EXPRESSION OF VASCULAR-PERMEABILITY FACTOR VASCULAR ENDOTHELIAL GROWTH-FACTOR BY MELANOMA-CELLS INCREASES TUMOR-GROWTH, ANGIOGENESIS, AND EXPERIMENTAL METASTASIS

Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) is an angiogenic cytokine expressed by many human and animal tu mors. Hypoxia often up-regulates VPF/VEGF expression further. To bette r define the role of VPF/VEGF in tumor biology, we screened tumorigeni c lines for those expressing minimal constitutive and hypoxia-inducibl e VPF/VEGF. Human melanoma SK-MEL-2 cells best fit these criteria and formed small, poorly vascularized tumors in immunodeficient mice. We t ransfected SK-MEL-2 cells stably with sense or antisense mouse VPF/VEG F cDNA or with vector alone. Cells transfected with sense VPF/VEGF (V) expressed and secreted large amounts of mouse VPF/VEGF and formed we ll-vascularized tumors with hyperpermeable blood vessels and minimal n ecrosis in nude/SCID mice. Antisense-transfected VPF/VEGF (V-) cells e xpressed reduced constitutive VPF/VEGF and no detectable mouse VPF/VEG F, and formed small, minimally vascularized tumors exhibiting extensiv e necrosis. Vector-alone transfectants (N1 cells) behaved like parenta l cells. V+ cells formed numerous lung tumor colonies in SCID mice, si milar to 50-fold more than N1 cells, whereas V- cells formed few or no ne. These experiments demonstrate that VPF/VEGF promotes melanoma grow th by stimulating angiogenesis and that constitutive VPF/VEGF expressi on dramatically promotes tumor colonization in the lung.