The Role of SDF-1 (Alpha) CXCR4/MMP in PC Bone Metastasis
Annual rept. 1 Mar 2003-28 Feb 2004
WAYNE STATE UNIV DETROIT MI
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Prostate cancer PC is the most commonly diagnosed solid malignancy and second leading cause of cancer death in US men. PC has a specific propensity to metastasize to bone. Mechanisms underlying organ-specific metastasis to bone likely include both chemoattractive homing phenomena and selective proliferative advantages of cancer cells in the marrow. Recent evidence implicates the chemokine SDF-1alpha and its receptor CXCR4 in organ-specific metastasis of breast cancer. Using several methods, we determined the expression of CXCR4 in prostate cancer bone tumor cells and cultured PC cells, and SDF-1alpha expression in human bone marrow stromal cells and human fetal bone tissue. In vitro treatment of PC cells with SDF-1alpha showed an increase in MMP-9 gene expression and protein secretion. Both P13 kinase and MAP kinase inhibitors abrogated SDF-la induced MMP-9 secretion in PC-3 cells, but P13 kinase inhibition is more potent abrogation of MMP-9 expression in PC- 3 cells. These data suggest that chemoattractive mechanisms mediated by SDF- 1 a and CXCR4 activate P13 kinase signaling pathway to release MMPs into local environment. Improved understanding of chemokine-receptor interactions and subsequent intracellular signaling pathways involved proteinase gene expression may lead to new therapeutic strategies aimed at interrupting the interactions between PC cells and bone.
- Anatomy and Physiology
- Medicine and Medical Research