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 includes two major ligands, (IGF-I and IGF-II), cell surface receptors, (the type I IGF receptor family as well as the type II IGF receptor), a family of high affinity binding proteins which regulate IGF availability to the receptors, (the IGFBPs), and a group of IGFBP proteases which cleave IGFBBPs and modulate IGF action. Human seminal plasma contains IGF-I and -II, IGFBP-2 and -4, as well as IGFBP3 fragments and IGFBP3 protease activity. A prostatic source for these IGF-axis molecules is likely. We have demonstrated the human prostate to contain all the elements of a functional IGF system. Prostate fibroblasts in primary culture (PC-F) express mRNA for IGF-II and produce IGF-II peptide in biologically active concentrations. This TGF-II appears to be of a high molecular weight (15kD) species. Prostate epithelial cells in primary culture (PC-E) express the type I IGF receptor. These cells also produce IGFBP-2 and -4, (on both mRNA and peptide levels), while PC-F secrete IGFBP-2,-3 and -4. PC-E are exquisitely sensitive to the mitogenic effects of IGFs. Finally, prostate specific antigen (PSA), secreted from PC- and found in seminal plasma, can function as a potent IGFBP3 protease. This IGFBP3 protease activity can remove the inhibitory effects of IGFBP3 on IGF-I induced PC-3 growth. We have recently shown that PC-F from patients with benign prostatic hypertrophy (BPH) hyper-express mRNA for IGF-II. This observation and other related findings suggest a regression of these fibroblasts to a state reminiscent of fetal fibroblasts. This molecular alteration in a critical component of the prostatic IGF axis in BPH patients may also be involved in the pathogenesis of abnormal prostate epithelial proliferation.