The role of growth factors in the development and growth of the prostate and seminal vesicle

Abstract

Summary Mesenchymal-epithelial interactions play a critical role in the development of the male urogenital tract in that mesenchyme induces and specifies patterns of epithelial morphogenesis, regulates epithelial proliferation, promotes epithelial cytodifferentiation, and induces and specifies epithelial functional or biochemical activity. Prostatic epithelial growth and development is dependent upon androgens. Analysis of tissue recombinants prepared with normal (wild-type) urogenital sinus mesenchyme plus Tfm (testicular feminization) epithelium has demonstrated that androgen-induced prostatic epithelial growth and ductal branching morphogenesis are elicited via paracrine influences from the androgen-receptor-positive mesenchyme. Since KGF has recently emerged as a prototypic paracrine mediator of mesenchymal-epithelial interactions, androgen-dependent prostatic development was investigated to determine the possible role of KGF using a serum-free organ culture method. For this purpose newborn rat ventral prostates (VP) were incubated in vitro in a serum basal-free medium supplemented with testosterone (T: 10 −8 M), human recombinant KGF, or a neutralizing monoclonal antibody to KGF (anti-KGF), alone or in combination. When T (10 −8 M) was added to the basal media, VPs grew and underwent extensive branching morphogenesis similar to that in situ . The anti-KGF (60 μg/ml) inhibited T-induced VP growth (DNA content) by 33% and reduced ductal endbuds by 62% after 6 days of culture. Neonatal rat VPs grown without T exhibited reduced growth and branching morphogenesis in comparison to those grown with T. When KGF (50 ng/ml) was added to the T-deficient media, VP growth was stimulated to a level approaching that elicited by T. Ductal endbuds were elevated from 23 (without T) to 60 (without T + KGF) per expiant which represents 73% of that observed in cultures grown with T. Given the facts: a) that KGF is produced by mesenchymal/fibroblastic cells and acts on epithelia; b) that androgens stimulate development and growth of the prostate via androgen-receptor-mediated processes: and c) that androgen receptors (AR) are only detected in the mesenchyme of the rat VP at birth, our data suggests that androgens regulate epithelial growth and development of the VP by acting on the AR+ mesenchymal cells to elicit the synthesis and secretion of KGF which in turn stimulates epithelial growth and development.