The Role of the CXCL12/CXCR4/CXCR7 Chemokine Axis in Cancer

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.

Keywords: C-X-C chemokine receptor type 4; C-X-C chemokine receptor type 7; C-X-C motif chemokine ligand 12; cancer progression; tumor microenvironment.

FIGURE 1

Proposed CXCL12/CXCR4/CXCR7 signaling pathways. After binding with CXCL12, CXCR4 activates downstream signaling through G proteins and GRKs. Dissociation of the G protein complexes subsequently triggers MAPK, ERK1/2, and AKT signaling pathways, thereby promoting cell survival and proliferation. GRKs mainly induce the recruitment of β-arrestin leading to CXCR4 internalization. CXCR7 could induce β-arrestin independently or through CXCR4/CXCR7 heterodimer, resulting in MAPK activation and CXCL12 scavenging. The question mark indicates that whether CXCR7 is coupled to G protein has been in debate.

FIGURE 2

Proposed positive feedback loops of CXCL12/CXCR4 signaling to enhance tumor cell proliferation. ERK1/2 MAPK activated by CXCL12/CXCR4 interaction induces c-Myc signaling, leading to CXCR4 upregulation with increased cancer cell proliferation. In addition, CXCL12 binding to CXCR4 triggers NFκB signaling, which induces SHH synthesis and release from the tumor cells. Secreted SHH promotes CXCL12 upregulation and release from the stromal cells after its binding to protein patched homolog (Ptch), which in turn activates CXCL12/CXCR4 axis in tumor cells.