The Impact of Androgen, Extracellular Matrix, and Stroma Upon Proliferation and Differentiation of Benign and Malignant Prostate Epithelial Cells

Abstract

Mesenchymal-epithelial interactions are thought to playa strategic role in androgen-induced regulation of prostate epithelial cell growth and differentiation. A more thorough understanding of this process has been facilitated by recent advances permitting the separation and cultivation of stromal/ epithelial elements from benign and malignant human prostate glands. Our laboratory has devised an in vitro system to selectively dissect those factors influencing the divergent phenotypes of proliferation and differentiation. The epithelial “targets” utilized in this study included: (1) benign prostatic epithelial cells (BPE) isolated from open prostatectomy specimens; and (2) the hormone-sensitive prostate cancer cell line, LNCaP. Growth was measured by sequential cell counts and differentiation was correlated with the ability of these epithelial cell populations to secrete prostate specific acid phosphatase (PSAP) and prostate specific antigen (PSA) into their respective conditioned medium. Major variables in our culture system included the presence/absence of dihydrotestosterone (DHT), basement membrane biomatrix (Matrigel), and/or stromal extracellular matrix (ECM). Observations relevant to BPE include: (1) the formation of distinct cell clusters when grown on Matrigel vs typical monolayer morphology when cultivated on plastic; (2) a modest increase in PSAP and PSA secretion in the presence of DHT and stromal conditioned media (SCM); and (3) maximal production of PSAP and PSA when these cells are grown on Matrigel in the presence of DHT and SCM. With respect to LNCaP cells, we observed: (1) growth on plastic in the presence of DHT was associated with marked proliferation and modest production of PSAP and PSA; and (2) when cultured on ECM derived from human prostate stromal cells, LNCaP demonstrated a reduced growth response to DHT but maximized their secretion of the two differentiation markers. Thus, this in vitro system may facilitate more detailed biochemical and morphological studies designed to probe the impact of stromal/epithelial interaction on the phenotypes of proliferation and differentiation involving both benign and malignant prostate systems.