Cxcr4, also known as fusin or CD184, is a 7-transmembrane helix G-protein-coupled receptor encoded by the Cxcr4 gene. It binds to its ligand, chemokine ligand 12 (CXCL12 or SDF-1), triggering multiple signaling pathways crucial for cell migration, hematopoiesis, cell homing, and retention in the bone marrow. It also directly controls the proliferation of non-hematopoietic cells and is involved in various physiological processes, such as the development of the immune system [1,2,4].

In cancer, overexpression of Cxcr4 in tumor tissues is highly correlated with tumor aggressiveness, metastasis, and recurrence, seen in cancers like breast, gastric, non-small cell lung, and gastrointestinal cancers. For example, in a meta-analysis of gastrointestinal cancer, overexpression of Cxcr4 was significantly associated with overall survival, and high Cxcr4 expression in esophageal, gastric, and colorectal cancers predicted a worse prognosis. In glioblastoma, Cxcr4 is maintained by intracellular pathways, associated with epithelial-mesenchymal transition, cancer stem cell generation and self-renewal, and is involved in aspects like radio-and chemotherapy resistance, cancer cell migration, tumor blood supply generation, and recruitment of vascular progenitor cells. In hematological malignancies, the Cxcr4/CXCL12 axis drives disease progression, boosts tumor cell survival, and promotes chemoresistance [2,3,5,6].

In conclusion, Cxcr4 is essential for multiple biological processes including cell migration, proliferation, and immune system development. Its role in various diseases, especially cancers, has been revealed through numerous studies. Understanding Cxcr4 from model-based research, though no KO/CKO mouse model-specific findings were in the provided abstracts, is crucial for developing therapeutic strategies to target diseases where Cxcr4 is dysregulated.

References:

1. Bianchi, Marco E, Mezzapelle, Rosanna. 2020. The Chemokine Receptor CXCR4 in Cell Proliferation and Tissue Regeneration. In Frontiers in immunology, 11, 2109. doi:10.3389/fimmu.2020.02109. https://pubmed.ncbi.nlm.nih.gov/32983169/

2. Yu, Jingjing, Zhou, Xu, Shen, Langtao. 2023. CXCR4-Targeted Radiopharmaceuticals for the Imaging and Therapy of Malignant Tumors. In Molecules (Basel, Switzerland), 28, . doi:10.3390/molecules28124707. https://pubmed.ncbi.nlm.nih.gov/37375261/

3. Richardson, Peter J. . CXCR4 and Glioblastoma. In Anti-cancer agents in medicinal chemistry, 16, 59-74. doi:. https://pubmed.ncbi.nlm.nih.gov/26299663/

4. Khamyath, Mélanie, Bonaud, Amélie, Balabanian, Karl, Espéli, Marion. 2023. [CXCR4 as a rheostat of humoral response]. In Medecine sciences : M/S, 39, 23-30. doi:10.1051/medsci/2022192. https://pubmed.ncbi.nlm.nih.gov/36692314/

5. Jiang, Qingtao, Sun, Yun, Liu, Xin. 2019. CXCR4 as a prognostic biomarker in gastrointestinal cancer: a meta-analysis. In Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals, 24, 510-516. doi:10.1080/1354750X.2019.1637941. https://pubmed.ncbi.nlm.nih.gov/31244335/

6. Martino, Enrica Antonia, Bruzzese, Antonella, Labanca, Caterina, Vigna, Ernesto, Gentile, Massimo. 2024. Investigational CXCR4 inhibitors in early phase development for the treatment of hematological malignancies. In Expert opinion on investigational drugs, 33, 915-924. doi:10.1080/13543784.2024.2388567. https://pubmed.ncbi.nlm.nih.gov/39096094/