Chapter Two - The Intricate Role of CXCR4 in Cancer

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Abstract

Chemokines mediate numerous physiological and pathological processes related primarily to cell homing and migration. The chemokine CXCL12, also known as stromal cell-derived factor-1, binds the G-protein-coupled receptor CXCR4, which, through multiple divergent pathways, leads to chemotaxis, enhanced intracellular calcium, cell adhesion, survival, proliferation, and gene transcription. CXCR4, initially discovered for its involvement in HIV entry and leukocytes trafficking, is overexpressed in more than 23 human cancers. Cancer cell CXCR4 overexpression contributes to tumor growth, invasion, angiogenesis, metastasis, relapse, and therapeutic resistance. CXCR4 antagonism has been shown to disrupt tumor–stromal interactions, sensitize cancer cells to cytotoxic drugs, and reduce tumor growth and metastatic burden. As such, CXCR4 is a target not only for therapeutic intervention but also for noninvasive monitoring of disease progression and therapeutic guidance. This review provides a comprehensive overview of the biological involvement of CXCR4 in human cancers, the current status of CXCR4-based therapeutic approaches, as well as recent advances in noninvasive imaging of CXCR4 expression.

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.).

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