THE IGF AXIS IN THE PROSTATE

The insulin-like growth factor (IGF) axis is a multi-component network of molecules involved in the regulation of cell growth. The axis incl udes two major ligands, (IGF-I and IGF-II), cell surface receptors, (t he type I IGF receptor family as well as the type II IGF receptor), a family of high affinity binding proteins which regulate IGF availabili ty to the receptors, (the IGFBPs), and a group of IGFBP proteases whic h cleave IGFBBPs and modulate IGF action. Human seminal plasma contain s IGF-I and -II, IGFBP-2 and -4, as well as IGFBP3 fragments and IGFBP 3 protease activity. A prostatic source for these IGF-axis molecules i s likely. We have demonstrated the human prostate to contain all the e lements of a functional IGF system. Prostate fibroblasts in primary cu lture (PC-F) express mRNA for IGF-II and produce IGF-II peptide in bio logically active concentrations. This TGF-II appears to be of a high m olecular weight (15kD) species. Prostate epithelial cells in primary c ulture (PC-E) express the type I IGF receptor. These cells also produc e IGFBP-2 and -4, (on both mRNA and peptide levels), while PC-F secret e IGFBP-2,-3 and -4. PC-E are exquisitely sensitive to the mitogenic e ffects of IGFs. Finally, prostate specific antigen (PSA), secreted fro m PC- and found in seminal plasma, can function as a potent IGFBP3 pro tease. This IGFBP3 protease activity can remove the inhibitory effects of IGFBP3 on IGF-I induced PC-3 growth. We have recently shown that P C-F from patients with benign prostatic hypertrophy (BPH) hyper-expres s mRNA for IGF-II. This observation and other related findings suggest a regression of these fibroblasts to a state reminiscent of fetal fib roblasts. This molecular alteration in a critical component of the pro static IGF axis in BPH patients may also be involved in the pathogenes is of abnormal prostate epithelial proliferation.