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
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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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    • "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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