Vascular endothelial growth factor-mediated autocrine stimulation of prostate tumor cells coincides with progression to a malignant phenotype

Vascular endothelial growth factor (VEGF), which is often produced at high levels by tumor cells, is a well-known mediator of tumor angiogenesis. VEGF receptor tyrosine kinases, KDR/Flk-1 and Flt-1, have been thought to be ex pressed exclusively by endothelial cells. in this study, we have used a pro state tumor progression series comprised of a differentiated rat prostate e pithelial cell line, NbE-1, and its highly motile clonal derivative, FB2. I njection of NbE-1 cells into the inferior vena cava of syngeneic rats indic ated that these cells are nontumorigenic. Using the same model, FB2 cells g enerated rapidly growing and well-vascularized tumors in the lungs. NbE-1 e xpressed marginal levels of VEGF, whereas high levels of VEGF protein were detected in FB2-conditioned medium and in FB2 tumors in vivo. Analysis of I -125-VEGF(165) binding to NbE-1 and FB2 cells indicated that only motile FB 2 cells expressed the VEGF receptor Flt-1. Consistent with this finding, ph ysiological concentrations of VEGF induced chemotactic migration in FB2 but not in NbE-1 cells. This is the first documentation of a functional Flt-1 receptor in prostate tumor cells. Our results suggest two roles for VEGF in tumor progression: a paracrine role as an angiogenic factor and a previous ly undescribed role as an autocrine mediator of tumor cell motility.