Angioprevention is Implicated in Resveratrol Chemoprevention of Experimental Hepatocarcinogenesis

Hepatocellular carcinoma (HCC), a hypervascular tumor, is one of the most common and lethal cancers worldwide. We previously showed that resveratrol, a dietary polyphenol, inhibits rat liver carcinogenesis through antioxidative and antiinfl ammatory mechanisms. As resveratrol possesses antiangiogenic properties, we hypothesize that it may exert chemoprevention of hepatocarcinogenesis by suppressing angiogenesis. The antiangiogenic effect of resveratrol was investigated by analyzing livers from our previous study in which resveratrol (50-300 mg/kg) exerted chemopreventive action against diethylnitrosamine (DENA)-induced rat liver tumorigenesis. Hepatic angiogenesis was evaluated by microvessel density (MVD) based on immunohistochemical staining of CD31-positive endothelial cells. The expression of hepatic vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) were determined by immunohistochemistry. Sixteen weeks following the administration of DENA, there was a substantial increase in hepatic MVD as compared to normal liver. A dramatic increase in hepatic VEGF and HIF-1α was observed in DENA-treated animals compared to normal counterparts. Treatment with resveratrol dose-dependently abrogated the DENA-induced increased MVD as well as the elevated expression of VEGF and HIF-1α. DENA-initiated hepatocarcinogenesis in rats exhibits substantial neovascularization possibly due to overexpression of VEGF upregulated by HIF-1α. Resveratrol exerts a remarkable angiosuppressive effect in DENA-evoked hepatocellular carcinogenesis. Resveratrol-mediated inhibition of angiogenesis could be achieved by suppressing VEGF expression through downregulation of HIF1α. These results, in conjunction with our previous fi ndings, provide evidence that angiosuppression is involved in resveratrol-mediated chemoprevention of rat liver carcinogenesis and support the potential use of this natural agent in the prevention and therapy of HCC.