ACINAR DIFFERENTIATION BY NONMALIGNANT IMMORTALIZED HUMAN PROSTATIC EPITHELIAL-CELLS AND ITS LOSS BY MALIGNANT-CELLS

Invasive prostatic carcinomas and prostatic intraepithelial neoplasia (PIN) are characterized by a loss of normal cell organization, cell po larity, and cell:cell and cell:basement membrane adhesion, The objecti ve of this study was to establish in vitro three-dimensional (3-D) cel l models which can be used to investigate mechanisms involved in acina r morphogenesis and differentiation in normal prostatic epithelium and their abnormalities in cancer cells, The process of acinar morphogene sis, including structural and functional differentiation, was investig ated by culture on basement membrane gels (Matrigel). The human papill omavirus 18 immortalized, non-tumorigenic cell line RWPE-1, the v-Ki-r as transformed, tumorigenic RWPE-2 cell line derived from RWPE-1 cells (see previous paper pp, 1221-1229) and the human prostatic carcinoma cell line DU-145 were used, When cultured on Matrigel, RWPE-2 cells re main as single cells or form small aggregates and DU-145 cells form la rge amorphous cell aggregates without any organization or lumen, In co ntrast, RWPE-1 cells form acini of polarized epithelium with a distinc t lumen, show a distinct laminin basement membrane, and express alpha 6 beta 1 integrins at their basal end, Exposure to conditioned medium from NIH 3T3 cultures accelerates glandular morphogenesis. Parallel cu ltures maintained as monolayers on plastic remain as monolayers. In th e presence of the synthetic androgen mibolerone, acinar cells express prostate specific antigen (PSA) as determined by immunostaining, We co nclude that normal prostate cells can undergo acinar morphogenesis whi le tumorigenic cells have lost this ability, The 3-D cultures provide physiologically relevant in vitro models for elucidating regulation of growth, morphogenesis and differentiation in the normal human prostat e, for defining heterotypic interactions in benign prostatic hyperplas ia and for establishing the basis for the loss of normal cell organiza tion in early neoplastic lesions such as PIN as well as during tumor p rogression in prostate cancer.