Role of Androgens and Extracellular Matrix in the Growth and Differentiation of Benign and Malignant Prostate Epithelial Cells

Abstract

Normal tissues maintain a balance between growth and differentiation. During normal adult life, the prostatic epithelium undergoes little net growth but synthesizes and secretes proteins such as prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) which are markers of differentiated function in the prostate. In prostatic neoplasia, regulation of prostate epithelial cell growth is diminished resulting in abnormal proliferation of the prostatic epithelium. the intra- and extracellular factors involved in promoting prostate epithelial growth and differentiation are poorly understood. Studies were undertaken in our laboratory to develop an in vitro system to selectively promote prostate epithelial cell growth or differentiation. Cultivation of freshly isolated epithelial cells from benign prostate on mesenchymal extracellular matrix (ECM) resulted in the formation of acinarlike structures as opposed to the characteristic monolayers observed on plastic. Differentiated morphology was further demonstrated by electron microscopic analysis showing the presence of apical microvilli, numerous secretory vesicles and hemidesmosome-like structures in epithelial cells cultured on ECM. Cultivation of epithelial cells on plastic resulted in a 10 fold increase in cell growth compared to cells grown on ECM. However, a four-fold increase in PSA and PAP secretions were noted following cultivation of epithelial cells on ECM compared to plastic in the presence of 10-nM dihydrotestosterone (DHT) and 1 mg/ml of prostate stromal cell conditioned medium (SCM). Similarly, cultivation of the prostate cancer celliine LNCAP on prostate stromal ECM resulted in promotion of differentiated function as indicated by acinar-like morphology, reduced growth and enhanced PSA/PAP secretion. Addition of DHT and SCM further promoted the ability of ECM to enhance differentiated properties in LNCAP. On plastic, addition of DHT stimulated an 8-fold increase in LNCAP growth compared to cells grown on ECM but had little impact on PSA/PAP secretion. These data show that: 1) cultivation of benign or malignant prostate epithelial cells on plastic will promote cell growth but not PSA/ PAP secretion; 2) prostate epithelial cells grown on ECM exhibit differentiated function as indicated by acinar-like morphology, reduced growth and increased PSA/PAP secretion and 3) addition of androgens and prostate stromal secretory products will greatly enhance PSA and PAP secretion by prostate epithelial cells on ECM.