Secretion of vascular endothelial growth factor in ovarian cancer.

Vascular endothelial growth factor (VEGF) is an important regulator of vascular endothelial cell function during vasculogenesis and tumor growth and is believed to play a major role in peritoneal fluid accumulation in ascites tumors. High VEGF production from primary tumors has been reported to correlate with increased metastatic spreading and worse prognosis compared to low VEGF secreting tumors. In addition, VEGF secretion has recently been proposed as one of the major factors responsible for defective immune function in cancer patients. In order to evaluate whether ovarian carcinomas actively secrete VEGF, in this study we have analyzed and quantified VEGF secretion in several fresh and established human ovarian carcinoma cell lines in vitro using a sensitive enzyme-linked immunosorbent assay (ELISA). In addition, VEGF levels were also evaluated in the ascitic fluids and plasma of six ovarian cancer patients. All fresh tumors secreted high levels of VEGF (mean = 5,046, range between 1,760 and 7,780 pg/ml/10(5) cells/48 hr) when compared to established ovarian carcinoma cell lines (mean = 493, range between 160 to 1,120 pg/ml/10(5) cells/48 hr) (p <0.02). Importantly, high grade malignancies were found to secrete larger amounts of VEGF (mean = 6,660 pg/ml) when compared to lower grade tumors (mean = 1,820 pg/ml) (p <0.01). Ascitic fluids from all patients were rich in VEGF (mean = 5,483, range between 1,300 and 11,200 pg/ml) and plasma levels of VEGF in ovarian cancer patients were significantly higher (mean = 408, range between 160 and 810 pg/ml) when compared with healthy individuals (mean = 46, range between 35 and 60 pg/ml) (p <0.01). Taken together, these data demonstrate that ovarian cancers secrete large amounts of VEGF in vitro and in vivo. This findings therefore suggest that this factor may play a crucial role in the genesis of ascitic fluid accumulation, angiogenesis and tumor induced immunosuppression in ovarian cancer patients. The design of anti-angiogenic treatment directed at blocking the action of VEGF may be a reasonable novel therapeutic approach in the treatment of ovarian cancer.