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Amaral A.T.A.,Institute Of Biomedical Research Of Salamanca Centro Of Investigacion Del Cancer | Amaral A.T.A.,University of Seville | Manara M.C.,CRS Sviluppo di Terapie Biomolecolari | Berghuis D.,Leiden University | And 9 more authors.
PLoS ONE | Year: 2014

Background: Ewing Sarcoma (EWS) is a mesenchymal-derived tumor that generally arises in bone and soft tissue. Intensive research regarding the pathogenesis of EWS has been insufficient to pinpoint the early events of Ewing sarcomagenesis. However, the Mesenchymal Stem Cell (MSC) is currently accepted as the most probable cell of origin. Materials and Methods: In an initial study regarding a deep characterization of MSC obtained specifically from EWS patients (MSC-P), we compared them with MSC derived from healthy donors (MSC-HD) and EWS cell lines. We evaluated the presence of the EWS-FLI1 gene fusion and EWSR1 gene rearrangements in MSC-P. The presence of the EWS transcript was confirmed by q-RT-PCR. In order to determine early events possibly involved in malignant transformation, we used a multiparameter quantitative strategy that included both MSC immunophenotypic negative/positive markers, and EWS intrinsic phenotypical features. Markers CD105, CD90, CD34 and CD45 were confirmed in EWS samples. Results: We determined that MSC-P lack the most prevalent gene fusion, EWSR1-FLI1 as well as EWSR1 gene rearrangements. Our study also revealed that MSC-P are more alike to MSC-HD than to EWS cells. Nonetheless, we also observed that EWS cells had a few overlapping features with MSC. As a relevant example, also MSC showed CD99 expression, hallmark of EWS diagnosis. However, we observed that, in contrast to EWS cells, MSC were not sensitive to the inhibition of CD99. Conclusions: In conclusion, our results suggest that MSC from EWS patients behave like MSC-HD and are phenotypically different from EWS cells, thus raising important questions regarding MSC role in sarcomagenesis. © 2014 Amaral et al. Source

Alfranca A.,Institute Salud Carlos III | Martinez-Cruzado L.,Hospital Universitario Central Of Asturias | Tornin J.,Hospital Universitario Central Of Asturias | Abarrategi A.,Institute Salud Carlos III | And 9 more authors.
Cellular and Molecular Life Sciences | Year: 2015

The bone is a complex connective tissue composed of many different cell types such as osteoblasts, osteoclasts, chondrocytes, mesenchymal stem/progenitor cells, hematopoietic cells and endothelial cells, among others. The interaction between them is finely balanced through the processes of bone formation and bone remodeling, which regulates the production and biological activity of many soluble factors and extracellular matrix components needed to maintain the bone homeostasis in terms of cell proliferation, differentiation and apoptosis. Osteosarcoma (OS) emerges in this complex environment as a result of poorly defined oncogenic events arising in osteogenic lineage precursors. Increasing evidence supports that similar to normal development, the bone microenvironment (BME) underlies OS initiation and progression. Here, we recapitulate the physiological processes that regulate bone homeostasis and review the current knowledge about how OS cells and BME communicate and interact, describing how these interactions affect OS cell growth, metastasis, cancer stem cell fate and therapy outcome. © 2015 Springer Basel. Source

Amaral A.T.,Institute Of Biomedical Research Of Salamanca Centro Of Investigacion Del Cancer | Ordonez J.L.,Institute Of Biomedical Research Of Salamanca Centro Of Investigacion Del Cancer | Otero-Motta A.P.,Institute Of Biomedical Research Of Salamanca Centro Of Investigacion Del Cancer | Garcia-Dominguez D.J.,Institute Of Biomedical Research Of Salamanca Centro Of Investigacion Del Cancer | And 3 more authors.
Advances in Anatomic Pathology | Year: 2014

Ewing Sarcoma is a developmental tumor characterized by balanced chromosomal translocations and formation of new fusion genes, which are the main hallmark of this rare entity. Despite the vast knowledge regarding the molecular aspects of this rare malignancy obtained in the last few years, including the discovery of new therapeutic targets, many questions still remain open. In this review we focus on the research on targeted therapies in this malignancy, and discussed some bottlenecks related to this such as the possible role of pathologists, the availability of samples, the lack of appropriate animal models, and the resources needed to carry out preclinical and clinical research. Copyright © 2013 by Lippincott Williams & Wilkins. Source

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