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Tumor Cell Plasticity in Ewing Sarcoma, an Alternative Circulatory System Stimulated by Hypoxia

¹ Angiogenesis Laboratory, Research Institute for Growth and Development, Departments of Pathology and Internal Medicine, Maastricht University and University Hospital Maastricht; ² Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands; ³ Children's Memorial Research Center, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; ⁴ Department of Renal Medicine, Imperial College London, London, United Kingdom; ⁵ Department of Pathology, University Hospital Leuven, Leuven, Belgium; ⁶ Stichting Laboratoria voor Pathologische Anatomie en Medische Microbiologie, Eindhoven, the Netherlands; ⁷ Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands; and ⁸ Laboratoire de Pathologie Moleculaire des Cancers, Paris, France

Requests for reprints: Arjan W. Griffioen, Angiogenesis Laboratory, Research Institute for Growth and Development, Departments of Pathology and Internal Medicine, Maastricht University and University Hospital Maastricht, Maastricht, the Netherlands. Phone: 31-43-3874630; Fax: 31-43-3876613; E-mail: aw.griffioen{at}path.unimaas.nl.

A striking feature of Ewing sarcoma is the presence of blood lakes lined by tumor cells. The significance of these structures, if any, is unknown. Here, we report that the extent of blood lakes correlates with poor clinical outcomes, whereas variables of angiogenesis do not. We also show that Ewing sarcoma cells form vessel-like tubes in vitro and express genes associated with vasculogenic mimicry. In tumor models, we show that there is blood flow through the blood lakes, suggesting that these structures in Ewing sarcoma contribute to the circulation. Furthermore, we present evidence that reduced oxygen tension may be instrumental in tube formation by plastic tumor cells. The abundant presence of these vasculogenic structures, in contrast to other tumor types, makes Ewing sarcoma the ideal model system to study these phenomena. The results suggest that optimal tumor treatment may require targeting of these structures in combination with prevention of angiogenesis. (Cancer Res 2005; 65(24): 11520-8)

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