CXCL12-CXCR4/CXCR7 Axis in Colorectal Cancer: Therapeutic Target in Preclinical and Clinical Studies

• Published in: International journal of molecular sciences 2021-07, Vol.22 (14), p.7371
• Main Authors: Khare, Tripti, Bissonnette, Marc, Khare, Sharad
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Bone marrow; Cancer; CD18 antigen; Cell surface; Chemokine CXCL12 - antagonists & inhibitors; Chemokine CXCL12 - metabolism; Chemokine receptors; Chemokines; Chemotherapy; Clinical trials; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; CXCL12; CXCL12 protein; CXCR4; CXCR4 protein; CXCR7; Cytokines; Dimerization; Drug development; Extracellular matrix; Fibroblasts; G protein-coupled receptors; Growth factors; Humans; Inhibitors; Ligands; Metastases; Metastasis; Mortality; Neoplasm Metastasis; Neutrophils; Proteins; Receptors, CXCR - antagonists & inhibitors; Receptors, CXCR - metabolism; Receptors, CXCR4 - antagonists & inhibitors; Receptors, CXCR4 - metabolism; Review; Rhodopsin; SDF-1 protein; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Solid tumors; Stem cells; therapeutics; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22147371

Chemokines are chemotactic cytokines that promote cancer growth, metastasis, and regulate resistance to chemotherapy. Stromal cell-derived factor 1 (SDF1) also known as C-X-C motif chemokine 12 (CXCL12), a prognostic factor, is an extracellular homeostatic chemokine that is the natural ligand for chemokine receptors C-X-C chemokine receptor type 4 (CXCR4), also known as fusin or cluster of differentiation 184 (CD184) and chemokine receptor type 7 (CXCR7). CXCR4 is the most widely expressed rhodopsin-like G protein coupled chemokine receptor (GPCR). The CXCL12-CXCR4 axis is involved in tumor growth, invasion, angiogenesis, and metastasis in colorectal cancer (CRC). CXCR7, recently termed as atypical chemokine receptor 3 (ACKR3), is amongst the G protein coupled cell surface receptor family that is also commonly expressed in a large variety of cancer cells. CXCR7, like CXCR4, regulates immunity, angiogenesis, stem cell trafficking, cell growth and organ-specific metastases. CXCR4 and CXCR7 are expressed individually or together, depending on the tumor type. When expressed together, CXCR4 and CXCR7 can form homo- or hetero-dimers. Homo- and hetero-dimerization of CXCL12 and its receptors CXCR4 and CXCR7 alter their signaling activity. Only few drugs have been approved for clinical use targeting CXCL12-CXCR4/CXCR7 axis. Several CXCR4 inhibitors are in clinical trials for solid tumor treatment with limited success whereas CXCR7-specific inhibitors are still in preclinical studies for CRC. This review focuses on current knowledge of chemokine CXCL12 and its receptors CXCR4 and CXCR7, with emphasis on targeting the CXCL12-CXCR4/CXCR7 axis as a treatment strategy for CRC.