Journal
ONCOGENE
Volume 30, Issue 3, Pages 334-345Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2010.418
Keywords
endoglin; tumor cell plasticity; transforming growth factor-beta; bone morphogenetic proteins; Ewing sarcoma; melanoma
Funding
- Centre of Biomedical Genetics, Dutch Cancer Society [RUL 2005-3371]
- Ludwig Institute for Cancer Research
- EC [504743, 518198, 018814]
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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 tubelike structures, a phenotype that has been linked to aggressive behavior and poor prognosis. We demonstrate here that the transforming growth factor (TGF)-beta 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-beta 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. Oncogene (2011) 30, 334-345; doi:10.1038/onc.2010.418; published online 20 September 2010
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