Small Interfering RNAs Induce Target-Independent Inhibition of Tumor Growth and Vasculature Remodeling in a Mouse Model of Hepatocellular Carcinoma

RNA interference mediated by small interfering RNAs (siRNAs) has emerged as a potential therapeutic approach to treat various diseases including cancer Recent studies with several animal models of post traumatic revascularization demonstrated that synthetic siRNAs may produce therapeutic effects m a target independent manner through the stimulation of the toll hike receptor 3 (TLR3)/interferon pathway and suppression of angiogenesis To analyze the impact of siRNAs on tumor angiogenesis we injected transgenic mice developing hepatocellular carcinoma (HCC) with either control siRNAs or siRNA targeting neuropilin 1 We found that treatment with these siRNAs led to a comparable reduction in tumor liver volume and to inhibition of tumor vasculature remodeling We further determined that TLR3 which recognizes double stranded siRNA was up regulated m mouse HCC Treatment of HCC mice with polyinosinic polycytidylic acid [poly(I C)], a TLR3 agonist led to both a reduction of tumor liver enlargement and a decrease in hepatic arterial blood flow indicating that TLR3 is functional and may mediate both anti angiogenic and anti tumor responses We also demonstrated that siRNAs increased interferon gamma levels in the liver In vitro interferon gamma inhibited proliferation of endothelial cells In addition we found that siRNAs inhibited endothelial cell proliferation and morphogenesis in an interferon gamma-independent manner Our results suggest that synthetic siRNAs inhibit target independently HCC growth and angiogenesis through the activation of the innate interferon response and by directly inhibiting endothelial cell function (Am J Pathol 2010 177 3192-3201 DOI 10 2353/ajpath 2010 100157)