A potential autocrine role for vascular endothelial growth factor in prostate cancer

Vascular endothelial growth factor (VEGF) is a peptide growth factor specific for the tyrosine kinase receptors VEGF receptor-1 and -2 (VEGFR-1 and R-2). Whereas VEGF has well-defined actions on the vasculature, including the stimulation of endothelial cell growth and motility and blood vessel permeability, the function of the VEGF/receptor pathway in other cell types is largely unknown. Recently, VEGFR-1 and R-2 expression has been reported in prostate tumor cells. In this study, we demonstrate that these receptors colocalize with VEGF in prostate tumor cells, prostatic intraepithelial neoplasia, and the basal cells of normal glands. Furthermore, in comparison with normal glands, the expression of VEGFR-1 and R-2 is increased in prostatic intraepithelial neoplasia and malignant cells in well and moderately differentiated prostate cancer but is decreased in poorly differentiated cancer. Culture of the prostate cancer cell line LNCaP in the presence of recombinant human VEGF165 resulted in a 50% increase in [(3)H]thymidine uptake by these cells and recruitment of quiescent cells into the cell cycle. This effect of recombinant human VEGF165 was abolished by neutralizing antisera to VEGFR-2. These data suggest that VEGF may not only mediate neovascularization associated with prostate cancer progression but may also directly stimulate prostate tumor cells via VEGFR-2-dependent autocrine and/or paracrine mechanisms.