Rapamycin Inhibits Hepatectomy-Induced Stimulation of Metastatic Tumor Growth by Reduction of Angiogenesis, Microvascular Blood Perfusion, and Tumor Cell Proliferation

Abstract

Liver regeneration after hepatectomy stimulates metastatic tumor growth through the release of potent growth factors. In the signaling cascades of several growth factors, mTOR is a downstream mediator, triggering cell survival and cell cycle progression. The mTOR inhibitor rapamycin (RAPA) has been shown to exhibit potent antitumor activities. However, it is unknown whether RAPA is capable of exerting these effects under the conditions of hepatectomy-associated liver regeneration. We therefore analyzed the effect of RAPA and cyclosporine A (CyA) on tumor growth characteristics after major hepatectomy using a mouse model of colorectal metastasis. Tumor growth was studied by using GFP-transfected CT26.WT colorectal cancer cells, which were implanted into the dorsal skinfold chambers of BALB/c-mice after 70% hepatectomy. The animals were treated daily with RAPA (1.5 mg/kg) or CyA (10 mg/kg). Tumors were analyzed for angiogenesis, microvascular blood perfusion, cell proliferation, apoptotic cell death, and tumor growth. RAPA significantly inhibited tumor growth compared with CyA and sham treatment. This was associated with a decreased microvascular density within the tumors and a markedly reduced microvascular blood perfusion. CyA only slightly reduced angiogenesis and tumor growth. The effects of RAPA were associated with a significant reduction of tumor cell proliferation, whereas manifestation of apoptotic cell death was not affected by the immunosuppressive treatment regimen. RAPA is capable of inhibiting angiogenesis, microvascular blood perfusion, and tumor growth of colorectal metastasis during hepatectomy-associated liver regeneration. Thus, targeting mTOR might represent an interesting strategy to prevent tumor recurrence after hepatectomy for colorectal metastasis.