Chemokine receptor trio: CXCR3, CXCR4 and CXCR7 crosstalk via CXCL11 and CXCL12

Abstract

Although chemokines are well established to function in immunity and endothelial cell activation and proliferation, a rapidly growing literature suggests that CXC Chemokine receptors CXCR3, CXCR4 and CXCR7 are critical in the development and progression of solid tumors. The effect of these chemokine receptors in tumorigenesis is mediated via interactions with shared ligands I-TAC (CXCL11) and SDF-1 (CXCL12). Over the last decade, CXCR4 has been extensively reported to be overexpressed in most human solid tumors and has earned considerable attention toward elucidating its role in cancer metastasis. To enrich the existing armamentarium of anti-cancerous agents, many inhibitors of CXCL12–CXCR4 axis have emerged as additional or alternative agents for neoadjuvant treatments and even many of them are in preclinical and clinical stages of their development. However, the discovery of CXCR7 as another receptor for CXCL12 with rather high binding affinity and recent reports about its involvement in cancer progression, has questioned the potential of “selective blockade” of CXCR4 as cancer chemotherapeutics. Interestingly, CXCR7 can also bind another chemokine CXCL11, which is an established ligand for CXCR3. Recent reports have documented that CXCR3 and their ligands are overexpressed in different solid tumors and regulate tumor growth and metastasis. Therefore, it is important to consider the interactions and crosstalk between these three chemokine receptors and their ligand mediated signaling cascades for the development of effective anti-cancer therapies. Emerging evidence also indicates that these receptors are differentially expressed in tumor endothelial cells as well as in cancer stem cells, suggesting their direct role in regulating tumor angiogenesis and metastasis. In this review, we will focus on the signals mediated by this receptor trio via their shared ligands and their role in tumor growth and progression.

Overexpression of CXCR4 promotes invasion and migration of non‑small cell lung cancer via EGFR and MMP‑9

“…Briefly, the Transwell inserts were coated with Matrigel (1 mg/ml; BD Biosciences) or Col-I (1.2 mg/ml, Sigma-Aldrich; Merck KGaA, catalog no. SAB4200678), and allowed to gel at 37˚C for 1 h. Subsequently, A549 cells (3x10 5 ) in 200 µl serum-free Dulbecco's modified Eagle's medium (Biowest, Nuaillé, France) were added to the top of the Transwell. Serum-free medium was then added to the lower chamber and incubated for 24 h at 37˚C.…”

“…CXC receptor 4 (CXCR4), considered as the only receptor of stromal-derived-factor-1 (also termed CXCL12), is an α-chemokine receptor (5). A number of studies have hypothesized that CXCR4 and CXCL12 increase the adhesive ability of tumors, as well as the degradation of the extracellular matrix (ECM) and basement membrane, which is beneficial to the invasion and metastasis of cancer cells (6)(7)(8)(9).…”

Secretion of IL‐1β from imatinib‐resistant chronic myeloid leukemia cells contributes to BCR–ABL mutation‐independent imatinib resistance

“…The chemokine CXCL12 (stromal cellderived factor-1) and its receptor CXCR4 play a major role in invasion, proliferation, angiogenesis, and metastasis. Recently, CXCR7 was identified as an alternate receptor for CXCL12 and CXCL11/I-TAC (interferon-inducible T-cell a chemoattractant) [42,43]. Both IL-1b and K562R culture medium significantly increased the production of CXCL11, whereas K562S culture medium did not (Fig.…”

Role of CXCL12/CXCR4-Mediated Circulating Fibrocytes in Pulmonary Fibrosis

“…The downstream intracellular signaling transduction pathways including Phosphatidylinositol 3-kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR), Rac1/extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MAPK), p38MAPK, stress-activated protein kinase (SAPK), c-Jun N-terminal kinase (JNK)/ activator protein-1 (AP-1), Janus kinase/signal transducers and activators of transcription (JAK/STAT). 45,46 CXCR4 is the predominant chemokine receptor on human fibrocytes. More and more evidence have indicated that substantial numbers of CXCR4 + fibrocytes can migrate and accumulate in lung in response to CXCL12 during pulmonary fibrosis.…”