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Open Access 01-12-2012 | Research

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

Authors: Dagmar Berghuis, Marco W Schilham, Susy J Santos, Suvi Savola, Helen J Knowles, Uta Dirksen, Karl-Ludwig Schaefer, Jukka Vakkila, Pancras CW Hogendoorn, Arjan C Lankester

Published in: Clinical Sarcoma Research | Issue 1/2012

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 suggested by our observations that i) CXCR4 expression correlated positively with tumor volume at diagnosis (p = 0.013), ii) CXCL12 was present within the microenvironment of virtually all cases, iii) CXCL12 induced proliferation of CXCR4-positive Ewing sarcoma cell lines, which could be abrogated by AMD3100. CXCR4 expression was not correlated with occurrence of metastatic disease. Also, therapy-naïve tumors demonstrated higher CXCR4 expression as compared to metastases (p = 0.027). Evaluation of in vivo hypoxia-inducible factor-1α expression and culture of cells under hypoxic conditions revealed no role for hypoxia in CXCR4 expression.

Conclusions

Together, our results imply a crucial role for the CXCR4-CXCL12 axis in auto- and/or paracrine growth stimulation. Integration of CXCR4-targeting strategies into first- and/or second-line treatment regimens may represent a promising treatment option for Ewing sarcoma.

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Title: The CXCR4-CXCL12 axis in Ewing sarcoma: promotion of tumor growth rather than metastatic disease
Authors: Dagmar Berghuis
Marco W Schilham
Susy J Santos
Suvi Savola
Helen J Knowles
Uta Dirksen
Karl-Ludwig Schaefer
Jukka Vakkila
Pancras CW Hogendoorn
Arjan C Lankester
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: Clinical Sarcoma Research / Issue 1/2012
Electronic ISSN: 2045-3329
DOI: https://doi.org/10.1186/2045-3329-2-24

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