Host deficiency in Vav2/3 guanine nucleotide exchange factors impairs tumor growth, survival, and angiogenesis in vivo.
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.
Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Dana M
DM
Brantley-Sieders
Guanglei
G
Zhuang
David
D
Vaught
Tanner
T
Freeman
Yoonha
Y
Hwang
Donna
D
Hicks
Jin
J
Chen
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D008546:Melanoma, Experimental / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology* / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D051567:Proto-Oncogene Proteins c-vav / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014184:Transplantation, Homologous; D047368:Tumor Burden; D014841:von Willebrand Factor / Q000378:metabolism
D051567:Proto-Oncogene Proteins c-vav; C490565:Vav2 protein, mouse; C496622:Vav3 protein, mouse; D014841:von Willebrand Factor