CXCL12/CXCR4 signaling activates Akt‐1 and MMP‐9 expression in prostate cancer cells: The role of bone microenvironment‐associated CXCL12

BACKGROUND Hematopoietic cells home to bone by means of chemo-attraction to marrow chemokines, and interaction of chemokines with their receptors leads to the expression/activation of adhesion molecules and proteases. Recent evidence suggests that similar mechanisms may be active in cancer metastasis. Previously, we showed that metalloproteases (MMPs), and in particular MMP-9, play a role in prostate cancer (PC) expansion in bone. METHODS We used a variety of methods including RT-PCR, immunohistochemistry, ELISA, gelatin zymography, cellular motility and invasion, and subcellular fractionation of PC cells applied to in vivo and in vitro models. RESULTS Here we showed that (a) CXCL12/CXCR4 axis is expressed in PC bone metastasis; (b) exogenous CXCL12 induced MMP-9 expression by PC cells; (c) bone stromal cells and bone tissue conditioned media induced the migration of PC cells in a CXCR4-dependent manner; (d) pharmacological inhibition of PI3 kinase and MAP kinase pathways abrogated CXCL12-induced MMP-9 expression and invasion of PC cells; (e) exogenous CXCL12 induced Akt1 phosphorylation is indispensable for proMMP-9 secretion, migration, and invasion of PC cells; (f) CXCR4 was localized to lipid rafts in PC cells and initiated Akt phosphorylation. CONCLUSIONS These data suggest that chemoattractive mechanisms involve migration of cancer cells towards bone tissue, and that cell signaling induced by binding of the chemokine to its receptor leads to the activation of multiple signaling pathways and subsequent secretion of MMP-9 into the local environment. These findings provide a link between chemoattractive mechanisms, growth of tumor cells in bone, and tumor-enhanced bone matrix turnover. © 2005 Wiley-Liss, Inc.