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Growth factors mediate glucocorticoid receptor function and dexamethasone-induced regression of osteoblastic lesions
M Koutsilieris1, C Reyes-Moreno, A Sourla
1Department of Experimental Physiology, Medical School, University of Athens, Greece.
Abstract:
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.
Insights
This study shows that insulin-like growth factor I (IGF-I), transforming growth factor beta 1 (TGF-β1), and urokinase-type plasminogen activator (uPA) mediate interactions between osteoblast and prostate cancer cells. Dexamethasone influences these factors, potentially leading to tumor regression.
Area of Science:
- Oncology
- Endocrinology
- Cell Biology
Background:
- Prostate cancer bone metastases often form osteoblastic lesions.
- The role of growth factors in mediating cell-cell interactions in these lesions is not fully understood.
- Glucocorticoid receptor (GR) signaling is implicated in managing hormone-refractory prostate cancer.
Purpose of the Study:
- To investigate the role of insulin-like growth factor I (IGF-I), transforming growth factor beta 1 (TGF-β1), and urokinase-type plasminogen activator (uPA) in cell-cell interactions between osteoblast-like and prostate cancer cells.
- To determine if these factors mediate glucocorticoid receptor (GR) function.
- To assess their involvement in dexamethasone-induced regression of osteoblastic tumors.
Main Methods:
- In vitro co-culture models using osteosarcoma cell lines (UMR 106, MG-63) and prostate cancer cells (PC-3) or their conditioned media.
- Treatment with exogenous growth factors (IGF-I, uPA) and dexamethasone.
- Neutralization experiments using anti-IGF-I antibodies.
- Analysis of mRNA expression for TGF-β1 and uPA in prostate cancer cells.
- Assessment of latent-TGF-β1 activation in osteoblast-like cells.
Main Results:
- Exogenous IGF-I, uPA, and prostate cancer cell conditioned media stimulated osteosarcoma cell proliferation, an effect blocked by anti-IGF-I antibodies.
- Dexamethasone reduced prostate cancer cell growth, increased TGF-β1 mRNA, and decreased uPA mRNA expression.
- Dexamethasone promoted osteoblastic tumor regression by activating latent-TGF-β1 and downregulating IGF-I mRNA in osteoblast-like cells.
Conclusions:
- uPA, TGF-β1, and IGF-I are key mediators of cell-cell interactions and GR function in osteoblastic metastases.
- Dexamethasone-induced regression of osteoblastic tumors in hormone-refractory prostate cancer may involve the differential regulation of these growth factors.