Targeting VCAM-1 for contributing to the prognosis of pancreatic cancer: the effect and underlying mechanisms

Research Project

Project/Area Number	17K07155
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Tumor biology
Research Institution	The University of Tokyo
Principal Investigator	Mizuno Suguru 東京大学, 医学部附属病院, 助教 (30771050)
Co-Investigator(Kenkyū-buntansha)	伊地知秀明東京大学, 医学部附属病院, 講師 (70463841)
Project Period (FY)	2017-04-01 – 2020-03-31
Project Status	Completed (Fiscal Year 2019)
Budget Amount *help	¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000) Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000) Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000) Fiscal Year 2017: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Keywords	膵癌 / VCAM-1 / 癌微小環境 / 癌関連血栓塞栓症 / がん微小環境
Outline of Final Research Achievements	Treating our pancreatic cancer model mice, which can recapitulate human disease, with neutralizing antibody to adhesion molecule VCAM-1 dramatically extended the overall survival (median survival time: control 61 days v.s. treating 253 days). Targeting VCAM-1 decreased intratumoral infiltration of inflammatory cells, which inhibited pancreatic cancer formation and progression. This model also highly frequently developed cancer-associated thromboembolism (CAT). The model mice and human patients with CAT showed elevated plasma VCAM-1 level and strong VCAM-1 staining in the thrombi, which suggested that pancreatic cancer cells produced VCAM-1 and elevated plasma VCAM-1 level, thereby promoting thrombus formation. These results indicates that targeting VCAM-1 can regulate pancreatic cancer progression and contribute to the better prognosis.
Academic Significance and Societal Importance of the Research Achievements	膵癌は年々増加傾向を示し、かつ最難治癌であり、その予後改善に寄与する治療法の確立は喫緊の課題である。本研究は、臨床の膵癌に近いモデルを用いて、担癌状態ながら、正に膵癌の生命予後を大きく改善させる結果を示し、進行期の膵癌の予後に寄与できる方法として社会的にも大きなインパクトを持つものと言える。学術的には、治療効果の機序として、予後不良因子である癌関連血栓塞栓症の制御および膵癌微小環境における炎症細胞浸潤の制御によることを明らかにした。本モデルが膵癌関連血栓塞栓症となり得ることも初めて示した。血中VCAM-1の予後予測および血栓診断のバイオマーカーとしての意義も明らかにした。