Functional significance of VEGFR-2 on ovarian cancer cells

Vascular endothelial growth factor receptor (VEGFR) has recently been discovered on ovarian cancer cells, but its functional significance is unknown and is the focus of this study. By protein analysis, A2780-par and HeyA8 ovarian cancer cell lines expressed VEGFR-1 and HeyA8 A2774, and SKOV3ipl expressed VEGFR-2. By in situ hybridization (ISH), 85% of human ovarian cancer specimens showed moderate to high VEGFR-2 expression, whereas only 15% showed moderate to high VEGFR-1 expression. By immunofluorescence, little or no VEGFR-2 was detected in normal ovarian surface epithelial cells, whereas expression was detected in 75% of invasive ovarian cancer specimens. To differentiate between the effects of tumor versus host expression of VEGFR, nude mice were injected with Sk.OV3ipl cells and treated with either human VEGFR-2 specific antibody (1121B), murine VEGFR-2 specific antibody (DC 101) or the combination. Treatment with 1121B reduced SKOV3ipl cell migration by 68% (p < 0.01) and invasion bv 72% (p < 0.01), but exposure to VEGFR-1 antibody had no effect. Treatment with 112IB effectively blocked VEGF-indueed phosphorylation of p130Cas. In vivo treatment with either DC.101. or 1121B significantly reduced tumor growth alone and in combination in the SKOV3ipl and A2774 models. Decreased tumor burden after treatment with DC 101 or 1121B correlated with increased tumor cell apoptosis, decreased proliferative index, and decreased microvessel density. These effects were significantly greater in the combination group (p < 0.0011. We show functionally active VEGFR-2 is present on most ovarian cancer cells. The observed anti-tumor activity of VEGF-targeted therapies may be mediated by both anti-angio-genic and direct anti-tumor effects.