisatsugu 徳島大学, 大学院医歯薬学研究部(医学系), 講師 (00437641)
• Co-Investigator(Kenkyū-buntansha): 埴淵 昌毅 徳島大学, 大学院医歯薬学研究部(医学系), 准教授 (80335794) ; 柿内 聡司 徳島大学, 大学院医歯薬学研究部(医学系), 非常勤講師 (50380100)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肺癌 / 悪性胸膜中皮腫 / 血管新生阻害薬 / 薬剤耐性 / 血管新生阻害剤

Outline of Final Research Achievements

This study aimed to clarify the mechanism of resistance to anti-angiogenic therapy in cancer. Bevacizumab exerts anti-angiogenic effects in cancer patients by inhibiting vascular endothelial growth factor (VEGF). However, its use is still limited due to the development of resistance to the treatment. In this study, using mouse model of malignant pleural mesothelioma, we found that fibroblast growth factor (FGF) 2 played important role in the resistance to bevacizumab. We identified fibrocytes as the producer of FGF2 in the tumor tissue. In clinical specimens of lung cancer, the number of fibrocyte was significantly increased in bevacizumab-treated tumors, and is correlated with the number of treatment cycles, as well as CD31-positive vessels. Our results identify fibrocytes as a promising cell biomarker and a potential therapeutic target to overcome resistance to anti-VEGF therapy.

Research Products

• [Journal Article] Fibrocyte-like cells mediate acquired resistance to anti-angiogenic therapy with bevacizumab (2015)
  • Author(s): Mitsuhashi A, Goto H, Saijo A, Trung VT, Aono Y, Ogino H, Kuramoto T, Tabata S, Uehara H, Izumi K, Yoshida M, Kobayashi H, Takahashi H, Gotoh M, Kakiuchi S, Hanibuchi M, Yano S, Yokomisa H, Sakiyama S, Nishioka Y
  • Journal Title: Nature Communications Volume: 6 Issue: 1 Pages: 8792-8792
  • DOI: 10.1038/ncomms9792
  • NAID: 120006999406
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Fibrocytes mediate acquired resistance to anti-angiogenic therapy with bevacizumab in thoracic tumors. (2016)
  • Author(s): Goto H, Mitsuhashi A, Saijo A, Kuramoto T, Tabata T, Aono Y, Uehara H, Hanibuchi M, Nishioka Y．
  • Organizer: ATS 2016 International Conference
  • Place of Presentation: サンフランシスコ（アメリカ合衆国）
  • Year and Date: 2016-05-15
  • Int'l Joint Research
• [Presentation] Mechanisms of acquired resistance to anti-angiogenic therapy and new insights toward the overcoming (2015)
  • Author(s): Yasuhiko Nishioka, Hisatsugu Goto
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08
  • Invited
• [Presentation] The role of fibrocytes in the resistance to anti-angiogenic therapy in malignant pleural mesothelioma and lung cancer (2015)
  • Author(s): Hisatsugu Goto, Atsushi Mitsuhashi, Atsuro Saijo, Yoshinori Aono, Hirokazu Ogino, Hirohisa Ogawa, Soji Kakiuchi, Masaki Hanibuchi, Yasuhiko Nishioka
  • Organizer: International Conference of Cancer Immunotherapy and Macrophages 2015
  • Place of Presentation: 東京大学伊藤国際学術センター（東京都文京区）
  • Year and Date: 2015-07-09
  • Int'l Joint Research
• [Presentation] 線維細胞（fibrocytes）が関わる血管新生阻害剤に対する獲得耐性メカニズム (2015)
  • Author(s): 三橋 惇志、後東 久嗣、西條 敦郎、埴淵 昌毅、西岡 安彦
  • Organizer: 第19回日本がん分子標的治療学会学術集会
  • Place of Presentation: 松山全日空ホテル（愛媛県松山市）
  • Year and Date: 2015-06-11
• [Presentation] The Role of Fibrocytes in the Acquired Resistance to Anti-Angiogenic Therapy with Bevacizumab in Malignant Pleural Mesothelioma (2015)
  • Author(s): Hisatsugu Goto, Atsushi Mitsuhashi, Atsuro Saijo, Takuya Kuramoto, Sho Tabata, Yoshinori Aono, Hisanori Uehara, Soji Kakiuchi, Masaki Hanibuchi, Yasuhiko Nishioka
  • Organizer: American Thoracic Society 2015 International Conference
  • Place of Presentation: Denｖer（アメリカ合衆国）
  • Year and Date: 2015-05-17
  • Int'l Joint Research
• [Presentation] Fibrocytes mediate acquired resistance to anti-angiogenic therapy with bevacizumab (2015)
  • Author(s): Hisatsugu Goto, Atsushi Mitsuhashi, Atsuro Saijo, Takuya Kuramoto, Sho Tabata, Yoshinori Aono, Soji Kakiuchi, Masaki Hanibuchi, Yasuhiko Nishioka
  • 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: 2015-04-18
• [Presentation] ベバシズマブに対する獲得耐性メカニズムとしての線維細胞（fibrocytes）の役割 (2014)
  • Author(s): 後東久嗣
  • 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: 2014-09-27
• [Presentation] ベバシズマブに対する獲得耐性メカニズムとしての線維細胞（fibrocytes）の役割 (2014)
  • Author(s): 後東久嗣
  • Organizer: 第18回日本がん分子標的治療学会学術集会
  • Place of Presentation: 仙台市情報・産業プラザ（宮城県仙台市）
  • Year and Date: 2014-06-27
• [Presentation] The role of fibrocytes in the resistance to anti-angiogenic therapy in malignant pleural mesothelioma and lung cancer. (2014)
  • Author(s): Hisatsugu Goto
  • Organizer: ATS 2014 International Conference
  • Place of Presentation: San Diego, CA
  • Year and Date: 2014-05-21
• [Presentation] 呼吸器疾患における慢性炎症と fibrocyte (2014)
  • Author(s): 後東久嗣
  • Organizer: 第54回日本呼吸器学会学術講演会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2014-04-27
• [Book] 分子呼吸器病 (2017)
  • Author(s): 後東久嗣，三橋惇志，西岡安彦
  • Total Pages: 119
  • Publisher: 先端医学社
• [Book] 分子呼吸器病 (2016)
  • Author(s): 後東久嗣，三橋敦志，西岡安彦
  • Total Pages: 137
  • Publisher: 先端医学社
• [Book] 呼吸と循環 (2016)
  • Author(s): 後東久嗣，青野純典，三橋惇志，西岡安彦
  • Total Pages: 208
  • Publisher: 医学書院
• [Book] 医学のあゆみ (2015)
  • Author(s): 後東 久嗣、西岡 安彦
  • Total Pages: 70
  • Publisher: 医歯薬出版株式会社
• [Remarks] 徳島大学大学院医歯薬学研究部呼吸器・膠原病内科学分野ホームページ
  • URL: http://www.sannai.umin.jp/