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Critical role of endoglin in tumor cell plasticity of Ewing sarcoma and melanoma

Oncogene volume 30, pages 334–345 (2011)Cite this article

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Abstract

Tumor cell plasticity enables certain types of highly malignant tumor cells to dedifferentiate and engage a plastic multipotent embryonic-like phenotype, which enables them to ‘adapt’ during tumor progression and escape conventional therapeutic strategies. This plastic phenotype of aggressive cancer cells enables them to express endothelial cell-specific markers and form tube-like structures, a phenotype that has been linked to aggressive behavior and poor prognosis. We demonstrate here that the transforming growth factor (TGF)-β co-receptor endoglin, an endothelial cell marker, is expressed by tumor cells and its expression correlates with tumor cell plasticity in two types of human cancer, Ewing sarcoma and melanoma. Moreover, endoglin expression was significantly associated with worse survival of Ewing sarcoma patients. Endoglin knockdown in tumor cells interferes with tumor cell plasticity and reduces invasiveness and anchorage-independent growth in vitro. Ewing sarcoma and melanoma cells with reduced endoglin levels showed reduced tumor growth in vivo. Mechanistically, we provide evidence that endoglin, while interfering with TGF-β signaling, is required for efficient bone morphogenetic protein, integrin, focal adhesion kinase and phosphoinositide-3-kinase signaling in order to maintain tumor cell plasticity. The present study delineates an important role of endoglin in tumor cell plasticity and progression of aggressive tumors.

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Acknowledgements

We thank the members of our research groups for help and suggestions during the course of this work. We are grateful to Margriet Ouwens for assistance with PI3K activity assays, Inge Briaire-de Bruijn for excellent technical assistance with the TMA histochemical analysis, Dagmar Berghuis for help with the patient's clinical characteristics, and David de Gorter for critical reading of the paper. This study was supported by grants from the Centre of Biomedical Genetics, Dutch Cancer Society (RUL 2005-3371), the Ludwig Institute for Cancer Research, and FP6 EC Integrated Projects: Angiotargeting (504743), EC STREP Tumor-Host-Genomics (518198) and EuroBoNeT (018814).

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Authors and Affiliations

  1. Department of Molecular Cell Biology, Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands

    E Pardali, E Wiercinska & P ten Dijke

  2. Department of Biomedical Engineering, Soft Tissue Biomechanics & Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands

    D W J van der Schaft

  3. Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands

    A Gorter & P C W Hogendoorn

  4. Department of Medical Oncology, Angiogenesis Laboratory, VU University Medical Center, Amsterdam, The Netherlands

    A W Griffioen

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  1. E Pardali
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Correspondence to E Pardali or P ten Dijke.

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Pardali, E., van der Schaft, D., Wiercinska, E. et al. Critical role of endoglin in tumor cell plasticity of Ewing sarcoma and melanoma. Oncogene 30, 334–345 (2011). https://doi.org/10.1038/onc.2010.418

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