ANDROGENS INDUCE THE EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH-FACTORIN HUMAN FETAL PROSTATIC FIBROBLASTS

Androgens are known to directly stimulate prostate cancer cell growth. We have previously reported that LNCaP prostate cancer cells were dep endent upon stromal coinoculation for growth in nude mice and that the stromal cells secreted a potent angiogenic factor, vascular endotheli al growth factor (VEGF), which stimulated tumor angiogenesis. Immunohi stochemical staining localized VEGF expression primarily to the stroma l cells of human fetal and adult hyperplastic prostates, with both str omal and epithelial cell VEGF expression in prostate cancer. In the pr esent studies, we test the hypothesis that androgens, in addition to t heir direct effects on prostate epithelial cells, have indirect effect s on these cells via up-regulation of stromal VEGF production and angi ogenesis. Primary cultures of human prostate fetal fibroblasts were tr eated with dihydrotestosterone (DHT), and the effects on VEGF messenge r RNA (mRNA) expression were determined by Northern blotting. DHT (10 nM) increased VEGF mRNA levels maximally after 2 h. Nuclear run-on tra nscription assays demonstrated a a-fold increase in the VEGF transcrip tion rate 2 h after the addition of DHT. VEGF mRNA stability was unaff ected by DHT addition. VEGF protein levels were determined by enzyme-l inked immunosorbent assay and were increased a-fold 4 h after DHT addi tion. These data indicate that androgens increase VEGF transcription a nd secretion of biologically active VEGF from human prostatic stroma. Androgens, therefore, may indirectly enhance prostate growth via up-re gulation of VEGF from the surrounding stroma.