Abstract
CXC chemokine receptor type 4 (CXCR4) is a member of the G protein-coupled receptors (GPCRs) superfamily and is specific for CXC chemokine ligand 12 (CXCL12, also known as SDF-1), which makes CXCL12/CXCR4 axis. CXCR4 interacts with its ligand, triggering downstream signaling pathways that influence cell proliferation chemotaxis, migration, and gene expression. The interaction also regulates physiological processes, including hematopoiesis, organogenesis, and tissue repair. Multiple evidence revealed that CXCL12/CXCR4 axis is implicated in several pathways involved in carcinogenesis and plays a key role in tumor growth, survival, angiogenesis, metastasis, and therapeutic resistance. Several CXCR4-targeting compounds have been discovered and used for preclinical and clinical cancer therapy, most of which have shown promising anti-tumor activity. In this review, we summarized the physiological signaling of the CXCL12/CXCR4 axis and described the role of this axis in tumor progression, and focused on the potential therapeutic options and strategies to block CXCR4.
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Abbreviations
- AA:
-
Aplastic anemia
- ACKR3:
-
Atypical chemokine receptor 3
- ADM:
-
Adriamycin
- AhR:
-
Hydrocarbon receptor
- ALL:
-
Acute myeloid leukemia
- AML:
-
Acute myeloid leukemia
- APL:
-
Acute promyelocytic leukemia
- BAD:
-
Bcl2-associated agonist of cell death
- bFGF:
-
Basic fibroblast growth factor
- Bim:
-
Bcl2 interacting mediator of cell death
- BM:
-
Bone marrow
- BMSC:
-
Bone marrow stromal cells
- CAF:
-
Carcinoma-associated fibroblast
- CLL:
-
Chronic lymphocytic leukemia
- CML:
-
Chronic myeloid leukemia
- COX-2:
-
Cyclooxygenase-2
- CRC:
-
Colorectal cancer
- CSC:
-
Cancer stem cell
- CXCL12:
-
CXC chemokine ligand 12
- CXCR4:
-
CXC chemokine receptor type 4
- DAG:
-
Diacylglycerol
- DR5:
-
Death receptors 5
- ECM:
-
Extracellular matrix
- EGF:
-
Epidermal growth factor
- EGFR:
-
Epidermal growth factor receptor
- EMT:
-
Epithelial-to-mesenchymal transition
- EPC:
-
Endothelial progenitor cell
- ERK:
-
Extracellular signal-regulated kinase
- FAK:
-
Focal adhesion kinase
- FDA:
-
Food and Drug Administration
- GBM:
-
Glioblastoma multiforme
- GDP:
-
Guanine nucleotide diphosphate
- GPCR:
-
G protein-coupled receptor
- GRK:
-
G protein-coupled receptor kinase
- GTP:
-
Guanine nucleotide triphosphate
- HCC:
-
Hepatocellular carcinoma
- HD:
-
Hodgkin disease
- HER2:
-
Human epidermal growth factor receptor 2
- HIF-1α:
-
Hypoxia-inducible factor 1-alpha
- HIV:
-
Human immunodeficiency virus
- HNSCC:
-
Head and neck squamous cell carcinoma
- HSC:
-
Hematopoietic stem cell
- IL:
-
Interleukin
- IP3:
-
Inositol (1,4,5)-trisphosphate
- JAK:
-
Janus kinase
- JNK:
-
C-Jun N-terminal kinase
- MAPK:
-
Mitogen-activated protein kinase
- Mcl-1:
-
Myeloid cell leukemia-1
- mCRPC:
-
Metastatic castration-resistant prostate cancer
- MDS:
-
Myelodysplastic syndrome
- MiRNA:
-
MicroRNA
- MM:
-
Multiple myeloma
- MMP:
-
Matrix metalloproteinase
- mTOR:
-
Mammalian target of rapamycin
- mTORC2:
-
MTOR complex 2
- NF-κB:
-
Nuclear factor-kappa B
- NHL:
-
Non-Hodgkin’s lymphoma
- NK:
-
Natural killer cell
- NSCLC:
-
Non-small cell lung cancer
- PAH:
-
Pulmonary artery hypertension
- PBSF:
-
Pre-B-cell growth stimulating factor
- PD1:
-
Programmed cell death protein 1
- PDX:
-
Patient-derived xenograft
- PI3K:
-
Phosphoinositide 3-kinase
- PIP2:
-
Phosphatidylinositol (4,5)-bisphosphate
- PKB (AKT):
-
Protein kinase B
- PKC:
-
Protein kinase C
- PLC-β:
-
Phospholipase C beta
- r/r AML:
-
Relapsed/refractory acute myeloid leukemia
- r/r MM:
-
Relapsed/refractory multiple myeloma
- RCC:
-
Renal cell carcinoma
- RGS:
-
Regulators of G protein signaling
- RTK:
-
Receptor tyrosine kinase
- SAPK:
-
Stress-activated protein kinase
- SCLC:
-
Small cell lung cancer
- SDF-1:
-
Stromal cell-derived factor 1
- SOC:
-
Standard of care
- STAT:
-
Signal transducer and activator of transcription
- TGFβ:
-
Transforming growth factor-beta
- TNBC:
-
Triple-negative breast cancer
- VEGF:
-
Vascular endothelial growth factor
- VEGFR:
-
Vascular endothelial growth factor receptor
- WHIM:
-
Warts, hypogammaglobulinemia, immunodeficiency, myelokathexis
- WM:
-
Waldenström macroglobulinemia
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Acknowledgement
The authors would like to thank the Deanship of Scientific Research at Umm Al-Qura University for supporting this work by Grant Code: (22UQU4331100DSR11).
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The authors would like to thank the Deanship of Scientific Research at Umm Al-Qura University for supporting this work by Grant Code: (22UQU4331100DSR11)". The authors are also grateful to Scientific Research Deanship at King Khalid University, Abha, Saudi Arabia for their financial support through the Large Research Group Project under grant number (RGP.02-87-43).
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SB, MD, AHA, MAH, IP, and KHK contributed to the hypothesis, data gathering, and writing the main text of the manuscript. IA, FA, ZHA, and MEA contributed to designing figures and tables. MEA, AAS, and YFM contributed to writing, scientific, and structural editing. RAS also reviewed and revised the text. BAK and BTF supervised the work and provided the comments and additional scientific information. All authors read and approved the final version of the work to be published.
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Mohammad Darvishi is co-first author.
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Bao, S., Darvishi, M., H Amin, A. et al. CXC chemokine receptor 4 (CXCR4) blockade in cancer treatment. J Cancer Res Clin Oncol 149, 7945–7968 (2023). https://doi.org/10.1007/s00432-022-04444-w
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DOI: https://doi.org/10.1007/s00432-022-04444-w