Objective. The goal of this study was to review the current literature on the biology of Ewing's sarcoma, including current treatments and the means by which an understanding of biological mechanisms could impact future treatments. Methods. A search of PubMed and The Cochrane Collaboration was performed. Both preclinical and clinical evidence was considered, but specific case reports were not. Primary research articles and reviews were analyzed with an emphasis on recent publications. Results. Ewing sarcoma is associated with specific chromosomal translocations and the resulting transcripts/proteins. Knowledge of the biology of Ewing sarcoma has been growing but has yet to significantly impact or produce new treatments. Localized cases have seen improvements in survival rates, but the same cannot be said of metastatic and recurrent cases. Standard surgical, radiation, and chemotherapy treatments are reaching their efficacy limits. Conclusion. Improving prognosis likely lies in advancing biomarkers and early diagnosis, determining a cell(s) of origin, and developing effective molecular therapeutics and antiangiogenic agents. Preclinical evidence suggests the utility of molecular therapies for Ewing sarcoma. Early clinical results also reveal potential for novel treatments but require further development and evaluation before widespread use can be advocated. 1. Introduction Ewing’s sarcoma family tumors (ESFT) include Ewing’s sarcoma (ES), peripheral primitive neuroectodermal tumors (PNET), and Askin tumors. These tumors are undifferentiated small blue round cell tumors that mainly appear in bone and less frequently in soft tissues [1, 2]. While these tumors are rare, accounting for less than 10% of all human malignancies, they are of the most aggressive and often occur in the long bones and pelvis where they can quickly metastasize to the bone marrow, lung, and other tissues [3, 4]. ES is the second most common bone cancer, most often occurring in Caucasian children, adolescents, and young adults, and is considered a high-grade malignancy [5–8]. Originally, it was thought that ES was derived from primitive neuroectodermal cells; however, there is much debate over the origin of ES. In this regard, endothelial, mesodermal, epithelial, neural, and mesenchymal cells have all been hypothesized as an origin, but there is substantial research indicating that mesenchymal stem cells (MSC) may be the original progenitor of Ewing tumor proliferation [9], and Ewing tumors most often harbor nonrandom balanced chromosomal translocations of the EWS gene on chromosome
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