Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function.
There is considerable controversy concerning the importance of tumor-derived angiogenic factors to the neovascularization of solid tumors. Tumor, endothelial, and stromal expression of vascular endothelial growth factor (VEGF) have been hypothesized to be critical for tumor angiogenesis. To determine the relative contribution of tumor versus nontransformed tissue expression of VEGF to tumor growth, we used gene targeting and cre-loxP recombination to generate embryonic stem cell lines in which VEGF can be conditionally deleted. These lines were used to derive mouse embryonic fibroblast lines with null mutations in both alleles of VEGF. Upon immortalization and H-ras transformation, we used these VEGF null fibroblasts to make fibrosarcomas in immunocompromised mice. We report that tumorigenic VEGF expression is critical for ras-mediated tumorigenesis, and the loss of tumorigenic expression causes dramatic decreases in vascular density and vascular permeability and increases in tumor cell apoptosis.
Grunstein
J
J
Department of Biology and Medicine, University of California, San Diego 92093, USA.
Roberts
W G
WG
Mathieu-Costello
O
O
Hanahan
D
D
Johnson
R S
RS
D000818:Animals; D002199:Capillary Permeability; D015687:Cell Hypoxia; D016228:Endothelial Growth Factors / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000473:pathology; D018390:Gene Targeting; D011905:Genes, ras; D008222:Lymphokines / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000209:etiology; D009389:Neovascularization, Pathologic / Q000209:etiology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors