OncoTargets and Therapy (May 2020)

FTY720 Suppresses Liver Tumor Growth and Metastasis by Reducing Circulating Regulating T Cells and Enhancing the Anti-Tumor Effect of Rapamycin

  • Li CX,
  • Yang XX,
  • Wang HW,
  • Li XC,
  • Ng KTP,
  • Lo CM,
  • Man K

Journal volume & issue
Vol. Volume 13
pp. 4743 – 4754

Abstract

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Chang Xian Li,1 Xin Xiang Yang,2 Hong Wei Wang,1 Xiang Cheng Li,1 Kevin Tak-Pan Ng,2 Chung Mau Lo,2 Kwan Man2 1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Nanjing, Jiangsu Province, People’s Republic of China; 2Department of Surgery, The University of Hong Kong, Hong Kong, People’s Republic of ChinaCorrespondence: Kwan ManDepartment of Surgery, The University of Hong Kong, L9-55, Faculty of Medicine Building, 21 Sassoon Road, Hong Kong, People’s Republic of ChinaTel +852 39179646Fax +852 39179634Email [email protected]: In this study, we aimed to study the effect of FTY720 treatment in reducing circulating Tregs level and then suppressing liver tumor metastasis after hepatectomy and I/R injury in animal models. Furthermore, we also investigated the synergistic anti-tumor effect of FTY720 combined with rapamycin on hepatocellular carcinoma.Methods: The effect of FTY720 on suppressing Tregs mobilization and tumor metastasis after hepatectomy was investigated in an orthotopic liver tumor rat model with hepatectomy and hepatic ischemia/reperfusion (I/R) injury. The synergistic anti-tumor effect of FTY720 combined with rapamycin was further explored both in in vitro functional study and in orthotopic liver tumor mouse model.Results: In rat model, hepatic I/R promoted tumor metastasis and increased circulating Tregs after hepatectomy. The treatment of FTY720 reduced liver tumor metastasis and the number of circulating Tregs. Furthermore, FTY720 enhanced the anti-tumor capacity of rapamycin by inhibiting tumor cell proliferation and migration in vitro and reducing tumor growth in vivo through suppressing hepatic stellate cell activation and tumor angiogenesis.Conclusion: FTY720 suppressed liver tumor growth and metastasis by reducing the population of circulating Tregs and enhancing the anti-tumor effect of rapamycin. It was suggested that FTY720 single or combined with rapamycin might provide novel insight for suppressing tumor growth and metastasis for HCC patients.Keywords: FTY720, rapamycin, regulatory T cells, hepatic ischemia/reperfusion, tumor recurrence

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