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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 Department of Pathology and Microbiology and 2 Epley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska; and 3 Cancer Center of People's Liberation Army, Xin Qiao Hospital, Third Military Medical University, Chongqing, PR China
Requests for reprints: Rakesh K. Singh, Department of Pathology and Microbiology, 985845 Nebraska Medical Center, Omaha, NE 68198-5845. Phone: 402-559-9949; Fax: 402-559-5551; E-mail: rsingh{at}unmc.edu.
Tumor production of vascular endothelial cell growth factor (VEGF)-C is associated with tumor lymphangiogenesis and lymph node metastasis. In this study, we examined the effects of small interfering RNA (siRNA)–mediated inhibition of VEGF-C on murine mammary tumor growth, metastasis, and survival. The mRNA and protein expression of VEGF-C in murine mammary tumor cells stably transfected with a VEGF-C siRNA vector were significantly lower compared with VEGF-C-control vector-transfected cells. Cl66-siVEGFC tumors had lower levels of lymphangiogenesis and lymph node and spontaneous lung metastasis than Cl66-control tumors. However, we did not observe significant differences in primary tumor growth and experimental lung metastasis between mice injected with Cl66-siVEGFC and Cl66-control cells. In addition, mice bearing Cl66-siVEGFC tumors lived significantly longer than mice bearing Cl66-control tumors. Furthermore, our data suggest that inhibition of VEGF-C modulates immune cell infiltration and their function, which might be critical in tumor immunity. In summary, our data show that inhibition of VEGF-C expression using siRNA-mediated gene silencing vectors reduces lymphangiogenesis and lymph node and spontaneous lung metastasis, and enhances survival.
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