The role of stromal-derived factor-1--CXCR7 axis in development and cancer

Abstract

Cancer metastasis is a major clinical problem that contributes to unsuccessful therapy. Augmenting evidence indicates that metastasizing cancer cells employ several mechanisms that are involved in developmental trafficking of normal stem cells. Stromal-derived factor-1 (SDF-1) is an important alpha-chemokine that binds to the G-protein-coupled seven-transmembrane span CXCR4. The SDF-1-CXCR4 axis regulates trafficking of normal and malignant cells. SDF-1 is an important chemoattractant for a variety of cells including hematopoietic stem/progenitor cells. For many years, it was believed that CXCR4 was the only receptor for SDF-1. However, several reports recently provided evidence that SDF-1 also binds to another seven-transmembrane span receptor called CXCR7, sharing this receptor with another chemokine family member called Interferon-inducible T-cell chemoattractant (I-TAC). Thus, with CXCR7 identified as a new receptor for SDF-1, the role of the SDF-1-CXCR4 axis in regulating several biological processes becomes more complex. Based on the available literature, this review addresses the biological significance of SDF-1's interaction with CXCR7, which may act as a kind of decoy or signaling receptor depending on cell type. Augmenting evidence suggests that CXCR7 is involved in several aspects of tumorogenesis and could become an important target for new anti-metastatic and anti-cancer drugs.

Figure 1. SDF-1 signaling through CXCR4 or CXCR7

Signaling of SDF-1 through both receptors depends on many factors, including: i) expression of both receptors on a population of target cells; ii) possible I-TAC competition with SDF-1 for receptor binding in CXCR7, iii) potential priming and sensitization of CXCR7 similarly to CXCR4 to SDF-1 stimulation by several small proinflammatory molecules (e.g., C3 complement cleavage fragments); and iv) possible CXCR4 signaling modulation by RGS proteins. Whether RGS proteins modulate CXCR7 signaling requires further study.

Figure 2. Different strategies to target the CXCR7-SDF-1/ITAC axis

Expression of CXCR7 and its responsiveness to the SDF-1/I-TAC gradient could be modulated at several levels. Accordingly, expression of CXCR4 could be inhibited at the transcriptional level siRNA or antisense oligodeoxynucleotides and at the protein receptor level by employing CXCR7 blocking antibodies or molecules (e.g., CCX451 and CCX751). Conversely, responsiveness of CXCR7 to an SDF-1 gradient could be affected similarly to CXCR4 by blocking CD26 by diprotin. It is not clear at this point whether CXCR7 is a lipid raft-associated receptor. If it is, then depletion of cell membrane cholesterol and thus inhibition of lipid raft formation (e.g., statins) would decrease responsiveness of CXCR7⁺ cells to an SDF-1 gradient.