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

• Published in: The American journal of pathology Vol. 177; no. 6; pp. 3192 - 3201
• Main Authors: Bergé, Mathieu, Bonnin, Philippe, Sulpice, Eric, Vilar, José, Allanic, David, Silvestre, Jean-Sébastien, Lévy, Bernard I, Tucker, Gordon C, Tobelem, Gérard, Merkulova-Rainon, Tatyana
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.12.2010; American Society for Investigative Pathology; American Society for Investigative Pathology / Elsevier
• Subjects: Animals; Biological and medical sciences; Carcinoma, Hepatocellular - blood supply; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell Proliferation - drug effects; Cells, Cultured; Down-Regulation - drug effects; Female; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Investigative techniques, diagnostic techniques (general aspects); Life Sciences; Liver Neoplasms - blood supply; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Targeted Therapy; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - prevention & control; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Regular; RNA Interference - physiology; RNA, Small Interfering - pharmacology; Tumor Burden - drug effects; Tumors; Animal model; RNA interference; Targeting; Rodentia; Hepatic disease; Hepatocellular carcinoma; siRNA; Malignant tumor; Remodeling; Vascularization; Gene silencing; Liver cancer; Vertebrata; Anatomic pathology; Mammalia; Tumor growth; Mouse; Digestive diseases; Inhibitor; Inhibition; Cancer
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2010.100157

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 posttraumatic revascularization demonstrated that synthetic siRNAs may produce therapeutic effects in a target-independent manner through the stimulation of the toll-like 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 in 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-γ levels in the liver. In vitro , interferon-γ inhibited proliferation of endothelial cells. In addition, we found that siRNAs inhibited endothelial cell proliferation and morphogenesis in an interferon-γ–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.