Host deficiency in Vav2/3 guanine nucleotide exchange factors impairs tumor growth, survival, and angiogenesis in vivo.

Brantley-Sieders DM, Zhuang G, Vaught D, Freeman T, Hwang Y, Hicks D, Chen J
Mol Cancer Res. 2009 7 (5): 615-23

PMID: 19435813 · PMCID: PMC2739740 · DOI:10.1158/1541-7786.MCR-08-0401

Vav guanine nucleotide exchange factors modulate changes in cytoskeletal organization through activation of Rho, Rac, and Cdc42 small GTPases. Although Vav1 expression is restricted to the immune system, Vav2 and Vav3 are expressed in several tissues, including highly vascularized organs. Here, we provide the first evidence that Vav2 and Vav3 function within the tumor microenvironment to promote tumor growth, survival, and neovascularization. Host Vav2/3 deficiency reduced microvascular density, as well as tumor growth and/or survival, in transplanted B16 melanoma and Lewis lung carcinoma models in vivo. These defects were due in part to Vav2/3 deficiency in endothelial cells. Vav2/3-deficient endothelial cells displayed reduced migration in response to tumor cells in coculture migration assays, and failed to incorporate into tumor vessels and enhance tumor volume in tumor-endothelial cotransplantation experiments. These data suggest that Vav2/3 guanine nucleotide exchange factors play a critical role in host-mediated tumor progression and angiogenesis, particularly in tumor endothelium.

MeSH Terms (19)

Animals Carcinoma, Lewis Lung Cell Line, Tumor Cell Movement Cell Proliferation Cell Survival Coculture Techniques Endothelial Cells Melanoma, Experimental Mice Mice, Inbred C57BL Mice, Knockout Mice, Nude Neoplasms, Experimental Neovascularization, Pathologic Proto-Oncogene Proteins c-vav Transplantation, Homologous Tumor Burden von Willebrand Factor

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