Mini-reviewThe Biology of Ewing sarcoma
Introduction
Ewing sarcoma, often referred to as Ewing’s sarcoma family tumors (ESFT) is the second most common bone malignancy after osteosarcoma, arising in children and young adults with a peak incidence at age 15. The frequency of Ewing sarcoma is 1–3 per million per year in the Western hemisphere, with a slight predominance in males. Although most Ewing sarcomas occur in bone and especially in the pelvis, the diaphyseal regions of the long bones and bones of the chest wall, 15% of primary ESFT may arise in a variety of extraosseous sites, including deep soft paravertebral, thoracic and proximal limb tissues, kidney, bladder, lung, prostate and the meninges [1]. Similar to several other sarcomas, ESFT displays an aggressive behavior with a tendency toward recurrence following resection and pronounced proclivity toward early hematogenous metastasis primarily to the lung, bone and bone marrow. Lymph node, liver and brain metastases are typically rare. Currently, Ewing sarcomas are treated with a combination of surgery, radiation and chemotherapy, but despite these multimodal approaches the survival rate remains poor: 50% at 5 years (25% when metastasis are present at diagnosis) and less than 30% at 10 years.
Section snippets
Histology
Morphologically, Ewing sarcoma is composed of sheets of small round cells with a high nuclear to cytoplasmic ratio and is often classified by pathologists into a group of small round blue cell tumors that include neuroblastoma, alveolar rhabdomyosarcoma and lymphoblastic lymphoma. The cells typically have scant, weakly eosinophilic cytoplasm that usually contains glycogen in the form of periodic-acid-Schiff-positive, diastase degradable granules, and round nuclei with evenly distributed
Molecular genetics
Based on the genetic mutations associated with their development, sarcomas are subdivided into two distinct classes. One class is composed of tumors bearing complex karyotypic abnormalities with no particular pattern. The second class, which includes Ewing sarcoma, encompasses tumors associated with unique chromosomal translocations that give rise to specific fusion genes. Ewing’s sarcoma is in 85% of cases associated with the translocation t(11;22)(q24;q12), which leads to the formation of the
The effect of EWS-FLI-1 expression in tumor development
A major impediment toward understanding sarcoma biology in general and in ESFT biology in particular, is the lack of adequate transgenic animal models. Thus far, development of a transgenic Ewing’s sarcoma model in mice has failed, probably because of the toxicity of EWS-FLI-1 and other EWS-associated fusions in most primary cells. However, recent work using a conditional lymphoid-specific EWS-ERG model of tumorigenesis has demonstrated that EWS-ERG expression in lineage-committed
Mechanism of action of EWS-FLI-1
Current opinion holds that EWS-FLI-1 as well as the other EWS-ETS fusion proteins function as aberrant transcription factors. This view is supported by observations that EWS-ETS proteins localize to the nucleus, bind DNA in site-specific manner and possess, in the EWS N-terminal domain, a powerful transcriptional activator that is severalfold more potent than the corresponding native FLI-1 domain displaced as a result of the chromosomal translocation.
Molecular analysis has revealed that several
The potential origin of Ewing sarcoma
From the preceding discussion, it appears obvious that at least two key issues still remain to be addressed in order to understand Ewing’s sarcoma biology: the identity of the cells from which ESFT originate, and which presumably display permissiveness for EWS-FLI-1-mediated transformation, and the possibility that EWS-FLI-1 is the unique initiating event in ESFT development. Although mutation of p53 and loss of p16INK4A/p14ARF have been documented in ESFT, they occur in a minority of tumors,
Future directions
The model systems used thus far have provided substantial insight into the biological properties of EWS-FLI-1 that may be relevant to transformation. The evidence that EWS-FLI-1 can transform mouse MPC to yield Ewing’s sarcoma-like tumors constitutes a quantum step toward understanding the cellular environment required for expression of its oncogenic potential. It also underscores the notion that a single genetic event in the appropriate cellular context may be sufficient for ESFT development.
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