Polyfunctionality of the CXCR4/CXCL12 axis in health and disease: Implications for therapeutic interventions in cancer and immune‐mediated diseases

Abstract

Historically the chemokine receptor CXCR4 and its canonical ligand CXCL12 are associated with the bone marrow niche and hematopoiesis. However, CXCL12 exhibits broad tissue expression including brain, thymus, heart, lung, liver, kidney, spleen, and bone marrow. CXCR4 can be considered as a node which is integrating and transducing inputs from a range of ligand-receptor interactions into a responsive and divergent network of intracellular signaling pathways that impact multiple cellular processes such as proliferation, migration, and stress resistance. Dysregulation of the CXCR4/CXCL12 axis and consequent fundamental cellular processes, are associated with a panoply of disease. This review frames the polyfunctionality of the receptor at a molecular, physiological, and pathophysiological levels. Transitioning our perspective of this axis from a single gene/protein:single function model to a polyfunctional signaling cascade highlights the potential for finer therapeutic intervention and cautions against a reductionist approach.

Tumor-to-tumor metastasis of diffuse large B cell lymphoma to gastric adenocarcinoma via CXCL12 (SDF-1)/CXCR4 axis: a case report

“…As for the mechanism by which one tumor metastasizes into another, it is reasonable to implicate the involvement of specific chemokines since a particular chemokine-receptor pair can serve as tissue-specific attractant molecules for tumor cells, promoting tumor cell migration to particular sites [ 7 – 9 ]. For example, a potential chemokine-receptor pair was examined by immunohistochemical staining in a patient with small cell lung carcinoma (SCLC) metastasizing to renal oncocytoma (RO) [ 10 ].…”

Unraveling the IGF System Interactome in Sarcomas Exploits Novel Therapeutic Options

“…The G protein-coupled receptor chemokine (C-X-C motif) receptor 4 (CXCR4) is the membrane receptor for the chemokine CXCL12 and was originally identified in peripheral blood leukocytes and other cell types like hematopoietic stem cells, stromal fibroblasts and tumor cells [246,247]. Ligand binding leads to the release of G protein subunits, which bind and activate phospholipase C, PI3K/Akt or Ras/MEK/ERK signaling pathways.…”

“…Ligand binding leads to the release of G protein subunits, which bind and activate phospholipase C, PI3K/Akt or Ras/MEK/ERK signaling pathways. In cancer, CXCR4-dependent signaling mediates various processes including cell survival, proliferation, migration, adhesion, stress resistance [247]. Various CXCR4 antagonist have been developed and tested in clinical trials.…”

“…A phase IIa trial is testing the safety profile, tolerability and pharmacodynamics effects of BL-8040 in combination with nelarabine for relapsed or refractory T-acute lymphoblastic leukemia/lymphoblastic lymphoma (NCT02763384). A phase I study will investigate the safety, tolerance and efficacy of CXCR4 modified CAR T cells in patients who failed standard treatment/refractory/relapsed multiple myeloma (NCT04727008) while the CXCR4 antagonist AMD3100 was tested in a variety of tumor types [247].…”

“…Crosstalk between the CXCR4 and IGF axis has been documented in embryonal development and cancer [247,248]. In embryonic germline stem cells, a reciprocal transactivation was observed between the IGF1/IGF1R and CXCL12/CXCR4 axes [248].…”