CXCR4 is a pleiotropic chemokine receptor which acts through its ligand CXCL12 to regulate diverse physiological processes. CXCR4/CXCL12 axis plays a pivotal role in proliferation, invasion, dissemination and drug resistance in multiple myeloma (MM). Apart from its role in homing, CXCR4 also affects MM cell mobilization and egression out of the bone marrow (BM) which is correlated with distant organ metastasis. Aberrant CXCR4 expression pattern is associated with osteoclastogenesis and tumor growth in MM through its cross talk with various important cell signalling pathways. A deeper insight into understanding of CXCR4 mediated signalling pathways and its role in MM is essential to identify potential therapeutic interventions. The current therapeutic focus is on disrupting the interaction of MM cells with its protective tumor microenvironment where CXCR4 axis plays an essential role. There are still multiple challenges that need to be overcome to target CXCR4 axis more efficiently and to identify novel combination therapies with existing strategies. This review highlights the role of CXCR4 along with its significant interacting partners as a mediator of MM pathogenesis and summarizes the targeted therapies carried out so far.
Keywords: AMC, Angiogenic monomuclear cells; BM, Bone marrow; BMSC, Bone marrow stromal cells; CAM-DR, Cell adhesion‐mediated drug resistance; CCR–CC, Chemokine receptor; CCX–CKR, Chemo Centryx–chemokine receptor; CD4, Cluster of differentiation 4; CL—CC, Chemokine ligand; CNS, Central nervous system; CSCs, Cancer stem cells; CTAP-III, Connective tissue-activating peptide-III; CXCL, CXC chemokine ligand; CXCR, CXC chemokine receptor; EGF, Epidermal growth factor; EMD, Extramedullary disease; EPC, Endothelial progenitor cells; EPI, Endogenous peptide inhibitor; ERK, Extracellular signal related kinase; FGF, Fibroblast growth factor; G-CSF, Granulocyte colony-stimulating factor; GPCRs, G protein-coupled chemokine receptors; HCC, Hepatocellular carcinoma; HD, Hodgkin's disease; HGF, Hepatocyte growth factor; HIF1α, Hypoxia-inducible factor-1 alpha; HIV, Human Immunodeficiency Virus; HMGB1, High Mobility Group Box 1; HPV, Human papillomavirus; HSC, Hematopoietic stem cells; IGF, Insulin-like growth factor; JAK/STAT, Janus Kinase signal transducer and activator of transcription; JAM-A, Junctional adhesion molecule-A; JNK, Jun N-terminal kinase; MAPK, Mitogen Activated Protein Kinase; MIF, Macrophage migration inhibitory factor; MM, Multiple myeloma; MMP, Matrix metalloproteinases; MRD, Minimal residual disease; NHL, Non-Hodgkin's lymphoma; OCL, Octeoclast; OPG, Osteoprotegerin; PI3K, phosphoinositide-3 kinase; PKA, protein kinase A; PKC, Protein kinase C; PLC, Phospholipase C; Pim, Proviral Integrations of Moloney virus; RANKL, Receptor activator of nuclear factor kappa-Β ligand; RRMM, Relapsed/refractory multiple myeloma; SFM-DR, Soluble factor mediated drug resistance; VEGF, Vascular endothelial growth factor; VHL, Von Hippel-Lindau; WHIM, Warts, Hypogammaglobulinemia, Infections, and Myelokathexis; WM, Waldenström macroglobulinemia.