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The CXCR4-CXCL12 axis in Ewing sarcoma: promotion of tumor growth rather than metastatic disease

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Author(s): Berghuis Dagmar | Schilham Marco W | Santos Susy J | Savola Suvi | Knowles Helen J | Dirksen Uta | Schaefer Karl-Ludwig | Vakkila Jukka | Hogendoorn Pancras CW | Lankester Arjan C

Journal: Clinical Sarcoma Research
ISSN 2045-3329

Volume: 2;
Issue: 1;
Start page: 24;
Date: 2012;
Original page

Keywords: Ewing sarcoma | CXCR4 | CXCL12 (stromal-cell derived factor-1 (SDF-1)) | Chemokine | Growth signaling | Hypoxia | Metastasis | Prognosis | Therapy

ABSTRACT
Abstract Background Chemokine receptor CXCR4, together with its ligand CXCL12, plays critical roles in cancer progression, including growth, metastasis and angiogenesis. Ewing sarcoma is a sarcoma with poor prognosis despite current therapies, particularly for patients with advanced-stage disease. Lungs and bone (marrow), organs of predilection for (primary/metastatic) Ewing sarcoma, represent predominant CXCL12 sources. Methods To gain insight into the role of the CXCR4-CXCL12 axis in Ewing sarcoma, CXCR4, CXCL12 and hypoxia-inducible factor-1α protein expression was studied in therapy-naïve and metastatic tumors by immunohistochemistry. CXCR4 function was assessed in vitro, by flow cytometry and proliferation/ cell viability assays, in the presence of recombinant CXCL12 and/or CXCR4-antagonist AMD3100 or under hypoxic conditions. Results Whereas CXCR4 was predominantly expressed by tumor cells, CXCL12 was observed in both tumor and stromal areas. Survival analysis revealed an (expression level-dependent) negative impact of CXCR4 expression (p 
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