Keratinocyte growth factor (KGF) can replace testosterone in the ductal branching morphogenesis of the rat ventral...

Prostatic growth occurs through ductal elongation and branching into the mesenchyme. Ductal branching morphogenesis in the prostate is elicited by androgens via mesenchymal-epithelial interactions mediated by paracrine influences from mesenchyme. The role of keratinocyte growth factor (KGF) was investigated in the developing prostate as KGF has been suggested to be a paracrine acting factor. KGF transcripts were detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in neonatal rat ventral prostates (VPs) in vivo, in VPs cultured in vitro, and in isolated VP mesenchyme. KGF receptor was detected in VP's by RT-PCR and was localized specifically to the epithelium by in situ hybridization. KGF was investigated as a potential paracrine mediator during androgen-induced prostatic development by examining neonatal rat VPs cultured for 6 days under serum-free conditions using a basal medium supplemented only with insulin and transferrin. When testosterone (10(-9) to 10(-8) M) was added to the basal medium, VPs grew and underwent ductal branching morphogenesis similar to that in situ. Neutralization of endogenous KGF with a monoclonal antibody to KGF (anti-KGF) or a soluble KGF receptor peptide inhibited androgen-stimulated VP growth (DNA content) and reduced the number of ductal end buds after 6 days of culture. When KGF (50 or 100 ng/ml) was added to the basal medium in the absence of testosterone, VP growth and ductal branching morphogenesis were stimulated. The number of ductal end buds was about 70% of that obtained with an optimal dose of testosterone (10(-8)M), and DNA content of VP's cultured with 100 ng/ml KGF was equivalent to that of glands cultured with testosterone. The stimulatory effect of KGF was partially blocked by cyproterone acetate, a steroidal anti-androgen. These data imply that KGF plays an important role as a mesenchymal paracrine mediator of androgen-induced epithelial growth and ductal branching morphogenesis in the rat VP.