BIOLOGICAL ACTIVITY OF IGF AND FGF IN THE HUMAN PROSTATE

University Of California San Francisco, San Francisco CA

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Abstract

DESCRIPTION The long-term objective of this research project is to develop a better understanding of the cell-cell signaling mechanisms involved in the development, maintenance and disease of the human prostate. The main goal of this application is to investigate the ontogeny and androgen regulation of insulin-like growth factors -1 (IGF-I) and -II, fibroblast growth factors -2 (FGF-2) and -7 and their receptors in the growing fetal and the growth-quiescent adult human prostate in vivo. Expression of these molecules in benign prostatic hyperplasia and prostate cancer will be assessed to determine whether IGF-I and -II and FGF-2 and -7 are involved in prostatic disease. The hypothesis of this project is that expression of specific growth factors is determined by a combination of androgen action and the differentiation state of the epithelial and stromal compartments of the prostate tissue. Androgens induce the expression of autocrine and paracrine acting growth factors which mediate specific developmental events in the prostate. Additionally, the pattern of growth factor expression varies, not only with developmental status but also with tissue pathology, to control local proliferation or growth quiescence. This hypothesis will be tested through the following specific aims: 1) analysis of the expression of FGF-2 and -7 and IGF-I and -II and their receptors by epithelium and mesenchyme during human prostatic growth and differentiation; 2) analysis of the expression of FGF-2 and -7 and IGF-I and -II and their receptors by epithelium and stroma in the growth quiescent human prostate; 3) analysis of the expression of FGF-2 and -7 and IGF-I and -II and their receptors in the epithelium and stroma of the human prostate following castration and subsequent androgenic stimulation; 4) the role of FGF-2 and -7 and IGF-I and-II in controlling prostatic mitogenesis and morphogenesis in vitro; and 5) analysis of the expression of FGF-2 and -7 and IGF-I and -II and their receptors in human prostatic disease. The models to pursue these aims will be subrenal capsule grafts of fetal and adult human prostate tissue and heterospecific tissue recombinants composed of rat urogenital sinus mesenchyme recombined with human prostate epithelium. We will also use explant culture and tissue from samples of benign prostatic hyperplasia and prostate cancer. Qualitative and quantitative analysis will be by RTPCR, species specific RT-PCR, RNase protection, Northern and Western blotting. Proteins will be localized by immunocytochemistry. The biological effects of the growth factors will be examined in vitro, using application of exogenous growth factors and blockade of their production and action.