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  • In a study performed simultaneously by another

    2019-10-09

    In a study performed simultaneously by another group, EWS-FLI-1 introduction into unsorted murine bone marrow-derived Parathyroid hormone (1-34) (human) resulted in tumors with various phenotypes including one that is consistent with that of Ewing sarcoma [68]. The tumors expressed markers associated with Ewing sarcoma and displayed more aggressive behavior upon subsequent loss of p53 [68]. Prior to these studies, work from Suzanne Baker’s laboratory showed that introduction of EWS-FLI-1 into p19ARF−/− MPCs resulted in a block in differentiation toward osteogenic and adipocytic lineages [69]. Together, these three independent studies provide solid evidence that EWS-FLI-1 expression may not only be implicated in the pathogenesis of ESFT but may constitute its initiating event. They also suggest that MPCs may provide the necessary permissiveness for the transforming potential of EWS-FLI-1. In other words, MPCs may be the right cells in the right place for EWS-FLI-1-mediated oncogenesis. Their capability to migrate from the bone marrow to most organs may help explain the extraosseous locations of Ewing’s sarcoma. The discovery that MPC transformed by EWS-FLI-1 upregulate IGF-1 and are dependent on IGF-1R signaling for survival is consistent with the behavior of Ewing sarcoma cells, which have been observed to require IGF-1 for growth [70] and to be among the most sensitive tumor cell types to IGF-1R inhibition [71], [72]. Moreover, functional IGF-1R expression has been shown to be a pre-requisite for EWS-FLI-1-mediated transformation [73], underscoring the importance of the IGF-1 pathway in the initial phase of ESFT development. Although IGF-1 upregulation was not sufficient to transform MPC in our model of ESFT, it is likely to be one of several factors directly or indirectly induced by EWS-FLI-1 that are implicated in MPC transformation and tumorigenicity. It is noteworthy that the age associated with the peak incidence of Ewing’s sarcoma coincides with augmented IGF-1 secretion in bone as a result of a burst in growth hormone production. IGF-1 induction could provide a survival signal that is essential during early cell transformation to circumvent EWS-FLI-1-induced growth arrest and apoptosis. Consistent with this notion, several studies, including our EWS-FLI-1-transformed MPC model, have suggested that IGF-1R blockade may provide a potentially relevant therapeutic avenue for Ewing’s sarcoma [67], [74]. These observations are of interest because conventional chemotherapeutic approaches for Ewing’s sarcoma control have failed to significantly improve its notoriously poor prognosis.
    Future directions
    02 – Organogenesis
    03 – Morphogenesis
    05 – Cellular and Embryonic Asymmetries
    06 – Cell Adhesion and Migration
    07 – Neural Networks
    09 – Stem Cells and Regeneration
    10 – Signal Transduction
    11 – Genomics and Imaging
    12 – Segmenting the Organism
    13 – Evolution of Developmental Mechanisms
    14 – Patterning and Induction
    15 – Stem Cells During Development