Tumor-derived CXCL8 signaling augments stroma-derived CCL2-promoted proliferation and CXCL12-mediated invasion of PTEN-deficient prostate cancer cells

摘要: Impaired PTEN function is a genetic hallmark of aggressive prostate cancers (CaP) and associated with increased CXCL8 expression signaling. The current aim was to further characterize biological responses mechanisms underpinning CXCL8-promoted progression PTEN-depleted cancer, focusing on characterizing the potential interplay between other disease-promoting chemokines resident within tumor microenvironment. Autocrine CXCL8-stimulation (i) CXCR1 CXCR2 in PTEN-deficient CaP cells suggesting self-potentiating signaling axis (ii) induced CXCR4 CCR2 PTEN-wild-type cells. In contrast, paracrine secretion CCL2 CXCL12 from stromal WPMY-1 fibroblasts monocytic macrophage-like THP-1 vitro studies demonstrated functional co-operation tumor-derived stromal-derived chemokines. CXCL12-induced migration PC3 CCL2-induced proliferation cancer were dependent upon intrinsic For example, co-culture experiments, CXCL12/CXCR4 but not CCL2/CCR2 supported fibroblast-mediated while underpinned monocyte-enhanced Combined inhibition both more effective inhibiting fibroblast-promoted cell motility repression attenuated CCL2-promoted We conclude that increases sensitivity responsiveness by concurrently upregulating receptor inducing chemokine synthesis. targeting may be required inhibit their multi-faceted actions promoting invasion CaP.