Antitumor Effect of Low-Dose of Rapamycin in a Transgenic Mouse Model of Liver Cancer
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Purpose: We investigate whether low-dose rapamycin is effective in preventing hepatocellular carcinoma (HCC) growth and treating HCC after tumor development in transgenic mice. Materials and Methods: We established transgenic mice with HCC induced by activated HrasG12V and p53 suppression. Trans genic mice were randomly assigned to five experimental groups: negative control, positive control, tacrolimus only, rapamycin only, and tacrolimus plus rapamycin. The mice were further divided into two groups according to time to commencement of im munosuppressant treatment: de novo treatment and post-tumor development. Results: In the de novo treatment group, marked suppression of tumor growth was observed in the rapamycin only group. In the post-tumor development group, the rapamycin only group displayed no significant suppression of tumor growth, compared to the positive control group. In T lymphocyte subset analysis, the numbers of CD4+effector T cells and CD4+ regulatory T cells were significantly lower in the positive control, tacrolimus only, and tacrolimus plus rapamycin groups than the negative control group. Immunohistochemical analysis revealed significantly higher expression of phosphorylated-mTOR, 4E-BP1, and S6K1 in the posi tive control group than in the rapamycin only group. Conclusion: Low-dose rapamycin might be effective to prevent HCC growth, but may be ineffective as a treatment option after HCC development.
Abstract
Purpose: We investigate whether low-dose rapamycin is effective in preventing hepatocellular carcinoma (HCC) growth and treating HCC after tumor development in transgenic mice. Materials and Methods: We established transgenic mice with HCC induced by activated HrasG12V and p53 suppression. Trans genic mice were randomly assigned to five experimental groups: negative control, positive control, tacrolimus only, rapamycin only, and tacrolimus plus rapamycin. The mice were further divided into two groups according to time to commencement of im munosuppressant treatment: de novo treatment and post-tumor development. Results: In the de novo treatment group, marked suppression of tumor growth was observed in the rapamycin only group. In the post-tumor development group, the rapamycin only group displayed no significant suppression of tumor growth, compared to the positive control group. In T lymphocyte subset analysis, the numbers of CD4+effector T cells and CD4+ regulatory T cells were significantly lower in the positive control, tacrolimus only, and tacrolimus plus rapamycin groups than the negative control group. Immunohistochemical analysis revealed significantly higher expression of phosphorylated-mTOR, 4E-BP1, and S6K1 in the posi tive control group than in the rapamycin only group. Conclusion: Low-dose rapamycin might be effective to prevent HCC growth, but may be ineffective as a treatment option after HCC development.
참고문헌 (30)
- Mehta N, "Liver transplantation for hepatocellular carcinoma. Working group report from the ILTS transplant oncology consensus conference", Transplantation, 104, pp.1136~1142 (2020)
- Lee DD, "Surveillance for HCC after liver transplantation : increased monitoring may yield aggressive treatment options and improved postrecurrence survival", Transplantation, 104, pp.2105~2112 (2020)
- Bodzin AS, "Predicting mortality in patients developing recurrent hepatocellular carcinoma after liver transplantation", Ann Surg, 266, pp.118~125 (2017)
- Lu X, "Role of the mammalian target of rapamycin pathway in liver cancer : from molecular genetics to targeted therapies", Hepatology, 73(Suppl 1), pp.49~61 (2021)
- Chew SA, "Liver cancer: current and future trends using biomaterials", Cancers (Basel), 11, pp.2026~ (2019)
- Nashan B, "mTOR inhibition and clinical transplantation: liver", Transplantation, 102(2S Suppl 1), pp.S19~S26 (2018)
- Schnitzbauer AA, "mTOR inhibition is most beneficial after liver transplantation for hepatocellular carcinoma in patients with active tumors", Ann Surg, 272, pp.855~862 (2020)
- Geissler EK, "Sirolimus use in liver transplant recipients with hepatocellular carcinoma : a randomized, multicenter, open-label phase 3 trial", Transplantation, 100, pp.116~125 (2016)
- De Simone P, "Use of everolimus in liver transplantation : recommendations from a working group", Transplantation, 101, pp.239~251 (2017)
- Guba M, "Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis : involvement of vascular endothelial growth factor", Nat Med, 8, pp.128~135 (2002)
- Selvarani R, "Effect of rapamycin on aging and age-related diseases-past and future", Geroscience, 43, pp.1135~1158 (2021)
- Zhang G, "High levels of foreign gene expression in hepatocytes after tail vein injections of naked plasmid DNA", Hum Gene Ther, 10, pp.1735~1737 (1999)
- Ju HL, "Transgenic mouse models generated by hydrodynamic transfection for genetic studies of liver cancer and preclinical testing of anti-cancer therapy", Int J Cancer, 138, pp.1601~1608 (2016)
- Diehl R, "Immunosuppression for in vivo research : state-of-the-art protocols and experimental approaches", Cell Mol Immunol, 14, pp.146~179 (2017)
- Herbst S, "A new and clinically relevant murine model of solid-organ transplant aspergillosis", Dis Model Mech, 6, pp.643~651 (2013)
- Kwong AJ, "OPTN", SRTR 2019 annual data report : liver, 2021, pp.21(Suppl 2), 208~315
- Lee SG, "Efficacy and safety of everolimus with reduced tacrolimus in liver transplant recipients : 24-month results from the pooled analysis of 2 randomized controlled trials", Transplantation, 105, pp.1564~1575 (2021)
- Zhu AX, "Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib : the EVOLVE-1 randomized clinical trial", JAMA, 312, pp.57~67 (2014)
- Galle PR, "Biology and significance of alpha-fetoprotein in hepatocellular carcinoma", Liver Int, 39, pp.2214~2229 (2019)
- Cillo U, "Role of blood AFP mRNA and tumor grade in the preoperative prognostic evaluation of patients with hepatocellular carcinoma", World J Gastroenterol, 11, pp.6920~6925 (2005)
- Lee JH, "Serum tumor markers provide refined prognostication in selecting liver transplantation candidate for hepatocellular carcinoma patients beyond the Milan criteria", Ann Surg, 263, pp.842~850 (2016)
- Hong G, "Alpha-fetoprotein and(18)F-FDG positron emission tomography predict tumor recurrence better than Milan criteria in living donor liver transplantation", J Hepatol, 64, pp.852~859 (2016)
- Li C, "Regulatory T cells in tumor microenvironment : new mechanisms, potential therapeutic strategies and future prospects", Mol Cancer, 19, pp.116~ (2020)
- Chi H, "Regulation and function of mTOR signalling in T cell fate decisions", Nat Rev Immunol, 12, pp.325~338 (2012)
- Wang Y, "Temsirolimus, an mTOR inhibitor, enhances anti-tumour effects of heat shock protein cancer vaccines", Br J Cancer, 104, pp.643~652 (2011)
- Sillito F, "Engineering CD4+ T cells to enhance cancer immunity", Cells, 9, pp.1721~ (2020)
- Cabrera R, "Hepatocellular carcinoma immunopathogenesis : clinical evidence for global T cell defects and an immunomodulatory role for soluble CD25(sCD25)", Dig Dis Sci, 55, pp.484~495 (2010)
- Villanueva A, "Pivotal role of mTOR signaling in hepatocellular carcinoma", Gastroenterology, 135, pp.1972~1983.E11 (2008)
- Ma XM, "Molecular mechanisms of mTOR-mediated translational control", Nat Rev Mol Cell Biol, 10, pp.307~318 (2009)
- Seeliger H, "Role of mTOR in solid tumor systems : a therapeutical target against primary tumor growth, metastases, and angiogenesis", Cancer Metastasis Rev, 26, pp.611~621 (2007)