SMOOTH MUSCLE-EPITHELIAL INTERACTIONS IN NORMAL AND NEOPLASTIC PROSTATIC DEVELOPMENT

A hypothesis is proposed that unifies prostatic developmental biology and carcinogenesis. The foundation of this hypothesis is the reciproca l interaction of epithelium and mesenchyme during prostatic developmen t followed thereafter by a reciprocal homeostatic interaction of epith elium and smooth muscle in adulthood. This smooth muscle-epithelial ce ll interaction is perturbed during prostatic carcinogenesis with adver se sequelae for both epithelium and smooth muscle. The following seque nce of events is proposed to occur: (1) Under the influence of androge ns, urogenital sinus mesenchyme (UGM) induces urogenital sinus epithel ium to undergo prostatic ductal morphogenesis and differentiation. (2) As prostatic epithelium differentiates, it in rum signals the UGM to differentiate into smooth muscle cells that closely surround the epith elial ducts. Differentiation of prostatic smooth muscle requires both an inductive signal from epithelium and androgens. (3) Once formed, pr ostatic smooth muscle participates in reciprocal homeostatic interacti ons. We propose that prostatic smooth muscle under the influence of an drogens signals to prostatic epithelium to maintain epithelial differe ntiation and to repress epithelial proliferation, while prostatic epit helium signals to prostatic smooth muscle to maintain smooth muscle di fferentiation. In adulthood, homeostasis is maintained through recipro cal interactions between smooth muscle and epithelial cells with minim al proliferation of either cell type. Prostatic carcinogenesis, which is initiated following genetic damage to prostatic epithelium, is surm ised to involve a sequential disruption in these reciprocal homeostati c interactions with ensuing dedifferentiation of both the emerging pro static carcinoma cells and smooth muscle. Thus, following genetic insu lt to prostatic epithelium the epithelium fails to signal appropriatel y to the smooth muscle, which then begins to dedifferentiate. As smoot h muscle differentiation begins to deviate, signaling from prostatic s mooth muscle to prostatic epithelium becomes anomalous resulting in pr ogressive loss of control over epithelial differentiation and prolifer ation. During progression of prostatic carcinogenesis a vicious cycle is established in which both prostatic epithelium and smooth muscle de differentiate. This hypothesis is based on the ontogeny of prostatic s mooth muscle differentiation during development and by the fact that t he amount of smooth muscle progressively diminishes in human prostatic adenocarcinomas during progression from low- to high-grade cancers. F inally, in experimental tissue recombinants in which various normal or neoplastic prostatic epithelia were grown in combination with embryon ic rat UGM, only normal (nonneoplastic) epithelia were capable of indu cing differentiation of prostatic smooth muscle in UGM. Based on sever al lines of evidence, it is now apparent that smooth muscle-epithelial interactions are the operative cell-cell interaction in the postnatal prostate which plays a key role in regulating epithelial differentiat ion, proliferation and carcinogenesis.