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

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 tubelike structures, a phenotype that has been linked to aggressive behavior and poor prognosis. We demonstrate here that the transforming growth factor (TGF)-b coreceptor 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-b 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.

High-Throughput Tyrosine Kinase Activity Profiling Identifies FAK as a Candidate Therapeutic Target in Ewing Sarcoma

“…Another study found that endoglin expression in Ewing sarcoma tumors is associated with increased expression of several proteins, including FAK, and is associated with poor outcome (38). Recently, a phosphoproteomics screen à , P < 0.05; Ãà , P < 0.01; ÃÃà , P < 0.001).…”

Prognostic significance of the preoperative serum levels of soluble form of endoglin in gastric cancer patients

“…Endoglin was also found to be expressed by tumor cells in Ewing sarcoma and melanoma. Endoglin expression in these two types of cancer correlated with tumor cell plasticity and participates in the formation of vascular-like structures (10). On the other hand; the strong expression of endoglin indicated a poor prognosis in gastric cancer (5).…”

CXCL14, CXCR7 expression and CXCR4 splice variant ratio associate with survival and metastases in Ewing sarcoma patients

“…For these high risk patients many markers have been suggested, but at present only classical markers, such as tumour location, are used in clinic [10]. EWS is recognised from the onset of its original description by James Ewing as a highly vascularised tumour and amongst many other pathways, chemokine and the TGF-B pathway might play a role for this excessive vascularisation pattern [11][12][13]. Besides angiogenesis, these pathways are involved in migration that might be reflected by the high metastatic propensity of EWS [1,13,14].…”

“…EWS is recognised from the onset of its original description by James Ewing as a highly vascularised tumour and amongst many other pathways, chemokine and the TGF-B pathway might play a role for this excessive vascularisation pattern [11][12][13]. Besides angiogenesis, these pathways are involved in migration that might be reflected by the high metastatic propensity of EWS [1,13,14]. In several tumour types a positive correlation between increased expression of CXCR4 and metastatic propensity was reported, but contradictory results were reported in EWS [15][16][17].…”