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CXC chemokine receptor 4 (CXCR4) blockade in cancer treatment

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  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

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).

Funding

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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    Authors and Affiliations

    1. The First Clinical Medical College, Xuzhou Medical University, 221000, Xuzhou, China

      Shunshun Bao

    2. Infectious Diseases and Tropical Medicine Research Center (IDTMRC), Department of Aerospace and Subaquatic Medicine, AJA University of Medicinal Sciences, Tehran, Iran

      Mohammad Darvishi

    3. Deanship of Scientific Research, Umm Al-Qura University, 21955, Makkah, Saudi Arabia

      Ali H Amin

    4. Zoology Department, Faculty of Science, Mansoura University, 35516, Mansoura, Egypt

      Ali H Amin

    5. Department of Physiotherapy, Cihan University-Erbil, Erbil, Kurdistan Region, Iraq

      Maysoon T. Al-Haideri

    6. An Independent Researcher, National Institute of Technology Durgapur, Durgapur, West Bengal, India

      Indrajit Patra

    7. Kazakh-Russian National Medical University, Almaty, Kazakhstan

      Khadisha Kashikova

    8. Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia

      Irfan Ahmad

    9. College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia

      Fahad Alsaikhan

    10. Department of Anesthesia Techniques, Al-Mustaqbal University College, Hillah, Iraq

      Zahraa Haleem Al-qaim

    11. College of Medicine, University of Al-Ameed, Karbala, Iraq

      Moaed E. Al-Gazally

    12. Virology Department, Faculty of Veterinary Medicine, The University of Tehran, Tehran, Iran

      Bahman Abedi Kiasari

    13. Dietary Supplements and Probiotic Research Center, Alborz University of Medical Sciences, Karaj, Iran

      Bahareh Tavakoli-Far

    14. Department of Physiology and Pharmacology, Faculty of Medicine, Alborz University of Medical Sciences, Karaj, Iran

      Bahareh Tavakoli-Far

    15. Rector, Ferghana Medical Institute of Public Health, Ferghana, Uzbekistan

      Akmal A. Sidikov

    16. Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq

      Yasser Fakri Mustafa

    17. Department of Neurosurgery, University Medical Center Tuebingen, Tübingen, Germany

      Reza Akhavan-Sigari

    18. Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University, Warsaw, Poland

      Reza Akhavan-Sigari

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    1. Shunshun Bao
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    Contributions

    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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    Correspondence to Bahman Abedi Kiasari or Bahareh Tavakoli-Far.

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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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