the cxcr4-cxcl12 axis in ewing sarcoma promotion of tumor growth rather than metastatic diseasecxcr4-cxcl12轴在尤因肉瘤促进肿瘤的生长,而非转移性疾病.pdf

Berghuis et al. Clinical Sarcoma Research 2012, 2:24 /content/2/1/24 CLINICAL SARCOMA RESEARCH RESEARCH Open Access The CXCR4-CXCL12 axis in Ewing sarcoma: promotion of tumor growth rather than metastatic disease 1,2 2 2 3 4 5 Dagmar Berghuis , Marco W Schilham , Susy J Santos , Suvi Savola , Helen J Knowles , Uta Dirksen , 6 3 1 2* Karl-Ludwig Schaefer , Jukka Vakkila , Pancras CW Hogendoorn and Arjan C Lankester 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 0.04). A role for the CXCR4-CXCL12 axis in Ewing sarcoma growth was sugg