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

Dagmar Berghuis12, Marco W Schilham2, Susy J Santos2, Suvi Savola3, Helen J Knowles4, Uta Dirksen5, Karl-Ludwig Schaefer6, Jukka Vakkila3, Pancras CW Hogendoorn1 and Arjan C Lankester2*

Author Affiliations

1 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands

2 Department of Pediatrics, Leiden University Medical Center, Albinusdreef 2, 2300, RC, Leiden, the Netherlands

3 Dept. of Pathology, Haartman Institute and HUSLAB, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

4 Botnar Research Center, Nuffield Orthopedic Center, University of Oxford, Oxford, United Kingdom

5 Dept. of Pediatric Hematology and Oncology, University Hospital Muenster, Münster, Germany

6 Institute of Pathology, Heinrich-Heine University, Düsseldorf, Germany

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Clinical Sarcoma Research 2012, 2:24  doi:10.1186/2045-3329-2-24

Published: 18 December 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.

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