CXCL12/CXCR4: a symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks

Abstract

Increasing evidence indicates that the tumor microenvironment has critical roles in all aspects of cancer biology, including growth, angiogenesis, metastasis and progression. Although chemokines and their receptors were originally identified as mediators of inflammatory diseases, it is being increasingly recognized that they serve as critical communication bridges between tumor cells and stromal cells to create a permissive microenvironment for tumor growth and metastasis. Thus, an important therapeutic strategy for cancer is to break this communication channel and isolate tumor cells for long-term elimination. Cytokine CXCL12 (also known as stromal-derived factor 1α) and its receptor CXCR4 represent the most promising actionable targets for this strategy. Both are overexpressed in various cancer types, and this aberrant expression strongly promotes proliferation, migration and invasion through multiple signal pathways. Several molecules that target CXCL12 or CXCR4 have been developed to interfere with tumor growth and metastasis. In this article, we review our current understanding of the CXCL12/CXCR4 axis in cancer tumorigenesis and progression and discuss its therapeutic implications.

Prognostic implication of antitumor immunity measured by the neutrophil–lymphocyte ratio and serum cytokines and angiogenic factors in gastric cancer

“…bFGF basic fibroblast growth factor, GRO-a melanoma growth stimulating activity a, IL-12Ra interleukin-12 receptor a, IL-12p70 interleukin -12 p70 In this study, we also found that SDF-1 was an independent prognostic factor in addition to the NLR. The interesting scope of the activities of SDF-1 regarding homeostasis of hematopoietic stem and progenitor cells in cancer induced by this chemokine has been highlighted by others [32,33]. SDF-1 (also known as CXCL12) has an important role in maintaining leukocyte homeostasis, especially for myeloid-derived suppressor cells, which includes trafficking and directing the migration of myeloidderived suppressor cells to immune-privileged organs or tumor microenvironments [34][35][36].…”

The Critical Role of PTEN/PI3K/AKT Signaling Pathway in Shikonin-Induced Apoptosis and Proliferation Inhibition of Chronic Myeloid Leukemia

“…SDF-1, also known as CXCL12 (chemokine C-X-C motif ligand 12), is a stromal cell-derived factor 1, which is the sole ligand of CXCR4 and a homeostatic chemokine, overexpressed in many human cancers [45,46]. Chemotaxis driven by CXCR4 and SDF-1 interactions has been shown to control various biological functions including cell adhesion, migration, and invasion [47]. Moreover, treatment with AMD3100, a selective CXCR4 antagonist, resulted in increased tumor apoptosis and knockdown of SDF-1, reducing cell proliferation and tumor growth [48].…”

CXCR4 Ligands: The Next Big Hit?

“…The role of CXCR4 in numerous physiologic and pathologic circumstances, such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis, has been elucidated (5). CXCR4 and CXCL12 play decisive roles in tumorigenesis, including the enhancement of cell proliferation, migration, and invasion; cancer cell-tumor microenvironment interactions; and angiogenesis (9)(10)(11).…”