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 function, such as insulin-like growth factor I (IGF-I), transforming growth factor beta 1 (TGF beta 1), and urokinase-type plasminogen activator (uPA) to act as mediators in cell-cell interactions between osteoblast-like cells and metastatic prostate cancer cells, in vitro. In addition, we assessed whether these growth substances can (a) mediate glucocorticoid 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 rat (UMR 106 cells) and human (MG-63 cells) osteosarcoma cells. This mitogenic activity was completely neutralized by anti-IGF-I specific antibody. In addition, dexamethasone decreased cell growth, up regulated TGF beta 1 mRNA, and down regulated uPA mRNA expression in prostate cancer cells. Furthermore, it inhibited cell growth by activating latent-TGF beta 1 in osteoblast-like cells. In addition, dexamethasone down regulated the expression of IGF-I mRNA in osteoblast-like cells. Therefore, it is conceivable that uPA, TGF beta 1 and IGF-I mediate at least in part cell-cell interactions and GR function in osteoblastic metastases. Conceivably, regression of the osteoblastic tumors produced by high-dose dexamethasone treatment in hormone-refractory prostate cancer patients is been mediated by differential regulation of growth factors, locally.
Koutsilieris
M
M
Department of Experimental Physiology, Medical School, University of Athens, Greece.
Reyes-Moreno
C
C
Sourla
A
A
Dimitriadou
V
V
Choki
I
I
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D017077:Culture Media, Conditioned; D003907:Dexamethasone / Q000494:pharmacology*; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008297:Male; D008934:Mitogens / Q000494:pharmacology; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology*; D012516:Osteosarcoma / Q000473:pathology; D011471:Prostatic Neoplasms / Q000473:pathology*; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology
D017077:Culture Media, Conditioned; D006133:Growth Substances; D008934:Mitogens; D011965:Receptors, Glucocorticoid; D016212:Transforming Growth Factor beta; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; D014568:Urokinase-Type Plasminogen Activator