We propose to investigate the pathophysiological role and the potential diagnostic importance of the insulin-like growth factors (IGFs), their receptors, and their binding proteins (IGFBPs) in the etiology and pathogenesis of benign prostatic hyperplasia (BPH). BPH is the most common proliferative disorder affecting men, and is a major cause of morbidity and health care expenditure in older men. At this time, however, there are no reliable biochemical markers of this disease available to clinicians caring for older men. The pathophysiology of BPH is not yet elucidated, but appear to be related to interactions between the stromal and epithelial components of the prostate and to involve locally produced growth factors. The IGFs are important mitogenic factors that have been shown to have autocrine-paracrine, as well as endocrine roles in normal and malignant cellular growth. The IGFs exert their actions by binding to specific cell surface receptors (IGF-R) which mediate cellular proliferation, and also bind to a family of specific IGFBPs which modulate IGF action on cells. Using primary human prostatic cell culture systems, we have established the presence of a fully functioning IGF axis within the prostate. This system includes IGF-II production by prostate stromal cells (PC-S), IGF binding to IGF-R and IGF action on prostate epithelial cells (PC-E), as well as IGFBP production and proteolysis. Thus, the human prostate comprises an autocrine-paracrine system of IGF interaction. Additionally, we have already identified several IGF related abnormalities in PC-S from BPH patients. These include a ten fold increase in the levels of expression of IGF-II mRNA, a four fold increase in the levels of expression of the IGF-R mRNA and a dramatic fall in the levels of the mRNA and peptide levels of IGFBP-2 coupled with an appearance of IGFBP-5 peptide and mRNA not seen in normal PC-S. These findings suggest that the PC-S in BPH patients harbors molecular abnormalities involving the IGF axis. These abnormalities may promote abnormal cellular proliferation via the IGF system. We plan to further characterize the IGF system in cultured prostate cells and in prostate tissue from BPH patients and from normal controls, in order to verify our preliminary findings, and to try to pinpoint the primary IGF-related molecular abnormality associated with BPH. Using specific methodologies for the identification of IGF related molecules, we will attempt to identify corresponding IGF and IGFBP markers in the sera and seminal plasma of men with BPH. We expect to observe specific elevations of PC-S-derived IGF-H and IGFBP-5 in the serum and/or seminal plasma of patients with BPH relative to age matched controls. The identification of specific, IGF-related abnormalities in cultured cells, tissues, and bodily fluids from BPH patients could have major diagnostic significance and may lead the way for earlier and more directed therapy for this common disease.
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