Elucidation of the regulatory mechanism of pancreatic cancer and development of novel therapeutic agents through cellular senescence of pancreatic stellate cells

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15956
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Tohoku University
• Principal Investigator: Tetsuya Takikawa 東北大学, 大学病院, 助教 (70836882)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: 膵癌 / 膵星細胞 / 細胞老化 / がん微小環境

Outline of Final Research Achievements

Human pancreatic stellate cells (hPSCs) were treated with hydrogen peroxide and gemcitabine to create senescent hPSCs. Treatment with the conditioned medium from senescent hPSCs enhanced the proliferation, migration, and invasion abilities of pancreatic cancer cells. A comparison of gene profiles between senescent and non-senescent hPSCs revealed an increase in chemokines such as CXCL1, CXCL2, and CXCL3. Inhibitors of these chemokines canceled the enhancing effects of the senescent hPSC conditioned medium on the proliferation, migration, and invasion abilities of pancreatic cancer cells. These findings suggest that senescent hPSCs may contribute to the acquisition of malignancy in pancreatic cancer cells via chemokines. We plan to search for senolytic drugs that selectively eliminate senescent hPSCs.

Free Research Field

膵がん

Academic Significance and Societal Importance of the Research Achievements

膵癌は早期診断が困難な上に化学療法や放射線療法の効果も限定的であるため、その5年
生存率は10%にも満たない。膵星細胞（PSC）は膵癌周囲の線維性間質形成に中心的な役割を果たしている細胞である。PSCには癌促進的PSCとが癌抑制的PSCが存在することが明らかになってきており、癌促進的PSCを選択的に死滅させる薬剤の開発が求められている。
近年、他の癌腫で癌周囲の老化細胞と癌細胞の制御機構の存在が報告されているが、PSCにおける細胞老化の意義は不明な点が多い。本研究は、老化PSCと膵癌細胞という新しい膵癌制御機構の解明とともに、老化PSCをターゲットとした全く新しい治療法への応用が期待される。