Androgenic effects on prostate specific antigen secretion by human fetal prostate are mediated by keratinocyte growth factor

Human prostate morphogenesis is dependent on androgens and stromal-epitheli al interactions. Keratinocyte growth factor (KGF) is a stromally derived me mber of the fibroblast growth factor family (FGF-7) that targets receptors (KGF-R) on epithelial cells and has been shown to be induced by androgens, The present studies were conducted in order to determine the role of KGF in androgen-induced stromally mediated human prostate epithelial cell develop ment. In situ hybridization localized the expression of KGF-R to fetal pros tate basal epithelial cells, Primary cultures of human fetal prostate strom al cells expressed low levels of KGF mRNA, Dihydrotestosterone (DHT) at a c oncentration of 10(-8) M induced a doubling of KGF mRNA expression in human fetal prostatic fibroblasts 12 h after addition. In order to test the effe cts of DHT and KGF on prostate development, prostate organ cultures derived from five male fetuses (16-21 weeks' gestation) were grown in serum-free, defined medium for 8 days with or without DHT or KGF, Neither DHT nor KGF e nhanced cellular proliferation, as measured by Ki-67 immunohistochemistry s taining. Prostate specific antigen (PSA), a serine protease responsible for liquefaction of the coagulum, is produced exclusively by differentiated pr ostate luminal epithelial cells, Quantitative measurements of PSA in organ culture medium demonstrated that both KGF and DHT enhanced PSA secretion si gnificantly, and the effects of both compounds were blocked by neutralizing antibodies to KGF, These results demonstrate that both DHT and KGF induce PSA secretion by human fetal prostate epithelial cells and that the androge nic effects are mediated by stromally derived KGF.