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Small interfering RNAs induce target-independent inhibition of tumor growth and vasculature remodeling in a mouse model of hepatocellular carcinoma.
- Source :
-
The American journal of pathology [Am J Pathol] 2010 Dec; Vol. 177 (6), pp. 3192-201. Date of Electronic Publication: 2010 Oct 22. - Publication Year :
- 2010
-
Abstract
- 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.
- Subjects :
- Animals
Carcinoma, Hepatocellular blood supply
Carcinoma, Hepatocellular genetics
Cells, Cultured
Down-Regulation drug effects
Female
Humans
Liver Neoplasms blood supply
Liver Neoplasms genetics
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Molecular Targeted Therapy
Neovascularization, Pathologic genetics
RNA Interference physiology
Tumor Burden drug effects
Carcinoma, Hepatocellular pathology
Cell Proliferation drug effects
Liver Neoplasms pathology
Neovascularization, Pathologic prevention & control
RNA, Small Interfering pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1525-2191
- Volume :
- 177
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- The American journal of pathology
- Publication Type :
- Academic Journal
- Accession number :
- 20971743
- Full Text :
- https://doi.org/10.2353/ajpath.2010.100157