Constitutive expression of CXCL12 in human colorectal carcinoma cells reduced orthotopic tumor formation and inhibited metastasis in severe combined immunodeficient mice.
Consistent with those data, decreased metastasis reflected diminished intracellular calcium signaling and chemotactic migration in response to exogenous CXCL12 independent of changes in CXCR4 expression.
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.