Abstract
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.
Highlights
The incidence and mortality rates of colorectal cancer (CRC) vary remarkably around the world
Recent review articles related to C-X-C motif chemokine ligand 12 (CXCL12)-chemokine receptor type 4 (CXCR4)/ chemokine receptor type 7 (CXCR7) axis are focused on cancers in general, our focus in this review is to summarize the role of this axis in CRC progression and metastasis
Based on recent research that the CXCL12–CXC chemokine receptor 4 (CXCR4)/CXC receptor 7 (CXCR7) axis is involved in survival, tumor growth, angiogenesis, metastasis, tumor microenvironment (TME), and drug resistance, it is considered a promising target for therapeutic intervention
Summary
The incidence and mortality rates of colorectal cancer (CRC) vary remarkably around the world. Cancers are comprised of transformed cells and non-malignant cells including cancerassociated fibroblasts (CAF), endothelial vasculature cells and tumor infiltrating cells (T-cells, macrophages, and neutrophils) These nonmalignant cells, as well as soluble factors (cytokines and growth factors (GF)), and the extracellular matrix form the tumor microenvironment (TME) [6,7]. Coupling of one of the intracellular loops of the receptor to G-proteins mediates receptor binding to the ligand followed by activation of a series of signal transduction pathways [18] Based on their chemokine ligands, chemokine receptors are divided into two subfamilies: conventional chemokine receptors (cCKR) and atypical chemokine receptors (ACKR) [19]. Structures of ACKRs are highly homologous to conventional GPCRs, except that the atypical receptors do not induce chemotaxis [19] Rather, these ACKRs regulate intracellular storage, extracellular bioavailability, and distribution of chemokines in polarized cells [27]
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