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Insights into EWS/ETS Proteins in Neuroblastoma Metastases and Ewing's Endothelioma

Explore the crucial functions of EWS/ETS proteins in tumor development and progression in Ewing's sarcoma, along with insights into the origins of Ewing's sarcoma cells and the involvement of additional alterations. Discover the impact of EWS/FLI1 on different cell types and its differentiation factor properties.

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Insights into EWS/ETS Proteins in Neuroblastoma Metastases and Ewing's Endothelioma

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  1. Neuroblastoma metastases in bones, with a criticism of Ewing’s endotheliomaH.C. Colville andR.A. WillisAm J Pathol 1933; 9:421

  2. Functions of EWS/ETS proteins • Owing to the combined action of the EWS transcriptional activator and the FLI1 DNA-binding domain, they function as either aberrant transcription factors or potent repressors, or by altering RNA processing • EWS/ETS proteins also require the collaboration of additional proteins to perform their functions (AP-1, Fos-Jun, RNA helicase-A,..) • Additionally, EWS/FLI1 engages in post-transcriptional processes

  3. EWS/ETS Targets • EWS/FLI1 controls different routes of tumor development, maintenance, and progression in ES: • cell proliferation and survival (activation of targets IGF1, MYC, NKX2.2, TOPK) • escape from growth inhibition, senescence, and apoptosis (inhibition of p21, p57kip, TGFBR2, IGFBP3) • up-regulation of critical genes involved in neural tube and neural crest development (NKX2.2, CCK)

  4. Histogenesis • Endothelial cell (Ewing J) • Primitive haematopoietic cell (Roome NW & Delaney PA, 1932) • Primitive multipotent mesenchymal cell(Dickman PS et al, 1982) • Neuroectodermal cell (Lipinski M, 1986; Cavazzana AO et al, 1987)

  5. Which Cells Originate ES? • Crucial issue for discovering the mechanisms involved in the genesis of EFT, and for the identification of reliable molecular markers and possible therapeutic targets • The cellular context contributes to the phenotype, because the introduction of EWS/ETS fusions into different cellular models results in diverse outcomes ranging from the induction of cell cycle arrest, or apoptosis, to dedifferentiation • This suggests that EWS/FLI1 is a potent differentiation factor that blocks a preexisting commitment, at the same time imposing neural differentiation

  6. Which Cells Originate ES? • The expression of neural markers in EFT points to either a potential mesenchymal or a neuroectodermal origin • The EWS/FLI1 fusion protein can transform primary bone marrow-derived mesenchymal cells to form ES-like tumors in mice • EWS/FLI1 induces murine MSC transformation even in the absence of other prooncogenic events, suggesting that its generation would be the initiating event in EFT pathogenesis • However, the induction of EWS/FLI1 does not transform human MSC, suggesting the involvement of additional alterations

  7. Primary Malignant Bone Tumours Frequency and Percentage Distribution (4148 Cases) • Osteosarcoma 1718 (41.4%) • Chondrosarcoma 1049 (25.2%) • Ewing’s Sarcoma 512 (12.3%) • Chordoma 356 (8.5%) • Fibrosarcoma 255 (6.1%) • Angiosarcoma 93 (2.2%) • MFH 83 (2.0%) Dahlin’s Bone Tumors, Fifth Ed. 1996

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