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

Clinical Sarcoma Research

Arjan C Lankester⁴  Pancras CW Hogendoorn⁵  Jukka Vakkila⁶  Karl-Ludwig Schaefer¹  Uta Dirksen³  Helen J Knowles²  Suvi Savola⁶  Susy J Santos⁴  Marco W Schilham⁴  Dagmar Berghuis⁴ 

[1] Institute of Pathology, Heinrich-Heine University, Düsseldorf, Germany;Botnar Research Center, Nuffield Orthopedic Center, University of Oxford, Oxford, United Kingdom;Dept. of Pediatric Hematology and Oncology, University Hospital Muenster, Münster, Germany;Department of Pediatrics, Leiden University Medical Center, Albinusdreef 2, 2300, RC, Leiden, the Netherlands;Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands;Dept. of Pathology, Haartman Institute and HUSLAB, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

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

Others  :  861569
DOI  :  10.1186/2045-3329-2-24

 received in 2012-10-16, accepted in 2012-11-24,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Berghuis et al.; licensee BioMed Central Ltd.

【 图 表 】

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