CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression

Abstract

Chemokines, small pro-inflammatory chemoattractant cytokines that bind to specific G-protein-coupled seven-span transmembrane receptors, are major regulators of cell trafficking and adhesion. The chemokine CXCL12 (also called stromal-derived factor-1) is an important α-chemokine that binds primarily to its cognate receptor CXCR4 and thus regulates the trafficking of normal and malignant cells. For many years, it was believed that CXCR4 was the only receptor for CXCL12. Yet, recent work has demonstrated that CXCL12 also binds to another seven-transmembrane span receptor called CXCR7. Our group and others have established critical roles for CXCR4 and CXCR7 on mediating tumor metastasis in several types of cancers, in addition to their contributions as biomarkers of tumor behavior as well as potential therapeutic targets. Here, we review the current concepts regarding the role of CXCL12 / CXCR4 / CXCR7 axis activation, which regulates the pattern of tumor growth and metastatic spread to organs expressing high levels of CXCL12 to develop secondary tumors. We also summarize recent therapeutic approaches to target these receptors and/or their ligands.

Figure 1. Chemokine family and their cognate receptors

Most chemokines can bind multiple receptors, and a single receptor can bind multiple chemokines. As shown in this case for most CC (green) and CXC (blue) chemokines. Decoy receptors (black) can also interact with multiple chemokines. By contrast, a minority of receptors (red) have only one ligand.

Figure 2. Schematic representation showing the role of microenvironment in tumor cell CXCR4 receptor activation in both the primary and metastatic sites

Molecular cross-talks between stroma and tumor cells in microenviroment may upregulate CXCR4 expression, which involve in tumorigenesis, and tumor cell intravasation. By CXCL12 gradients chemoattrcting of organ secretion, CXCR4-positive tumor cells in circulation may be responsible for the process of extravasation, and organ-specific metastasis. Abbreviation: CXL12 (SDF-1), stroma-derived factor; TGF-β, transforming growth factor-β; ECM, extracellular matric; IFN-γ, interferon-γ; NF-κB, nuclear factor κB; MMP-2,9, matrix metalloproteinase-2,9.