Identification of molecular mechanism underlying inflammatory-related carcinogenesis through activating the stroma in gastric cancer

• Project/Area Number: 18K08543
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Kumamoto University
• Principal Investigator: Miyake Keisuke 熊本大学, 病院, リサーチ・スペシャリスト (10814759)
• Co-Investigator(Kenkyū-buntansha): 石本 崇胤 熊本大学, 病院, 特任准教授 (00594889) ; 有馬 浩太 熊本大学, 病院, 非常勤診療医師 (10792616) ; 泉 大輔 熊本大学, 病院, 非常勤診療医師 (60594877) ; 今村 裕 公益財団法人がん研究会, 有明病院 消化器外科, 医長 (70583045) ; 日比 泰造 熊本大学, 大学院生命科学研究部(医), 教授 (10338072)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 胃癌 / 癌関連線維芽細胞 / 腫瘍間質 / 胃がん / 癌関連繊維芽細胞 / 炎症 / 繊維芽細胞 / 腫瘍微小環境 / ストローマ細胞 / 炎症性発癌

Outline of Final Research Achievements

The purpose of this study was to clarify the molecular mechanism of gastric cancer carcinogenesis and progression caused as a result of stromal cell reactivity and stromal activation in an inflammatory environment. First, fibroblasts were stimulated with inflammatory cytokines, and the culture supernatant was used to stimulate gastric cancer cells. As a result, the cytokine-stimulated culture supernatant was more proliferative and infiltrative than the unstimulated culture supernatant. It turned out to promote. Subsequent comprehensive gene expression analysis by RNA-Seq revealed that activated fibroblasts promote the growth of gastric cancer through the secretion of IL-6, IL-24 and LIF. From the above results, it was clarified that chronic inflammation activates fibroblasts and enhances the growth and infiltration of gastric cancer through secretions at present.

Academic Significance and Societal Importance of the Research Achievements

これまで腫瘍微小環境に存在する線維芽細胞（CAFs）の働きによって癌細胞の増殖・浸潤が増長されることが報告されてきたが、本研究によって慢性炎症による繊維芽細胞の活性化が癌細胞のさらなる増殖・浸潤の増長を引き起こすことを明らかにした。

Research Products

• [Journal Article] Inflammation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination (2021)
  • Author(s): Yasuda T, Koiwa M, Yonemura A, Miyake K, Kariya R, Kubota S, Yokomizo-Nakano T, Yasuda-Yoshihara N, Uchihara T, Itoyama R, Bu L, Fu L, Arima K, Izumi D, Iwagami S, Eto K, Iwatsuki M, Baba Y, Yoshida N, Ohguchi H, Okada S, Matsusaki K, Sashida G, Takahashi A, Tan P, Baba H, Ishimoto T.
  • Journal Title: Cell Reports Volume: 34 Issue: 8 Pages: 108779-108779
  • DOI: 10.1016/j.celrep.2021.108779
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Extracellular Vesicles from Cancer-Associated Fibroblasts Containing Annexin A6 Induces FAK-YAP Activation by Stabilizing β1 Integrin, Enhancing Drug Resistance (2020)
  • Author(s): Uchihara T, Miyake K, Yonemura A, Komohara Y, Itoyama R, Koiwa M, Yasuda T, Arima K, Harada K, Eto K, Hayashi H, Iwatsuki M, Iwagami S, Baba Y, Yoshida N, Yashiro M, Masuda M, Ajani Jaffer A, Tan Patrick, Baba H, Ishimoto T
  • Journal Title: Cancer Research Volume: 80 Issue: 16 Pages: 3222-3235
  • DOI: 10.1158/0008-5472.can-19-3803
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Biological heterogeneity and versatility of cancer-associated fibroblasts in the tumor microenvironment. (2019)
  • Author(s): Bu L, Baba H, Yoshida N, Miyake K, Yasuda T, Uchihara T, Tan P, Ishimoto T
  • Journal Title: Oncogene Volume: 38 Pages: 4887-4901
  • Peer Reviewed
• [Journal Article] Inhibition of 15-PGDH causes Kras-driven tumor expansion through prostaglandin E2-ALDH1 signaling in the pancreas (2018)
  • Author(s): Arima Kota、Ohmuraya Masaki、Miyake Keisuke、Koiwa Mayu、Uchihara Tomoyuki、Izumi Daisuke、Gao Feng、Yonemura Atsuko、Bu Luke、Okabe Hirohisa、Imai Katsunori、Hashimoto Daisuke、Baba Yoshifumi、Chikamoto Akira、Yamashita Yo-ichi、Furukawa Toru、Araki Kimi、Baba Hideo、Ishimoto Takatsugu
  • Journal Title: Oncogene Volume: 38 Issue: 8 Pages: 1211-1224
  • DOI: 10.1038/s41388-018-0510-y
  • Peer Reviewed
• [Presentation] 腫瘍微小環境に依存する胃がん浸潤性増殖機構の解明 (2019)
  • Author(s): 石本 崇胤、三宅 慧輔、米村 敦子、安田 忠仁、伊東山 瑠美、内原 智幸、吉田 直矢、馬場 秀夫
  • Organizer: 第78回 日本癌学会学術総会
• [Presentation] Activated-stroma by cancer-related inflammation enhances gastric cancer progression through activation of STAT1/3 signaling (2018)
  • Author(s): 三宅 慧輔、内原 智幸、江藤 二男、有馬 浩太、安田 忠仁、付 凌峰、米村 敦子、岩槻 政晃、馬場 祥史、宮本 裕士、吉田 直矢、馬場 秀夫、石本 崇胤
  • Organizer: 第41回日本分子生物学会