Twenty Years on: What Do We Really Know about Ewing Sarcoma and What Is the Path Forward?

Abstract

Ewing sarcoma (ES) is a highly aggressive bone and soft-tissue tumor with peak incidence among adolescents and young adults. Despite advances in local control and systemic chemotherapy, metastatic relapse after an initial clinical remission remains a significant clinical problem. In addition, metastasis at the time of presentation or at relapse continues to be the leading cause of death for patients diagnosed with ES. Since the discovery of the pathognomonic EWS-FLI1 fusion gene more than 20 years ago, much about the molecular and cellular biology of ES pathogenesis has been learned. In addition, more recent exploitation of advances in stem cell and developmental biology has provided key insights into the cellular origins of ES and the role of epigenetic deregulation in tumor initiation and maintenance. Nevertheless, the mechanisms that drive tumor relapse and metastasis remain largely unknown. These gaps in our knowledge continue to hamper the development of novel therapeutic strategies that may improve outcomes for patients with relapsed and metastatic disease. In this article we review the current status of ES biology research, highlighting areas of investigation that we consider to have the greatest potential to yield findings that will translate into clinically significant advances.

Figure 1. Model of ES Initiation

An EWS-ETS fusion gene is created by a chromosomal translocation event during cell division. If the event occurs in a cell type that is tolerant of the fusion oncoprotein, such as a mesenchymal (MSC) or neural crest (NCSC) stem or progenitor cell, in a supportive microenvironment, such as developing bone, tumor initiation can begin. Initiation of malignant transformation downstream of the EWS-ETS fusion gene is dependent on both molecular and cellular changes that, in concert, lead to maintenance of an immature cell state, epigenetic deregulation, and unlimited proliferative capacity. Secondary changes evolve over time that support clonal selection and expansion and ultimately lead to full malignant transformation. These secondary changes likely evolve in response to developmental and growth factor stimuli and occur on a cellular background of epigenetic instability. Latency between the original EWS-ETS fusion event and presentation of ES can be either brief or very prolonged depending on the stochastic nature of secondary changes and their relative potency as pro-oncogenic drivers.

Figure 2. Biology of ES Progression

It is likely that all ES cells have the capacity to invade and metastasize as a consequence of the inherent migratory nature of their stem cells of origin. Plasticity in response to cell intrinsic (e.g. metabolic and genotoxic) and cell extrinsic (e.g. hypoxia, nutrient deprivation) stress is a key biologic feature of normal stem cells that is necessary for maintenance of stemness and unlimited proliferative capacity. ES cells, by nature of their cell of origin and epigenetic deregulation, are highly plastic and dynamically respond to stress. Adaptive, reversible responses to stress contribute to metastasis, therapy resistance, and relapse. Epigenetic evolution over time results in the selective outgrowth of clones that have reversibly, or irreversibly, adopted phenotypic changes that are heritably passed on to daughter cells. In this way, metastatic and drug resistant clones emerge in the absence of additional mutation. Finally, irreversible genetic changes that confer a growth advantage, such as loss of tumor suppressor genes or gain of copy number alterations, will be selected for over time and selective pressure for creation and expansion of these clones will be promoted by the DNA damaging effects of chemotherapy.