Antitumor Effect of Low-Dose of Rapamycin in a Transgenic Mouse Model of Liver Cancer

We investigate whether low-dose rapamycin is effective in preventing hepatocellular carcinoma (HCC) growth and treating HCC after tumor development in transgenic mice.We established transgenic mice with HCC induced by activated HrasG12V and p53 suppression. Transgenic 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 immunosuppressant treatment: de novo treatment and post-tumor development.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 positive control group than in the rapamycin only group.Low-dose rapamycin might be effective to prevent HCC growth, but may be ineffective as a treatment option after HCC development.