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

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.

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Atypical Chemokine Receptors in Cardiovascular Disease

Thrombosis and Haemostasis ◽

10.1055/s-0038-1676988 ◽

2019 ◽

Vol 119 (04) ◽

pp. 534-541 ◽

Cited By ~ 4

Author(s):

Selin Gencer ◽

Emiel van der Vorst ◽

Maria Aslani ◽

Christian Weber ◽

Yvonne Döring ◽

...

Keyword(s):

G Protein ◽

Chemokine Receptors ◽

Cellular Response ◽

Current Knowledge ◽

G Protein Coupled Receptors ◽

Signalling Pathways ◽

Atherosclerosis Development ◽

G Protein Coupled ◽

Precise Role

AbstractInflammation has been well recognized as one of the main drivers of atherosclerosis development and therefore cardiovascular diseases (CVDs). It has been shown that several chemokines, small 8 to 12 kDa cytokines with chemotactic properties, play a crucial role in the pathophysiology of atherosclerosis. Chemokines classically mediate their effects by binding to G-protein-coupled receptors called chemokine receptors. In addition, chemokines can also bind to atypical chemokine receptors (ACKRs). ACKRs fail to induce G-protein-dependent signalling pathways and thus subsequent cellular response, but instead are able to internalize, scavenge or transport chemokines. In this review, we will give an overview of the current knowledge about the involvement of ACKR1–4 in CVDs and especially in atherosclerosis development. In the recent years, several studies have highlighted the importance of ACKRs in CVDs, although there are still several controversies and unexplored aspects that have to be further elucidated. A better understanding of the precise role of these atypical receptors may pave the way towards novel and improved therapeutic strategies.

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Human G Protein–Coupled Receptor Gpr-9-6/Cc Chemokine Receptor 9 Is Selectively Expressed on Intestinal Homing T Lymphocytes, Mucosal Lymphocytes, and Thymocytes and Is Required for Thymus-Expressed Chemokine–Mediated Chemotaxis

Journal of Experimental Medicine ◽

10.1084/jem.190.9.1241 ◽

1999 ◽

Vol 190 (9) ◽

pp. 1241-1256 ◽

Cited By ~ 352

Author(s):

Brian A. Zabel ◽

William W. Agace ◽

James J. Campbell ◽

Heidi M. Heath ◽

David Parent ◽

...

Keyword(s):

Small Intestine ◽

T Lymphocytes ◽

G Protein ◽

Chemokine Receptor ◽

Chemokine Receptors ◽

Intraepithelial Lymphocytes ◽

Mucosal Immune Response ◽

G Protein Coupled Receptor ◽

Cc Chemokine ◽

G Protein Coupled

TECK (thymus-expressed chemokine), a recently described CC chemokine expressed in thymus and small intestine, was found to mediate chemotaxis of human G protein–coupled receptor GPR-9-6/L1.2 transfectants. This activity was blocked by anti–GPR-9-6 monoclonal antibody (mAb) 3C3. GPR-9-6 is expressed on a subset of memory α4β7high intestinal trafficking CD4 and CD8 lymphocytes. In addition, all intestinal lamina propria and intraepithelial lymphocytes express GPR-9-6. In contrast, GPR-9-6 is not displayed on cutaneous lymphocyte antigen–positive (CLA+) memory CD4 and CD8 lymphocytes, which traffic to skin inflammatory sites, or on other systemic α4β7−CLA− memory CD4/CD8 lymphocytes. The majority of thymocytes also express GPR-9-6, but natural killer cells, monocytes, eosinophils, basophils, and neutrophils are GPR-9-6 negative. Transcripts of GPR-9-6 and TECK are present in both small intestine and thymus. Importantly, the expression profile of GPR-9-6 correlates with migration to TECK of blood T lymphocytes and thymocytes. As migration of these cells is blocked by anti–GPR-9-6 mAb 3C3, we conclude that GPR-9-6 is the principal chemokine receptor for TECK. In agreement with the nomenclature rules for chemokine receptors, we propose the designation CCR-9 for GPR-9-6. The selective expression of TECK and GPR-9-6 in thymus and small intestine implies a dual role for GPR-9-6/CCR-9, both in T cell development and the mucosal immune response.

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Dynamic Cholesterol-Conditioned Dimerization of the G Protein Coupled Chemokine Receptor Type 4

PLoS Computational Biology ◽

10.1371/journal.pcbi.1005169 ◽

2016 ◽

Vol 12 (11) ◽

pp. e1005169 ◽

Cited By ~ 49

Author(s):

Kristyna Pluhackova ◽

Stefan Gahbauer ◽

Franziska Kranz ◽

Tsjerk A. Wassenaar ◽

Rainer A. Böckmann

Keyword(s):

G Protein ◽

Chemokine Receptor ◽

Receptor Type ◽

G Protein Coupled

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Chemokine sequestration by atypical chemokine receptors

Biochemical Society Transactions ◽

10.1042/bst0341009 ◽

2006 ◽

Vol 34 (6) ◽

pp. 1009-1013 ◽

Cited By ~ 32

Author(s):

C.A.H. Hansell ◽

C.V. Simpson ◽

R.J.B. Nibbs

Keyword(s):

Chemokine Receptor ◽

Chemokine Receptors ◽

Inflammatory Responses ◽

Critical Role ◽

Cell Trafficking ◽

Leucocyte Migration ◽

Acquired Immune Responses ◽

G Protein Coupled ◽

Receptor Family

Leucocyte migration is essential for robust immune and inflammatory responses, and plays a critical role in many human diseases. Chemokines, a family of small secreted protein chemoattractants, are of fundamental importance in this process, directing leucocyte trafficking by signalling through heptahelical G-protein-coupled receptors expressed by the migrating cells. However, several mammalian chemokine receptors, including D6 and CCX-CKR (ChemoCentryx chemokine receptor), do not fit existing models of chemokine receptor function, and do not even appear to signal in response to chemokine binding. Instead, these ‘atypical’ chemokine receptors are biochemically specialized for chemokine sequestration, acting to regulate chemokine bioavailability and thereby influence responses through signalling-competent chemokine receptors. This is of critical importance in vivo, as mice lacking D6 show exaggerated cutaneous inflammatory responses and an increased susceptibility to the development of skin cancer. CCX-CKR, on the other hand, is predicted to modulate homoeostatic lymphocyte and dendritic cell trafficking, key migratory events in acquired immune responses that are directed by CCX-CKR-binding chemokines. Thus studies on ‘atypical’ chemokine receptors are revealing functional and biochemical diversity within the chemokine receptor family and providing insights into novel mechanisms of chemokine regulation.

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Faculty Opinions recommendation of VPAC1 (vasoactive intestinal peptide (VIP) receptor type 1) G protein-coupled receptor mediation of VIP enhancement of murine experimental colitis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.8363956.8809054 ◽

2011 ◽

Author(s):

Joseph Pisegna

Keyword(s):

Vasoactive Intestinal Peptide ◽

G Protein ◽

Experimental Colitis ◽

Receptor Type ◽

G Protein Coupled Receptor ◽

G Protein Coupled ◽

Vip Receptor

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The relevance of adhesion G protein-coupled receptors in metabolic functions

Biological Chemistry ◽

10.1515/hsz-2021-0146 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Isabell Kaczmarek ◽

Tomáš Suchý ◽

Simone Prömel ◽

Torsten Schöneberg ◽

Ines Liebscher ◽

...

Keyword(s):

G Protein ◽

Drug Targets ◽

Metabolic Diseases ◽

Current Knowledge ◽

G Protein Coupled Receptors ◽

Specific Expression ◽

Physiological Functions ◽

Metabolic Functions ◽

Central Nervous Systems ◽

G Protein Coupled

Abstract G protein-coupled receptors (GPCRs) modulate a variety of physiological functions and have been proven to be outstanding drug targets. However, approximately one-third of all non-olfactory GPCRs are still orphans in respect to their signal transduction and physiological functions. Receptors of the class of Adhesion GPCRs (aGPCRs) are among these orphan receptors. They are characterized by unique features in their structure and tissue-specific expression, which yields them interesting candidates for deorphanization and testing as potential therapeutic targets. Capable of G-protein coupling and non-G protein-mediated function, aGPCRs may extend our repertoire of influencing physiological function. Besides their described significance in the immune and central nervous systems, growing evidence indicates a high importance of these receptors in metabolic tissue. RNAseq analyses revealed high expression of several aGPCRs in pancreatic islets, adipose tissue, liver, and intestine but also in neurons governing food intake. In this review, we focus on aGPCRs and their function in regulating metabolic pathways. Based on current knowledge, this receptor class represents high potential for future pharmacological approaches addressing obesity and other metabolic diseases.

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The G Protein-Coupled Receptor Kinases (GRKs) in Chemokine Receptor-Mediated Immune Cell Migration: From Molecular Cues to Physiopathology

Cells ◽

10.3390/cells10010075 ◽

2021 ◽

Vol 10 (1) ◽

pp. 75

Author(s):

Marta Laganà ◽

Géraldine Schlecht-Louf ◽

Françoise Bachelerie

Keyword(s):

G Protein ◽

Chemokine Receptor ◽

Immune Cell ◽

Neutrophil Migration ◽

G Protein Coupled Receptor ◽

Receptor Kinases ◽

Immune Cell Migration ◽

And Migration ◽

G Protein Coupled ◽

Gpcr Desensitization

Although G protein-coupled receptor kinases (GRKs) have long been known to regulate G protein-coupled receptor (GPCR) desensitization, their more recently characterized functions as scaffolds and signalling adapters underscore that this small family of proteins governs a larger array of physiological functions than originally suspected. This review explores how GRKs contribute to the complex signalling networks involved in the migration of immune cells along chemokine gradients sensed by cell surface GPCRs. We outline emerging evidence indicating that the coordinated docking of several GRKs on an active chemokine receptor determines a specific receptor phosphorylation barcode that will translate into distinct signalling and migration outcomes. The guidance cues for neutrophil migration are emphasized based on several alterations affecting GRKs or GPCRs reported to be involved in pathological conditions.

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