Critical role of endoglin in tumor cell plasticity of Ewing sarcoma and melanoma.
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.
Pardali
E
E
Department of Molecular Cell Biology, Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands. E.Pardali@lumc.nl
van der Schaft
D W J
DW
Wiercinska
E
E
Gorter
A
A
Hogendoorn
P C W
PC
Griffioen
A W
AW
ten Dijke
P
P
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D017931:DNA Primers; D000071063:Endoglin; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D012512:Sarcoma, Ewing / Q000473:pathology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
D015703:Antigens, CD; D019485:Bone Morphogenetic Proteins; D017931:DNA Primers; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; D019869:Phosphatidylinositol 3-Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases