KERATINOCYTE GROWTH-FACTOR (KGF) CAN REPLACE TESTOSTERONE IN THE DUCTAL BRANCHING MORPHOGENESIS OF THE RAT VENTRAL PROSTATE

Prostatic growth occurs through ductal elongation and branching into t he mesenchyme. Ductal branching morphogenesis in the prostate is elici ted by androgens via mesenchymal-epithelial interactions mediated by p aracrine influences from mesenchyme. The role of keratinocyte growth f actor (KGF) was investigated in the developing prostate as KGF has bee n suggested to be a paracrine acting factor. KGF transcripts were dete cted by reverse transcriptase-polymerase chain reaction (RT-PCR) in ne onatal 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 hybri dization. KGF was investigated as a potential paracrine mediator durin g 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. Neutralizatio n 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 morphogene sis were stimulated. The number of ductal end buds was about 70% of th at obtained with an optimal dose of testosterone (10(-8) M), and DNA c ontent of VP's cultured with 100 ng/ml KGF was equivalent to that of g lands cultured with testosterone. The stimulatory effect of KGF was pa rtially blocked by cyproterone acetate, a steroidal anti-androgen. The se data imply that KGF plays an important role as a mesenchymal paracr ine mediator of androgen-induced epithelial growth and ductal branchin g morphogenesis in the rat VP.