Rapamycin inhibits hepatectomy-induced stimulation of metastatic tumor growth by reduction of angiogenesis and tumor cell proliferation

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Background: Liver regeneration after hepatectomy (Phx) for colorectal liver metastases stimulates metastatic tumor growth through the release of potent growth factors. The mTOR inhibitor rapamycin (RAPA) has been shown to exhibit potent anti-tumor activities in experimental models. However, it is unknown whether RAPA is also capable of exerting these effects under the conditions of hepatectomy-associated liver regeneration. We therefore analyzed tumor growth characteristics and neovascularization after RAPA or cyclosporine A (CyA) treatment after liver resection in a model of colorectal metastasis in mice. Methods: 1×105 GFP-transfected CT26.WT colorectal cancer cells were implanted into the dorsal skinfold chambers of syngeneic BALB/c mice, followed by a 70% Phx. Thereafter, animals were assigned to 3 groups: the first group received 1.5 mg/kg/d RAPA intraperitoneally (i.p.), the second group received 10 mg/kg/d CyA i.p. and the third group received sham treatment. Tumor growth, neovascuarization, leukocyte adhesion, tumor cell proliferation and apoptotic cell death were studied using intravital fluorescence microscopy and immunohistochemistry during a 12-day observation period. Results: CyA treatment induced a slight but not significant decrease of tumor growth compared to controls, whereas RAPA significantly inhibited tumor growth. This finding was associated with a significantly reduced microvascular density within the tumors and a strongly diminished microvascular blood perfusion. Leukocyte adhesion within the tumor microvessels was significantly attenuated after CyA but in particular after RAPA treatment. Immunohistochemistry revealed a significant reduction of tumor cell proliferation after RAPA treatment compared to controls. In contrast, CyA only slightly reduced the number of proliferating tumor cells. Apoptotic cell death was not affected by the immunosuppressive treatment regimens. Conclusion: These results clearly indicate that RAPA is capable of inhibiting tumor growth of colorectal metastasis also during hepatectomy-associated liver regeneration. This effect is most probably caused by the reduction of angiogenesis and microvascular blood perfusion.