Development of novel therapeutic agents targeting cancer-associated fibroblasts (CAFs) via suppression of fibrosis in pancreatic cancer.

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K16529
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Gunma University
• Principal Investigator: Araki Kenichiro 群馬大学, 大学院医学系研究科, 助教 (60431706)
• Research Collaborator: Shirabe Ken ; Ishii Norihiro ; Harimoto Norifumi ; Kubo Norio ; Watanabe Akira ; Igarashi Takamichi ; Tsukagoshi Mariko ; Umezawa Kazuo
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: 癌関連線維芽細胞 / コノフィリン / 膵癌

Outline of Final Research Achievements

Cancer-associated fibroblasts (CAF) are responsible for fibrotic stroma and promote cancer progression. Conophylline (CnP) extracted from the leaves of a tropical plant reduced liver and pancreatic fibrosis by suppression of stellate cells. We showed that CAF stimulated indicators of pancreatic cancer malignancy, such as proliferation, invasiveness, and chemoresistance. CnP suppressed CAF activity and proliferation, and inhibited the stimulating effects of CAF on pancreatic cancer cells. CnP decreased the various cytokines involved in cancer progression, such as IL-6, IL-8, CCL2, and CXCL12, secreted by CAF. In vivo, CAF promoted tumor proliferation and desmoplastic formation in a mouse xenograft model, CnP reduced desmoplasia of tumors composed of pancreatic cancer cells + CAF, and combination therapy of CnP with gemcitabine inhibited tumor proliferation. CnP is a therapeutic strategy of combination therapy with anticancer drugs to overcome refractory pancreatic cancers.

Free Research Field

消化器外科学

Academic Significance and Societal Importance of the Research Achievements

コノフィリンによる線維化抑制作用により、膵癌の癌関連線維芽細胞（CAF）が制御され、膵癌の増殖や腫瘍進展が抑制された。またコノフィリンによってCAFから分泌が抑制されるサイトカインを同定し、一連の作用機序が解明された。細胞・動物実験ともに制癌剤耐性実験から制癌剤にコノフィリンを併用することによる治療効果の上乗せが確認された。よって、膵癌の既存治療にはない革新的な治療に結びつく可能性がある。