Prostatic epithelial cells in vivo are polarized both structurally and functionally. However, investigation of the role of polarized epithelial cell secretions in the regulation of normal and aberrant growth has been hindered by a lack of an appropriate experimental system. Preliminary studies in this research proposal demonstrate that normal and neoplastic prostatic epithelial cells can be, grown as polarized confluent epithelial sheets in bicameral culture chambers in a manner that better mimics their in vivo counterparts. In addition, the apical and basal surfaces of the prostatic epithelial cells grown in the bicameral chambers can bc independently monitored and experimentally modified, thereby allowing investigation of the role of polarized secretion from these cells in the physiology of normal and malignant growth. In particular, the aims of this research proposal are 1/ to further develop the bicameral culture chamber system thereby facilitating investigation of 2/ the role of paracrine interactions between epithelial cells and stromal cells in the regulation of normal and aberrant growth, and 3/ to test the hypothesis that oncogenic transformation may be associated with a loss of polarity, or polarity reversal or protein secretion in a basolateral direction. Indeed, epithelial cell transformation has been associated with a morphological loss of polarity (anaplasia) in the prostate for many years. In this context, a functional association between oncogenic transformation and polarity reversal of protease secretion could play a role in overwhelming the extracellular matrix of the underlying basement membrane, thereby enhancing extracellular matrix degradation that has been associated with metastasis. In addition, a transformation associated polarity reversal of protein secretion could potentially explain the elevated titers of prostatic acid phosphatase in the serum of patients with prostatic carcinomas. These experiments should provide significant new information on the mechanisms involved in the paracrine regulation of prostatic growth. Secondly, these experiments may demonstrate a transformation associated polarity reversal of protein secretion, and how such a transformation associated phenomena may facilitate metastasis, and explain elevated titers of prostatic acid phosphatase in the serum of patients with prostatic carcinomas. In this context, the long term objectives of this research proposal are to elucidate the mechanisms which are involved in the regulation of normal and aberrant prostatic growth, and therefore, may be manipulated in order to modify and control such aberrant growth.
