Impact of intraperitoneal tumor microenvironment on peritoneal dissemination of gastric cancer via involvement of extracellular vesicles

• Project/Area Number: 18K08679
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Okayama University
• Principal Investigator: Kagawa Shunsuke 岡山大学, 大学病院, 准教授 (00362971)
• Co-Investigator(Kenkyū-buntansha): 吉田 龍一 岡山大学, 大学病院, 助教 (80534768)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 胃癌 / 腹膜播種 / 細胞外小胞体 / 腫瘍微小環境 / 腫瘍関連マクロファージ / 癌微小環境 / マクロファージ / IL-6

Outline of Final Research Achievements

Macrophages promoting tumor progression are present in the peritoneal cavity of gastric cancer patients with peritoneal dissemination. In this study, we investigated the effect of gastric cancer-derived extracellular vesicles (EVs) on the mechanism by which macrophages differentiate into tumor-promoting forms. EV was extracted from ascites of the gastric cancer patient and culture supernatant of the gastric cancer cell. Their purified EVs induced differentiation into tumor-promoting macrophages when applied to peripheral blood mononuclear cells. Macrophages differentiated with gastric cancer-derived EVs promoted the migration of gastric cancer cells, and these EVs possessed STAT3 protein. These results suggest that gastric carcinoma-derived EVs can affect macrophage differentiation and are factors that form the peritoneal environment to promote tumors.

Academic Significance and Societal Importance of the Research Achievements

治療法の進歩にもかかわらず、胃癌の腹膜播種は今なお極めて難治である。新たな治療戦略の開発のために新たな病態の解明が求められている。その病態の新たな側面を解明するため、本研究では腹腔内環境に着目して解析した。我々の研究では胃癌患者の腹腔内に存在している細胞外小胞体が、マクロファージに作用し、腫瘍を促進する腹腔内環境の形成に加担していることを示すことができ、胃癌腹膜播種の病態解明につながる新しい知見が得られた。

Research Products

• [Journal Article] Extracellular vesicles shed from gastric cancer mediate protumor macrophage differentiation (2021)
  • Author(s): Ito Atene、Kagawa Shunsuke、Sakamoto Shuichi、Kuwada Kazuya、Kajioka Hiroki、Yoshimoto Masashi、Kikuchi Satoru、Kuroda Shinji、Yoshida Ryuichi、Tazawa Hiroshi、Fujiwara Toshiyoshi
  • Journal Title: BMC Cancer Volume: 21 Issue: 1 Pages: 102-114
  • DOI: 10.1186/s12885-021-07816-6
  • NAID: 120006980466
  • Peer Reviewed / Open Access
• [Journal Article] Targeting neutrophil extracellular traps with thrombomodulin prevents pancreatic cancer metastasis (2021)
  • Author(s): Kajioka Hiroki、Kagawa Shunsuke、Ito Atene、Yoshimoto Masashi、Sakamoto Shuichi、Kikuchi Satoru、Kuroda Shinji、Yoshida Ryuichi、Umeda Yuzo、Noma Kazuhiro、Tazawa Hiroshi、Fujiwara Toshiyoshi
  • Journal Title: Cancer Letters Volume: 497 Pages: 1-13
  • DOI: 10.1016/j.canlet.2020.10.015
  • NAID: 120007188794
  • Peer Reviewed
• [Journal Article] Clinical Impact of Sarcopenia on Gastric Cancer. (2019)
  • Author(s): Kuwada K, Kuroda S, Kikuchi S, Yoshida R, Nishizaki M, Kagawa S, Fujiwara T.
  • Journal Title: Anticancer Research Volume: 39 Issue: 5 Pages: 2241-2249
  • DOI: 10.21873/anticanres.13340
  • Peer Reviewed
• [Journal Article] Endoscopic Ultrasound-Guided Transgastric Drainage of an IntraAbdominal Abscess following Gastrectomy. (2019)
  • Author(s): Kikuchi S, Kubota T, Kuroda S, Nishizaki M, Kagawa S, Kato H, Okada H, Fujiwara T.
  • Journal Title: Clinical endoscopy Volume: 52 Issue: 4 Pages: 373-376
  • DOI: 10.5946/ce.2018.134
  • Peer Reviewed
• [Journal Article] Comparison of the Effects of Epidural Analgesia and Patient-controlled Intravenous Analgesia on Postoperative Pain Relief and Recovery After Laparoscopic Gastrectomy for Gastric Cancer. (2019)
  • Author(s): Kikuchi S, Kuroda S, Nishizaki M, Matsusaki T, Kuwada K, Kimura Y, Kagawa S, Morimatsu H, Fujiwara T.
  • Journal Title: Surgical laparoscopy, endoscopy & percutaneous techniques Volume: 29 Issue: 5 Pages: 405-408
  • DOI: 10.1097/sle.0000000000000605
• [Journal Article] Intraperitoneal cancer-immune microenvironment promotes peritoneal dissemination of gastric cancer. (2019)
  • Author(s): Sakamoto S, Kagawa S, Kuwada K, Ito A, Kajioka H, Kakiuchi Y, Watanabe M, Kagawa T, Yoshida R, Kikuchi S, Kuroda S, Tazawa H, Fujiwara T.
  • Journal Title: Oncoimmunology Volume: 8 Issue: 12 Pages: e1671760-e1671760
  • DOI: 10.1080/2162402x.2019.1671760
  • NAID: 120006767321
  • Peer Reviewed
• [Journal Article] Visualization of epithelial-mesenchymal transition in an inflammatory microenvironment?colorectal cancer network (2019)
  • Author(s): Ieda Takeshi、Tazawa Hiroshi、Okabayashi Hiroki、Yano Shuya、Shigeyasu Kunitoshi、Kuroda Shinji、Ohara Toshiaki、Noma Kazuhiro、Kishimoto Hiroyuki、Nishizaki Masahiko、Kagawa Shunsuke、Shirakawa Yasuhiro、Saitou Takashi、Imamura Takeshi、Fujiwara Toshiyoshi
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 16378-16378
  • DOI: 10.1038/s41598-019-52816-z
  • Peer Reviewed / Open Access
• [Journal Article] The epithelial-to-mesenchymal transition induced by tumor-associated macrophages confers chemoresistance in peritoneally disseminated pancreatic cancer (2018)
  • Author(s): Kuwada Kazuya、Kagawa Shunsuke、Yoshida Ryuichi、Sakamoto Shuichi、Ito Atene、Watanabe Megumi、Ieda Takeshi、Kuroda Shinji、Kikuchi Satoru、Tazawa Hiroshi、Fujiwara Toshiyoshi
  • Journal Title: Journal of Experimental & Clinical Cancer Research Volume: 37 Issue: 1 Pages: 307-307
  • DOI: 10.1186/s13046-018-0981-2
  • Peer Reviewed / Open Access
• [Journal Article] Integrated fluorescent cytology with nano-biologics in peritoneally disseminated gastric cancer. (2018)
  • Author(s): Watanabe M, Kagawa S, Kuwada K, Hashimoto Y, Shigeyasu K, Ishida M, Sakamoto S, Ito A, Kikuchi S, Kuroda S, Kishimoto H, Tomida S, Yoshida R, Tazawa H, Urata Y, Fujiwara T
  • Journal Title: Cancer Science Volume: 109 Issue: 10 Pages: 3263-3271
  • DOI: 10.1111/cas.13760
  • Peer Reviewed / Open Access
• [Presentation] 好中球細胞外トラップはHMGB1 を介して膵癌にEMT を誘導し，肝転移を助長する (2020)
  • Author(s): 梶岡裕紀、香川俊輔、田澤大、國土泰孝、村岡篤、藤原俊義
  • Organizer: 第120回日本外科学会学術集会
• [Presentation] 好中球と血小板の相互作用が胆管癌の悪性形質転換を促進する (2020)
  • Author(s): 吉本匡志、香川俊輔、梶原義典、西山岳芳、李云成、岡林弘樹、菊地覚次、黒田新士、田澤大、藤原俊義
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] The reciprocal interaction between neutrophil extracellular traps and cancer cells impact on their malignant potentials (2019)
  • Author(s): H. Kajioka, S. Kagawa, A. ito, K. Kuwada, S. Kikuchi, S. Kuroda, R. Yoshida, H. Tazawa, T. Fujiwara
  • Organizer: AACR Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] Neutrophil extracellular traps promote liver metastasis of gastrointestinal cancer through the induction of EMT. (2019)
  • Author(s): H. Kajioka, S. Kagawa, A. Ito, K. Kuwada, S. Kikuchi, S. Kuroda, R. Yoshida, H. Tazawa, T. Fujiwara
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Extracellular vesicles in the ascites from gastric cancer patients play critical roles to promote peritoneal dissemination in the intraperitoneal cancer microenvironment (2018)
  • Author(s): Atene Ito, shunsuke kagawa, Shuichi Sakamoto, Kazuya Kuwada, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Hiroshi Tazawa and Toshiyoshi Fujiwara
  • Organizer: AACR Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] IL6 derived from intraperitoneal macrophages is involved in peritoneal dissemination of gastric cancer (2018)
  • Author(s): Shunsuke Kagawa, Shuichi Sakamoto, Kazuya Kuwada, Atene Ito, Hiroki Kajioka, Shinji Kuroda, Satoru Kikuchi, Ryuichi Yoshida, Hiroshi Tazawa, Toshiyoshi Fujiwara
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Extracellular vesicles from gastric cancer promote peritoneal dissemination via M2 differentiation of macrophages. (2018)
  • Author(s): Atene Ito, Shunsuke Kagawa, Hiroki Kajioka, Shuichi Sakamoto, Kazuya Kuwada, Satoru Kikuchi, Shinji Kuroda, Masahiko Nishizaki, Ryuichi Yoshida, Hiroshi Tazawa, Toshiyoshi Fujiwara
  • Organizer: 第77回日本癌学会学術総会