Impact of chemokine signals in the tumor microenvironment of pancreatic cancer

• Project/Area Number: 16K07109
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Juntendo University (2017-2018); The University of Tokyo (2016)
• Principal Investigator: ISAYAMA Hiroyuki 順天堂大学, 医学部, 教授 (70376458)
• Co-Investigator(Kenkyū-buntansha): 伊地知 秀明 東京大学, 医学部附属病院, 講師 (70463841)
• Research Collaborator: SANO Makoto
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 膵癌 / ケモカインシグナル / CXCR2 / ノックアウトマウス / 膵発癌モデル / 微小環 / 微小環境 / CCR2 / ケモカイン

Outline of Final Research Achievements

Pancreatic cancer is one of the most deadly cancers. Understanding the biology and development of therapeutics contributing to the prognosis are urgently needed. Previously, we found that both pancreatic cancer cells and cancer-associated fibroblasts produce CXC chemokines that enhance cell invasion and migration each other, thereby promoting cancer progression. In this study, global Cxcr2 heterozygous knockout in a clinically-relevant murine pancreatic cancer model was achieved and analyzed. It demonstrated significant survival extension of the cancer-bearing mice, accompanied by decreased microvessel invasion of the cancer cells. We also observed a shift of immune-inflammatory microenvironment: decreased tumor-infiltrated neutrophils and myeloid-derived suppressor cells (MDSCs) and increased M1/M2 ratio of the tumor-infiltrated macrophages, which resulted in increased apoptosis of the tumor cells.

Academic Significance and Societal Importance of the Research Achievements

膵癌は、最も予後不良な最難治癌であり、罹患数・癌死数とも増加の一途を示しているため、膵癌の病態理解および予後改善につながる知見は、社会的にもインパクトが大きい。膵癌は間質の増生・著明な線維化が組織学的に大きな特徴であり、癌の微小環境における腫瘍・間質間の相互作用が予後を含めた病態に深く関わっていると考えられるが、間質をいかに制御すべきかについてはまだ確立されていない。本研究では、CXCケモカインシグナル阻害による腫瘍間質相互作用の抑制が、膵癌における免疫炎症系微小環境のシフトを生じ、生命予後改善に寄与することが示され、微小環境の制御を通じた膵癌制御の新たなメカニズムを示した。

Research Products

• [Journal Article] Blocking CXCLs?CXCR2 axis in tumor?stromal interactions contributes to survival in a mouse model of pancreatic ductal adenocarcinoma through reduced cell invasion/migration and a shift of immune-inflammatory microenvironment (2019)
  • Author(s): Sano Makoto、Ijichi Hideaki、Takahashi Ryota、Miyabayashi Koji、Fujiwara Hiroaki、Yamada Tomoharu、Kato Hiroyuki、Nakatsuka Takuma、Tanaka Yasuo、Tateishi Keisuke、Morishita Yasuyuki、Moses Harold L.、Isayama Hiroyuki、Koike Kazuhiko
  • Journal Title: Oncogenesis Volume: 8 Issue: 2 Pages: 8-8
  • DOI: 10.1038/s41389-018-0117-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Blocking CXCLs-CXCR2 axis in tumor-stromal interaction contributes to the survival in a mouse model of pancreatic cancer (2018)
  • Author(s): 佐野誠、伊地知秀明、立石敬介、多田稔、小池和彦
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 膵癌におけるCXCLs/CXCR2阻害は癌免疫環境を修飾し生存に寄与する (2018)
  • Author(s): 佐野誠、伊地知秀明、立石敬介、多田稔、伊佐山浩通、小池和彦
  • Organizer: 第49回日本膵臓学会大会
• [Presentation] Blocking CXCLs-CXCR2 axis contributes to the survival in a mouse model of pancreatic ductal adenocarcinoma via reduced invasion and a shift of immune-inflammatory microenvironment (2018)
  • Author(s): Sano Makoto, Ijichi Hideaki , Takahashi Ryota, Miyabayashi Koji, Tateishi Keisuke, Isayama Hiroyuki, Harold L Moses, Koike Kazuhiko
  • Organizer: AACR Special Conference: Pancreatic Cancer 2018
  • Int'l Joint Research