Chapter Two - The Intricate Role of CXCR4 in Cancer
Introduction
Chemokines are a family of cytokines defined by their ability to induce gradient-dependent directional chemotaxis and are secreted by a variety of stromal and epithelial cells (Howard et al., 1996, Smith et al., 2012). These small proteins (8–10 kDa) possess a common structural feature of conserved cysteine residues at the N-terminus (Baggiolini, 1998). Based on the number and relative spacing of the N-terminal cysteine residues, chemokines are divided into CXC, CX3C, CC, and C subfamilies with CXC chemokines characterized by one amino acid (X) between the two N-terminal cysteine residues (C) and CX3C chemokines with two N-terminal cysteine residues separated by three amino acids, etc. (Le, Zhou, Iribarren, & Wang, 2004). To date, nearly 50 chemokines have been discovered (Balkwill, 2004a, Viola and Luster, 2008). Chemokines exert their biological function through interaction with chemokine receptors, seven transmembrane G-protein-coupled receptors (GPCRs; Gilman, 1987), present on the target cells (Baggiolini, 1998). Chemokine receptors are grouped into four different families as CXC, CX3C, CC, and XC based on the chemokines they primarily interact with for signaling. Thus far, nearly 20 chemokine receptors have been identified (Balkwill, 2004a, Gilman, 1987, Pierce et al., 2002, Viola and Luster, 2008). The large number of chemokines, compared to chemokine receptors, implies considerable redundancy in chemokine receptor interactions with multiple ligands binding to the same receptor and vice versa. The chemokine receptor 4 (CXCR4) is unique in that it exclusively interacts with the endogenous ligand CXCL12 (Oberlin et al., 1996).
CXCR4, also known as “fusin,” is one of the most well-studied chemokine receptors due to its earlier found role as a coreceptor for HIV entry (Feng, Broder, Kennedy, & Berger, 1996). The chemokine stromal cell-derived factor-1, now renamed as CXCL12, was established as the specific ligand for CXCR4 (Bleul et al., 1996, Oberlin et al., 1996). Although CXCL12 is the only known chemokine that binds CXCR4, recent studies suggest that extracellular ubiquitin also acts as an immune modulator through CXCR4-mediated signaling (Saini et al., 2010, Tripathi et al., 2013). Although CXCR4 is known to bind only CXCL12, in 2005 another chemokine receptor CXC receptor 7 (CXCR7, ACKR3, RDC1, CMKOR1, or GPR159) was established as a receptor for CXCL12 (Balabanian et al., 2005, Burns et al., 2006). CXCR7 functions to control the CXCL12 gradients through high-affinity binding and rapid degradation (Hoffmann et al., 2012). Thus, the role of the CXCR4–CXCR7–CXCL12 axes has become more intricate in the regulation of numerous biological processes involving cell survival and migration. Comprehensive studies will be required to delineate the exact role of CXCR4–CXCR7–CXCL12 axes in cell migration. Roles of CXCR7 and CXCL12 in biology and disease have been reviewed in detail by others (Hattermann and Mentlein, 2013, Liao et al., 2013, Sun et al., 2010).
Section snippets
CXCR4/CXCL12 Signaling
CXCL12 binding to CXCR4 initiates various downstream signaling pathways that result in a plethora of responses (Fig. 2.1) such as increase in intracellular calcium, gene transcription, chemotaxis, cell survival, and proliferation (Ganju et al., 1998), which will be briefly discussed here. Chemokine receptors are pertussis toxin-sensitive GTP-binding proteins of Gi type. After chemokine binding, the heterotrimeric G protein is activated by the exchange of GDP for GTP and dissociates into the
Expression and Physiological Functions of the CXCR4/CXCL12 Axis
CXCR4 is commonly expressed on most hematopoietic cell types including macrophages, monocytes, T and B lymphocytes, neutrophils, hematopoietic, endothelial progenitor, and stem cells in the blood or bone marrow, dendritic cells, Langerhans cells (Bleul, Farzan, et al., 1996, Zabel et al., 1999), vascular endothelial cells (Gupta, Lysko, Pillarisetti, Ohlstein, & Stadel, 1998), neurons and neuronal stem cells (Hesselgesser et al., 1997), microglia and astrocytes (He et al., 1997), as well as
Role of CXCR4 in Cancer
Although initial studies were centered on the participation of CXCR4 in HIV infection of T-cells, its connection to cancer became an intense research topic with the discovery of its involvement in B-cell trafficking and tissue localization in chronic leukemia patients (Burger et al., 1999, Mohle et al., 1999) as well as regulation of organ-specific metastasis in breast cancer models (Muller et al., 2001). CXCR4 is overexpressed in more than 23 different types of human cancers including kidney,
CXCR4 Antagonists as Therapeutic and Imaging Agents
Considering the critical role of the CXCR4/CXCL12 axis in various disease states, there is currently significant interest in the discovery and development of antagonists and imaging probes for therapeutic targeting and noninvasive monitoring of CXCR4 expression. Reports on CXCR4 and CXCL12 NMR and homology models have contributed significantly to our understanding of CXCR4–ligand interactions, thereby facilitating the development of highly specific CXCR4 inhibitors. A recent study by Wu et al.
CXCL12-based peptides
CXCL12 binds both CXCR4 and CXCR7 receptors and is commonly utilized in in vitro competition binding assays and a natural choice to derive peptides that bind to CXCR4 (Kryczek et al., 2007, Sun et al., 2011). As a result, several CXCL12-derived peptides were developed as therapeutics based on known CXCR4/CXCL12 interactions. CTCE-9908, a 17-amino acid peptide analogue of CXCL12, has been shown to reduce the growth and adhesion of tumor cells as well as metastatic dissemination of cancer cells
Conclusion
Diverse roles of CXCR4 in different types of cancers as well as in HIV infection and other pathological states have established CXCR4 as an important target for therapeutic intervention. Interaction of cancer cells with the tumor microenvironment, which protects the malignant cells from cytotoxic chemotherapy, is becoming an attractive target for improved anticancer treatment. CXCR4 antagonists through disruption of tumor–stromal cell interactions could play a significant role in sensitizing
Acknowledgments
This work was supported by R01CA166131 (S. N.), The Alexander and Margaret Stewart Trust (S. N.), DOD W81XWH-12-BCRP-IDEA (S. N.), and DOD W81XWH-13-BCRP-POSTDOCTORAL FELLOWSHIP (B. B. A.).
References (296)
- et al.
Identification of the cytoplasmic domains of CXCR4 involved in Jak2 and STAT3 phosphorylation
Journal of Biological Chemistry
(2005) - et al.
Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma
Blood
(2007) - et al.
Contribution of CXCR4 and SMAD4 in predicting disease progression pattern and benefit from adjuvant chemotherapy in resected pancreatic adenocarcinoma
Annals of Oncology
(2012) - et al.
The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes
Journal of Biological Chemistry
(2005) The significance of cancer cell expression of the chemokine receptor CXCR4
Seminars in Cancer Biology
(2004)- et al.
CXCR4 is a good survival prognostic indicator in multiple myeloma patients
Leukemia Research
(2013) - et al.
The chemokine receptor CXCR4 and the metalloproteinase MT1-MMP are mutually required during melanoma metastasis to lungs
American Journal of Pathology
(2009) - et al.
CXCR4 antagonist 4 F-benzoyl-TN14003 inhibits leukemia and multiple myeloma tumor growth
Experimental Hematology
(2011) - et al.
Targeted non-covalent self-assembled nanoparticles based on human serum albumin
Biomaterials
(2012) Chemokines and chemokine receptors in chronic lymphocytic leukemia (CLL): From understanding the basics towards therapeutic targeting
Seminars in Cancer Biology
(2010)
Chronic lymphocytic leukemia B cells express functional CXCR4 chemokine receptors that mediate spontaneous migration beneath bone marrow stromal cells
Blood
Effect of short hairpin RNA-induced CXCR4 silence on ovarian cancer cell
Biomedicine & Pharmacotherapy
High chemokine receptor CXCR4 level in triple negative breast cancer specimens predicts poor clinical outcome
Journal of Surgical Research
Functional expression of CXC chemokine receptor-4 mediates the secretion of matrix metalloproteinases from mouse hepatocarcinoma cell lines with different lymphatic metastasis ability
International Journal of Biochemistry & Cell Biology
Recent advances on the use of the CXCR4 antagonist plerixafor (AMD3100, Mozobil) and potential of other CXCR4 antagonists as stem cell mobilizers
Pharmacology & Therapeutics
Discovery of novel, highly potent and selective beta-hairpin mimetic CXCR4 inhibitors with excellent anti-HIV activity and pharmacokinetic profiles
Bioorganic & Medicinal Chemistry
Rapid mobilization of functional donor hematopoietic cells without G-CSF using AMD3100, an antagonist of the CXCR4/SDF-1 interaction
Blood
Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma
Blood
CXCR4 chemokine receptor mediates prostate tumor cell adhesion through alpha5 and beta3 integrins
Neoplasia
The role of post-translational modifications of the CXCR4 amino terminus in stromal-derived factor 1 alpha association and HIV-1 entry
Journal of Biological Chemistry
CXCR4/CCR5 down-modulation and chemotaxis are regulated by the proteasome pathway
Journal of Biological Chemistry
Characterization of the molecular pharmacology of AMD3100: A specific antagonist of the G-protein coupled chemokine receptor, CXCR4
Biochemical Pharmacology
Chemokine and chemokine receptor expression in kidney tumors: Molecular profiling of histological subtypes and association with metastasis
Journal of Urology
The alpha-chemokine, stromal cell-derived factor-1alpha, binds to the transmembrane G-protein-coupled CXCR-4 receptor and activates multiple signal transduction pathways
Journal of Biological Chemistry
Pancreatic stellate cells increase the invasion of human pancreatic cancer cells through the stromal cell-derived factor-1/CXCR4 axis
Pancreatology
Inhibition of CXCL12/CXCR4 autocrine/paracrine loop reduces viability of human glioblastoma stem-like cells affecting self-renewal activity
Toxicology
Preclinical evaluation of a CXCR4-specific Ga-68-labelled TN14003 derivative for cancer PET imaging
Bioorganic & Medicinal Chemistry
Chemokine receptors in human endothelial cells. Functional expression of CXCR4 and its transcriptional regulation by inflammatory cytokines
Journal of Biological Chemistry
Fibronectin increases matrix metalloproteinase 9 expression through activation of c-Fos via extracellular-regulated kinase and phosphatidylinositol 3-kinase pathways in human lung carcinoma cells
Journal of Biological Chemistry
[Tc-99 m]O-2-AMD3100 as a SPECT tracer for CXCR4 receptor imaging
Nuclear Medicine and Biology
The influence of tumor-host interactions in the stromal cell-derived factor-1/CXCR4 ligand/receptor axis in determining metastatic risk in breast cancer
The American Journal of Pathology
Chemokine receptor inhibition by AMD3100 is strictly confined to CXCR4
FEBS Letters
An infernal trio: The chemokine CXCL12 and its receptors CXCR4 and CXCR7 in tumor biology
Annals of Anatomy
Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer
Cell Stem Cell
Cancer facts and figures 2014
The chemokine SDF-1 is a chemoattractant for human CD34 + hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34 + progenitors to peripheral blood
Journal of Experimental Medicine
Chemokine receptor CXCR4 expression and prognosis in patients with metastatic prostate cancer
Cancer Science
The evolving concept of cancer and metastasis stem cells
Journal of Cell Biology
CXCL12/CXCR4-axis dysfunctions: Markers of the rare immunodeficiency disorder WHIM syndrome
Disease Markers
Chemokines and leukocyte traffic
Nature
Cancer and the chemokine network
Nature Reviews. Cancer
Microenvironmental regulation of chemokine (C-X-C-motif) receptor 4 in ovarian carcinoma
Molecular Cancer Research
Antigenically distinct conformations of CXCR4
Journal of Virology
CXCR4 and SDF-1 expression in B-cell chronic lymphocytic leukemia and stage of the disease
Annals of Hematology
Exploring the role of cancer stem cells in radioresistance
Nature Reviews. Cancer
Defective p38 mitogen-activated protein kinase signaling impairs chemotaxic but not proliferative responses to stromal-derived factor-1alpha in acute lymphoblastic leukemia
Cancer Research
CXCR4 neutralization, a novel therapeutic approach for non-Hodgkin’s lymphoma
Cancer Research
Highly tumorigenic lung cancer CD133 + cells display stem-like features and are spared by cisplatin treatment
Proceedings of the National Academy of Sciences of the United States of America
The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry
Nature
A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1)
Journal of Experimental Medicine
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