Abstract
Prostate cancer metastasizes to bone in 80% of patients suffering from advanced disease. The nature of bone lesions is predominantly osteoblastic resulting in severe bone pain, hypocalcemia and nerve compression syndromes. Transforming growth factor-beta (TGFβ), which is a multifunctional cytokine, is a critical regulator of osteogenesis. Our group has recently shown that TGFβ signaling helps in promoting osteoblastic metastasis by a novel human prostate cancer cell line, PacMetUT1. TGFβ has been suggested to be one of the physiological upregulatory factors of bone aromatase in human osteoblast-like cells. Recent data further implicates an aberrant aromatase expression and estrogen signaling in the development of prostate malignancy. However, the effect of TGFβ superfamily ligands on aromatase expression and estrogen production and the mechanism by which osteoblastic lesions are formed have not been intensively investigated in prostate cancer cells. We hypothesize that TGFβ and other growth factors released from tumor cells can induce aromatase gene expression and activity in bone cells leading to an enhanced estradiol synthesis which would in turn lead to an increase in bone formation as estrogen is a known osteogenic factor. We examined the effect of TGFβ and BMP-4/7 on aromatase expression and osteogenic differentiation of pre-osteoblastic cells in vitro. Treatment with TGFβ 1 and BMP-4/7 resulted in an increase in aromatase expression in both mouse pre-osteoblasts and human bone marrow-derived mesenchymal stem cells. Treatment with letrozole (aromatase inhibitor) as well as an anti-estrogen (ICI 182, 780) resulted in a decrease in osteoblastic differentiation of mesenchymal stem cells as measured by alkaline phosphatase activity assay and expression of osteogenic markers by quantitative real-time PCR analysis. Furthermore, 17-β estradiol treatment of PacMetUT1 cells resulted in an enhanced anchorage-dependent and independent cell growth in vitro. This effect was very significantly inhibited by tamoxifen treatment, which is a selective estrogen receptor modulator. 17-β estradiol also induced a change in cell morphology of PacMetUT1 cells with a reduction in E-cadherin expression. Our results demonstrate an aromatase-mediated induction in osteogenesis by TGFβ superfamily ligands in the pre-osteoblastic cells and a stimulatory effect of estrogen signaling on PacMetUT1 cell tumorigencity in vitro. Future studies will delineate whether the induction of aromatase mediates osteoblastic bone metastasis of prostate cancer cells in vivo and if combination treatment of TGFβ and aromatase inhibitors can be used as a novel therapeutic strategy, to alleviate bone metastasis in prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B106.
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