Abstract
Chemokines are a family of small, secreted cytokines which regulate a variety of cell functions. The C-X-C motif chemokine ligand 12 (CXCL12) binds to C-X-C chemokine receptor type 4 (CXCR4) and C-X-C chemokine receptor type 7 (CXCR7). The interaction of CXCL12 and its receptors subsequently induces downstream signaling pathways with broad effects on chemotaxis, cell proliferation, migration, and gene expression. Accumulating evidence suggests that the CXCL12/CXCR4/CXCR7 axis plays a pivotal role in tumor development, survival, angiogenesis, metastasis, and tumor microenvironment. In addition, this chemokine axis promotes chemoresistance in cancer therapy via complex crosstalk with other pathways. Multiple small molecules targeting CXCR4/CXCR7 have been developed and used for preclinical and clinical cancer treatment. In this review, we describe the roles of the CXCL12/CXCR4/CXCR7 axis in cancer progression and summarize strategies to develop novel targeted cancer therapies.
Highlights
Chemokines are small secreted peptides with molecular weights in the range of 8–12 kD (Rollins, 1997)
This review summarizes the downstream cell signaling transduction of CXCL12/CXCR4/CXCR7 axis and the role of CXCL12 axis in tumor progression, growth, survival, angiogenesis, metastasis, and chemoresistance
There are four possible mechanisms by which CXCL12/CXCR4 regulates tumor angiogenesis: 1) upregulates vascular endothelial growth factor (VEGF) expression in tumor tissue through the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway; 2) reduces the expression of glycolytic enzyme phosphoglycerate kinase 1 (PGK1) which suppresses the secretion of VEGF; 3) upregulates several angiogenesis-associated genes in cancer cells; and 4) directs the recruitment of endothelial progenitor cells to the vicinity of neovascularization
Summary
Chemokines are small secreted peptides with molecular weights in the range of 8–12 kD (Rollins, 1997). There are four possible mechanisms by which CXCL12/CXCR4 regulates tumor angiogenesis: 1) upregulates vascular endothelial growth factor (VEGF) expression in tumor tissue through the PI3K/Akt signaling pathway; 2) reduces the expression of glycolytic enzyme phosphoglycerate kinase 1 (PGK1) which suppresses the secretion of VEGF; 3) upregulates several angiogenesis-associated genes in cancer cells; and 4) directs the recruitment of endothelial progenitor cells to the vicinity of neovascularization. CXCL12 secreted by carcinoma-associated fibroblasts (CAFs) stimulates tumor growth directly, acting through CXCR4 expressed by breast cancer cells and promoting invasiveness (Orimo et al, 2005). Further investigation indicated that SELNs induce the activation of NFκB, the expression and secretion of CXCL12, and stimulation of CXCR4/AKT survival pathway, resulting in protection of these tumor cells from death (Beloribi-Djefaflia et al, 2015). A deep understanding of CXCL12 axis in therapeutic applications would be beneficial for future translation of CXCL12, CXCR4, and CXCR7 inhibitors into clinical use
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