Endoglin in Ewing sarcoma: from the biological relevance to a clinical strategy
|Álava Casado, Enrique de
Monteiro Amaral, Ana Teresa
|Universidad de Sevilla. Departamento de Citología e Histología Normal y Patológica
|Endoglin (ENG) is a mesenchymal stem cell (MSC) marker highly expressed
mainly in active endothelium and certain cancer types. This transmembrane
protein is shed to the extracellular compartment by the matrix ...
Endoglin (ENG) is a mesenchymal stem cell (MSC) marker highly expressed mainly in active endothelium and certain cancer types. This transmembrane protein is shed to the extracellular compartment by the matrix metalloproteinase 14 (MMP14). Previously, ENG was identified in patient samples from Ewing sarcoma (ES), a bone/soft tissue neoplasia with a putative MSC origin. ES is a predominant paediatric malignancy with high incidence of metastasis at diagnosis, around 30% patients, associated with poor prognosis. This scenario is worsened by the fact that current chemotherapeutic treatments fail to achieve a significant impact on advanced disease. On-target therapies emerge strongly appealing in the clinical setting of ES. Given that a high percentage of patients presented ENG expression at the cell surface, antibody-drug conjugates (ADCs) against ENG were studied. Anti-ENG ADCs exerted an ENG-dependent and dose-dependent anti-proliferative effect in both in vivo and in vitro ES models. These results suggest that the use of ENG-ADC might have potential benefits in ES. As the expression of ENG and MMP14 was variable amongst ES patients, a survival study was assessed in a cohort of 82 patients categorised according to their clinical stage (primary, post chemotherapy primary, metastasis and relapse). Both ENG and MMP14 were associated with worse prognosis. Functional assays revealed that ENG regulates migration, probably through the correct assembly of actin in filaments and filopodia, with a concomitant effect on the adhesive capacity of the cell. Furthermore, ENG was confirmed to be important in the activation of focal adhesion signalling, by favouring focal adhesion kinase phosphorylation and protein kinase C expression. Overall, these results suggest that ENG exerts a main role as an adaptor protein in the correct migration machinery of ES cells, prompting the aggressiveness of the disease.
|Puerto Camacho, M.P. (2021). Endoglin in Ewing sarcoma: from the biological relevance to a clinical strategy. (Tesis Doctoral Inédita). Universidad de Sevilla, Sevilla.