Development of innovative treatment targeting liver cancer associated fibroblast

Research Project

Project/Area Number	18K16299
Research Category	Grant-in-Aid for Early-Career Scientists
Allocation Type	Multi-year Fund
Review Section	Basic Section 55020:Digestive surgery-related
Research Institution	Gunma University
Principal Investigator	Tsukagoshi Mariko 群馬大学, 大学院医学系研究科, 助教 (60781317)
Project Period (FY)	2018-04-01 – 2020-03-31
Project Status	Completed (Fiscal Year 2019)
Budget Amount *help	¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000) Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000) Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords	癌関連線維芽細胞 / 肝癌 / Conophylline / 薬剤耐性 / サイトカイン / 癌微小環境 / 肝細胞癌 / 肝星細胞 / コノフィリン
Outline of Final Research Achievements	Hepatocellular carcinoma (HCC) is a malignancy that is challenging to treat. Cancer-associated fibroblasts (CAFs) are reported to promote the malignant behavior of HCC cells. Conophylline (CnP) has been reported to suppress activated hepatic stellate cells in liver fibrosis. We aimed to determine whether CnP is useful in suppressing tumor growth in HCC. CAFs promoted the proliferation and invasion of HCC cells. CnP suppressed activated CAFs and inhibited the HCC-promoting effects of CAFs. CnP significantly reduced the levels of cancer-promoting cytokines secreted by CAFs. An in vivo study demonstrated that combined therapy with CnP and sorafenib against CAFs and HCC cells showed the strongest inhibition of tumor growth compared with the control and single treatment groups. Combination therapy with CnP and existing anti-cancer agents may be a promising therapeutic strategy in overcoming refractory HCC with activated CAFs.
Academic Significance and Societal Importance of the Research Achievements	肝癌は予後不良で、明らかなウイルス肝炎感染を伴わない肝癌が増加傾向であり、新たな治療戦略が求められている。近年、癌の微小環境における癌細胞と周囲間質との相互作用の重要性が報告され、癌関連線維芽細胞(CAF)の機能が注目されている。本研究ではCAFの役割を明らかにし、Conophylline(CnP)の線維化抑制によるCAFの制御の可能性を検討し、肝癌に対する新たな治療戦略を開発することを目的とした。研究の結果、CnPによりCAFの活性が抑制され、肝癌の進展が抑制できる可能性が示された。今後、発癌の抑制や既存制癌剤併用による治療効果の増強など、革新的治療に結びつく可能性がある。