GROWTH-FACTORS MEDIATE GLUCOCORTICOID RECEPTOR FUNCTION AND DEXAMETHASONE-INDUCED REGRESSION OF OSTEOBLASTIC LESIONS IN HORMONE-REFRACTORY PROSTATE-CANCER

We investigated the ability of important regulators of osteoblast func tion, such as insulin-like growth factor I (IGF-I), transforming growt h factor beta 1 (TGF beta 1), and urokinase-type plasminogen activator (uPA) to act as mediators in cell-cell interactions between osteoblas t-like cells and metastatic prostate cancer cells, in vitro. In additi on, we assessed whether these growth substances can (a) mediate glycoc orticoid receptor (GR) function and (b) be implicated in dexamethasone -induced regression of osteoblastic tumors. Exogenous IGF-I, rat/human uPA, and PA-III (rat)/PC-3 (human) prostate cancer cells conditioned media (CM) stimulated the proliferation of mt (UMR 106 cells) and huma n (MG-63 cells) osteosarcoma cells. This mitogenic activity was comple tely neutralized by anti-IGF-I specific antibody. In addition, dexamet hasone decreased cell growth, up regulated TGF beta 1 mRNA, and down r egulated uPA mRNA expression in prostate cancer cells. Furthermore, it inhibited cell growth by activating latent-TGF beta 1 in osteoblast-l ike cells. In addition, dexamethasone down regulated the expression of lGF-I mRNA in osteoblast-like cells. Therefore, it is conceivable tha t uPA, TGF beta 1 and IGF-I mediate at least in part cell-cell interac tions and GR function in osteoblastic metastases. Conceivably, regress ion of the osteoblastic tumors produced by high-dose dexamethasone tre atment in hormone-refractory prostate cancer patients is been mediated by differential regulation of growth factors, locally.