Benign prostatic hypertrophy (BPH) occurs in the majority of elderly men and contributes significantly to the morbidity and mortality of this population. Although sex steroids are known to play an essential role in human prostatic growth, previous in vitro studies have failed to demonstrate a direct mitogenic effect of androgens or estrogens on human prostatic cells. Several growth factors, however, have been shown to stimulate prostatic epithelial and fibroblast cell growth in culture. This application proposes to study the interactive effects of sex steroids and growth factors on separate cultures of non-cancerous human prostatic epithelial and fibroblast cells as well as co-cultures of epithelial and fibroblast cells. The hypotheses of this proposal are that growth factors stimulate prostatic growth directly while sex steroids enhance growth indirectly, via the enhanced production of growth factors from specific cell types. Androgens target the prostatic acinar cells while estrogens act upon the prostatic basal cells. In addition, sex steroids, particularly androgens, may delay the onset of senescence in prostatic fibroblasts thereby rendering them more sensitive to the proliferative effects of growth factors. Stromal-epithelial interactions are essential in these interactive effects of sex steroids and growth factors.
In Aim I, it will be determined if several growth factors, including basic fibroblast growth factor (bFGF), epidermal growth factor (EGF) and insulin- like growth factor I (IGF-1) increase prostatic cellular proliferation and/or change the levels or cellular distribution of the mRNAs for the androgen and estrogen receptors.
In Aim 2, it will be determined whether sex steroids change the level or cellular distribution of the MRNAS for BFGF, EGF and IGF-1 in human prostatic epithelial (acinar and basal) and/or fibroblast cells. In addition, the effect of sex steroids on prostatic fibroblast senescence in vitro will be determined. To achieve these specific aims, the techniques of northern blot analysis and in situ hybridization combined with immunocytochemistry will be carried out on primary cultures of human prostatic epithelial and fibroblast cells derived from BPH surgical specimens. These studies may lead to new insights into the pathogenesis and treatment of benign prostatic hypertrophy.
|Levine, A C; Wang, J P; Ren, M et al. (1996) Immunohistochemical localization of steroid 5 alpha-reductase 2 in the human male fetal reproductive tract and adult prostate. J Clin Endocrinol Metab 81:384-9|
|Kirschenbaum, A; Ren, M; Erenburg, I et al. (1994) Estrogen receptor messenger RNA expression in human benign prostatic hyperplasia: detection, localization, and modulation with a long-acting gonadotropin-releasing hormone agonist. J Androl 15:528-33|