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 (GPCRs), are major regulators of cell trafficking and adhesion. The chemokine CXCL12 [also called stromal-derived factor-1 (SDF-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.

Elevated expression of CXCR4 and correlation with clinicopathological features and prognosis of non-small cell lung cancer patients: a meta-analysis

“…The potential relationship between CXCR4 and NSCLC prognosis has been widely investigated; additionally, the significant role of CXCR4 in the proliferation and metastasis of various human tumors has also been demonstrated (Sun et al, 2010;Liang et al, 2014). In this meta-analysis, we attempted to explore the association between the levels of CXCR4 expression and the clinicopathological features and prognosis of NSCLC.…”

Role of CXCR7 and Effects on CXCL12 in SiHa Cells and Upregulation in Cervical Squamous Cell Carcinomas in Uighur Women

“…The significance of the CXCL12/CXCR4 axis in cervical cancer invasion and metastasis has been widely investigated (Huang et al, 2013). In addition to CXCR4, CXCR7 was a recently identified and as a second, high-affinity receptor for CXCL12, which was originally cloned on the basis of its homology with conserved domains of G-protein coupled seven-span transmembrane receptors (Sun et al, 2010;Zabel et al, 2011). This receptor is highly expressed by a variety of cancers, including breast, liver, and lung (Heinrich et al, 2012;Xue et al, 2013;Roy et al, 2014), as well as cervical cancer (Huang et al, 2013).…”

“…In particular, the stromal cell-derived factor-1 (CXCL12) is a broadly expressed cytokine that plays crucial roles in cellular migration, and are capable of coordinating multiple aspects of the cell migration machinery, which interact with G protein-coupled receptors to activate downstream signaling pathways that enhance cancer cell growth, migratory behavior, and cell survival (Sun et al, 2010;Shen et al, 2013), and it is also regulate the chemotactic responses of cells that are essential for organogenesis and immunity through the orchestration of cell movement from one location to another (Heinrich et al, 2012;Roy et al, 2014). CXCR4 and CXCR7 are two receptors of CXCL12 that have been identified.…”

Chemokines and their receptors in lung cancer progression and metastasis

“…In addition, CXCR4 might act to the transcriptional factor 5T4 downstream in EMT and consequently in migration (Damelin et al, 2011). Hence, high expression of CXCL12/CXCR4 is correlated with poor prognosis in NSCLC (Suzuki et al, 2008), and a substantial body of literature supports the fact that interruption of this ligand-receptor interaction can inhibit cancer cell migration and metastasis (Burger and Kipps, 2006;Sun et al, 2010;Xie et al, 2014).…”