The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor 48109, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 03/2008; 283(7):4283-94. DOI: 10.1074/jbc.M707465200
Source: PubMed


Several reports have recently documented that CXCR7/RDC1 functions as a chemokine receptor for SDF-1/CXCL12, which regulates
a spectrum of normal and pathological processes. In this study, the role of CXCR7/RDC1 in prostate cancer (PCa) was explored.
Staining of high density tissue microarrays demonstrates that the levels of CXCR7/RDC1 expression increase as the tumors become
more aggressive. In vitro and in vivo studies with PCa cell lines suggest that alterations in CXCR7/RDC1 expression are associated with enhanced adhesive and invasive
activities in addition to a survival advantage. In addition, it was observed that CXCR7/RDC1 levels are regulated by CXCR4.
Among the potential downstream targets of CXCR7/RDC1 are CD44 and cadherin-11, which are likely to contribute to the invasiveness
of PCa cells. CXCR7/RDC1 also regulates the expression of the proangiogenic factors interleukin-8 or vascular endothelial
growth factor, which are likely to participate in the regulation of tumor angiogenesis. Finally, we found that signaling by
CXCR7/RDC1 activates AKT pathways. Together, these data demonstrate a role for CXCR7/RDC1 in PCa metastasis and progression
and suggest potential targets for therapeutic intervention.

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    • "The JAK/STAT or ERK1/2 cascades mediated CXCL12 proliferative effects in NPCs in vitro, along with other signaling pathways. NO, EPO and metalloprotease activity (MMP2/9 or ADAM17), or CXCL12 availability, regulate CXCR4/CXCR7 chemokine function in NPCs, since CXCR7 expression was found to be regulated by the membrane levels of CXCR4 (Wang et al., 2008). On the other hand, EPO induces NPC migration via the CXCR4/CXCL12 axis, while the NO donor DETA-NONOate promotes SVZ neuroblast cell migration through CXCL12 and Ang1 in the SVZ, supporting their role in CNS repair (Cui et al., 2007). "
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    ABSTRACT: In the adult brain, Neural Progenitor Cells (NPCs) reside in the subventricular zone (SVZ) of the lateral ventricles, the dentate gyrus and the olfactory bulb. Following CNS insult, NPCs from the SVZ can migrate along the rostral migratory stream (RMS), a migration of NPCs that is directed by proinflammatory cytokines. Indeed, cells expressing CXCR4 follow a homing signal that ultimately leads to neuronal integration and CNS repair, although such molecules can also promote NPC quiescence. The ligand, SDF1 alpha (or CXCL12) is one of the chemokines secreted at sites of injury that it is known to attract NSC-derived neuroblasts, cells that express CXCR4. In function of its concentration, CXCL12 can induce different responses, promoting NPC migration at low concentrations while favoring cell adhesion via EGF and the alpha 6 integrin at high CXCL12 concentrations. However, the preclinical effectiveness of chemokines and their relationship with NPC mobilization requires further study, particularly with respect to CNS repair. Indeed, NPC migration may also be affected by the release of cytokines or chemokines induced by local inflammation, through autocrine or paracrine mechanisms, as well as through erythropoietin (EPO) or nitric oxide (NO) release. CXCL12 activity requires G-coupled proteins and the availability of its ligand may be modulated by its binding to CXCR7, for which it shows a stronger affinity than for CXCR4. © 2014 Wiley Periodicals, Inc.
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    • "Previous studies have demonstrated that SDF-1 (stromal cell-derived fac- tor-1 or CXCL12) and its receptor, CXCR4 represent a major mechanism in PCa's metastasis to bone [1] [2]. We have recently shown that the binding of CXCL12 to CXCR4 activates the expression of receptors which facilitate the localization of disseminated tumor cells (DTCs) to the bone marrow microenvironment [3] [4]. "

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    • "Based on its ability to rapidly sequester and degrade CXCL12 and thus to suppress CXCR4 activity, CXCR7 was firstly proposed to be a decoy receptor [54] [55] [56] [57]; currently, this activity is considered only a part of the possible mechanisms by which CXCR7 modulates cellular functions [22]. Indeed, emerging evidence suggests that CXCR7 can promote cell motility [58] [59] [60] and trigger intracellular signals in different human normal and cancer cell types [61] [62] [63] [64]. In particular, CXCR7 activates Akt, MAP kinase (MAPK), and JAK/STAT3 cascades, either by direct modulation, through a í µí»½-arrestindependent pathway [20] [65], or after heterodimerization with CXCR4 [59, 66–69]. "
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