title: Down-regulation of vascular endothelial cell growth factor-C expression using small interfering RNA vectors in mammary tumors inhibits tumor lymphangiogenesis and spontaneous metastasis and enhances survival.
abstract: 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.
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5845, USA.
authors.forename: Zhengtang
authors.initials: Z
authors.lastname: Chen
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Varney
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Backora
authors.forename: Kenneth
authors.initials: K
authors.lastname: Cowan
authors.forename: Joyce C
authors.initials: JC
authors.lastname: Solheim
authors.forename: James E
authors.initials: JE
authors.lastname: Talmadge
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D020868:Gene Silencing; D005822:Genetic Vectors / Q000235:genetics; D016130:Immunophenotyping; D008175:Lung Neoplasms / Q000235:genetics / Q000517:prevention & control / Q000556:secondary; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology / Q000628:therapy; D034741:RNA, Small Interfering / Q000235:genetics*; D042582:Vascular Endothelial Growth Factor C / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D042582:Vascular Endothelial Growth Factor C; C467483:vascular endothelial growth factor C, mouse