Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of adolescents and children that frequently infiltrates the bone marrow (BM). We have demonstrated that the a-chemokine stromal-derived factor (SDF)-1-CXCR4 axis (

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Cancer Res
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Cancer Res.
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) plays an important role in RMS metastases. With the recent description of CXCR7, a new receptor for SDF-1 that also binds the interferon-inducible T cell-alpha chemoattractant (ITAC) chemokine, we become interested in the role of the CXCR7-SDF-1/ITAC axis in RMS metastasis. To address this issue, we evaluated 7 highly metastatic alveolar RMS (ARMS) and 3 less metastatic embryonal RMS (ERMS) cell lines. We found that all RMS cell lines express CXCR7 in contrast to CXCR4, which was expressed by 7 of 10 RMS cell lines only. CXCR4 was expressed at a much higher level by highly metastatic ARMS lines while CXCR7 was expressed at a high level on the less metastatic ERMS lines. More importantly, CXCR7 receptor on RMS cell lines was functional after stimulation with ITAC and SDF-1 as evidenced by MAPKp42/44-, AKT-, and STAT-3 phosphorylation, chemotaxis, cell motility, and adhesion assays. We also noticed that CXCR7 undergoes rapid internalization after stimulation with SDF-1 and ITAC, is a lipid raft-associated receptor, and, surprisingly, has a downregulated expression in response to hypoxia. We also noticed that similarly to CXCR4, signaling from activated CXCR7 was not associated with increased RMS proliferation or cell survival. Thus, we conclude that both CXCR4 and CXCR7 are not affecting proliferation of RMS cells; however they play an important role in both SDF-1- and ITAC-directed metastasis. For the first time, we also identify ITAC as a new regulatory chemokine that is actively involved in this process. In conclusion, since CXCR7 is more important in adhesion and becomes down-regulated during hypoxia, this changes the balance in SDF-1 signaling through both receptors (CXCR7/CXCR4). As a result, SDF-1 activates more robust CXCR4 receptor, which promotes chemotactic responses of RMS cells. As a biological consequence, this switch in SDF-1 receptor signaling increases the metastatic potential of RMS by mobilizing tumor cells to egress from the tumor into the peripheral blood and lymph and migrate to new tissue locations. We also conclude that targeting of the CXCR-SDF-1 axis alone without simultaneous blockage of CXCR7 will be an inefficient strategy to inhibit metastasis of RMS cells. This is currently being tested in our laboratories in immunodeficient mice inoculated with human RMS cells.

Topics:
cxcr4 receptors, rhabdomyosarcoma, stromal cell-derived factor 1, neoplasm metastasis, chemokines, adhesions, cancer, hypoxia, chemotactic factors, human leukocyte interferon

Disclosures: No relevant conflicts of interest to declare.

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2008, The American Society of Hematology
2008
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