Provided by Ewing Sarcoma Family of Tumors Lead contributors: Carlos Rodriguez-Galindo, MD, Fariba Navid, MD, Joseph Khoury, MD Matthew Krasin, MD St. Jude Children’s Research Hospital Memphis, Tennessee, United States of America Jaume Mora, MD Hospital Sait Joan de Deu Barcelona, Spain Algemir Brunetto, MD Hospital de Clinicas Porto Alegre, Brazil A. Introduction The term Ewing sarcoma family of tumors (ESFT) defines a group of small round cell neoplasms of neuroectodermal origin, that manifests as a continuum of neurogenic differentiation, with Ewing sarcoma of bone representing the least differentiated, and primitive neuroectodermal tumor and peripheral neuroepithelioma the most differentiated forms. ESFT comprise 3% of all pediatric malignancies, and are rare in the nonwhite population.1 The cell of origin has yet to be identified and some hypotheses have been proposed. Potential candidates include endothelial, pericytic, myeloid, mesenchymal, and neuroectodermal cells.2 However, it is currently accepted that either a mesenchymal stem cell or an early primitive neuroectodermal cell that has retained its ability for multilineage differentiation could be the cells of origin for this tumor. Even though they were described as different entities in the past, it is now recognized that the ESFT constitute a single group of neurally derived neoplasms with unique cytogenetic, immunohistochemical and molecular features.2,3 Most patients with localized disease survive with current aggressive treatment but up to 80% of patients with metastases disease die because of disease progression.4 A. References 1 Gurney JG, Swensen AR, Bulterys M. Malignant bone tumors. In: Ries LAG et al (eds). Cancer incidence and survival among children and adolescents: United States SEER program 1975- 1995, National Cancer Institute, SEER Program. NIH Pub. No. 99-4649. Bethesda, MD, 1999. 2 Dehner LP. Primitive neuroectodermal tumor and Ewing's sarcoma. Am J Surg Pathol 1993; 17:1-13. 3 de Alava E, Gerald WL. Molecular biology of the Ewing's sarcoma/primitive neuroectodermal tumor family. J Clin Oncol 2000; 18:204-213. 4 Cotterill SJ, Ahrens S, Paulussen M, Jürgens HF, Voûte PA, Gadner H et al. Prognostic factors in Ewing's tumor of bone: Analysis of 975 patients from the European Intergroup Cooperative Ewing's Sarcoma Study Group. J Clin Oncol 2000; 18:3108-3114. B. Epidemiology and Pathogenesis ESFT of bone is the second most common bone malignancy in children after osteosarcoma occurring in 2.9 cases per million.1 It is extremely uncommon in the first five years of age and it peaks in the second decade of life.1 The disease is slightly more common in males with a male/female ratio of 1.3:1. ESFT is predominantly seen in Caucasians, and distinctly uncommon in the African-American population.1 The incidence of this tumor is also lower in Hispanic and Asian populations.2 Page 2 of 31 However, there is no clear evidence that ESFT is associated with any environmental factor, disease, familial predisposition syndrome. Some cases of ESFT occurring as a second malignancy were reported after retinoblastoma, non-Hodgkin lymphoma, leukemia, Hodgkin’s disease and Wilms tumor. 3 The elucidation of the pathogenesis of ESFT has been limited by our ignorance about the cell of origin of this tumor. A recent study,4 showed that bone marrow-derived stromal cells transduced with EWS/ETS fusion proteins could recapitulate some features of ESFT, such as osteogenic and adipogenic differentiation and expression of neural markers. It was critical for our understanding of the pathogenesis of this tumor, the identification of recurring chromosomal translocations involving the N- terminus transactivation domain of the EWS gene on chromosome 22 band q12 with the C-terminus DNA-binding domain of an ETS family of transcription factors. The ETS family fusion partner most commonly detected is FLI-1 on chromosome 11 band q24 followed by ERG on chromosome 21 band q22 and less commonly FEV, ETV1 and E1AF.5,6 The resulting fusion protein from the rearrangement of these genes has been postulated in the tumorigenesis of ESFT. In this tumor, genetic alterations, growth factor and apoptotic signaling pathways have been shown to play a role in its pathogenesis. EWS/ETS fusion proteins have been recognized as playing a central role in this process and some downstream potential targets of these fusion proteins have been identified. The contribution of each of these proteins and their targets, as well as their mechanism of action requires further elucidation. EWS-FLI1 has been well characterized. FLI1 is a transcription factor and contains a sequence specific DNA binding domain, GGA(A/T). FLI1 plays a role in embryonic development, hematopoiesis, cell growth and differentiation, as well as tumorigenesis. The fusion product of these two genes, EWS and FLI-1, can cause neoplastic transformation in a number of in vitro and in vivo experimental systems.7 Page 3 of 31 EWS is an RNA-binding protein whose function is unclear. When ESFT cell lines are transduced in culture or animal models with anti-sense oligonucleotides, small interfering RNAs (siRNA) or competitive inhibitors to EWS-FLI1, they demonstrate growth inhibition as well as increased susceptibility to chemotherapy induced apoptosis.8,9 The fusion protein binds to target genes in a sequence- specific fashion determined by FLI-1, but these genes are controlled by EWS regulatory domains, a more potent transcriptional activator than FLI-1.10 This aberrant gene regulation appears to result in the transforming properties of EWS-FLI1. The critical genes modulated by EWS-FLI1 that contribute to the oncogenesis are not known. There are several in-frame EWS-FLI1 chimeric transcripts. The most common fusions involve fusion of EWS exon 7 with FLI1 exon 6 (type 1) and fusion of EWS exon 7 with FLI1 exon 5 (type 2) with a relative frequency of 60% and 25%, respectively.11 Compared to other types, type1 fusion may be a weaker trans-activation type, probably justifying the better outcome that these patients have.12,13,18 The karyotype of ESFT cells is not restricted to the rearrangement involving chromosome 22. Other aberrations such as trisomies in chromosome 8 and 12 and an unbalanced1,14 translocation have also been repeatedly observed in ESFT.15,16,17 The biologic and clinical significance of these abnormalities are not known. Primarily homozygous deletions usually associated with loss of p15 and ARF genes, have been detected in a variable proportion of patient with ESFT.18 Some of these findings were correlated with poor overall survival.19,20 Dysregulation of growth factor and apoptotic pathways have also been reported in the pathogenesis of ESFT and the insulin-like growth factor (IGF) signaling pathway the most completely studied so far. Insulin-like growth factors, IGFI and IGFII, primarily mediate their effects through the insulin-like growth factor I receptor (IGFIR). IGFIR are found on the surface of most ESFT.21 Page 4 of 31 Activated IGFIR results in a number of different responses that are mediated by two primary pathways, mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3-K).22 Impairment of IGFIR function by antisense strategies, antibodies, or dominant negative constructs ameliorates its effects on proliferation, migration, angiogenesis, metastasis, and transformation as well as enhancing chemosensitivity of ESFT cells to conventional cytotoxic drugs.21,23,24 Therefore, it may be hypothesized that IGF signaling plays a crucial role in the tumorigenesis of ESFT. IGFIR is necessary for the transforming ability of EWS/ETS fusion proteins.25 Furthermore, it was recently suggested that EWS/FLI1 binds to the promoter region of insulin-like growth factor binding protein-3 (IGFBP-3), a negative regulator of IGF-I signaling, causing repression of its activity demonstrating a direct link between IGF-1 signaling and EWS-FLI1.8 Basic fibroblast growth factor (bFGF, a family of heparin-binding polypeptide growth factors that are important in neuronal development) and its receptors are also expressed in ESFT. However, its role in ESFT remains to be determined.26,27 C-KIT and its ligand, stem cell factor (SCF) as well as PDGFRβare expressed in some ESFT.28,29 Playing some role in cell proliferation, transformation and motility of ESFT and may serve as novel targets for therapy since pharmacological modulation of this pathway is available. 29,30 Death inducing ligands for TNF-related apoptosis-inducing ligand (TRAIL), Fas-ligand, and tumor necrosis factor (TNF) were also studied in this tumor.31 However, not all ESFT that express death receptors are sensitive to TRAIL. It has been shown that32 in the presence of a DNA demethylating agent, apoptosis can be induced in TRAIL insensitive ESFT cells. Page 5 of 31 B. References 1 Gurney JG, Swensen AR, Bulterys M. Malignant bone tumors. In Ries LAG et al (eds). Cancer incidence and survival among children and adolescents: United States SEER program 1975- 1995, National Cancer Institute, SEER Program. NIH Pub. No. 99-4649. Bethesda, MD, 1999. 2 Parkin DM, Stiller CA, Nectoux J. International variations in the incidence of childhood bone tumours. Int J Cancer 1993; 53:371-376. 3 Spunt S, Harper J, Krasin M, Billups C, Rodriguez-Galindo C. Ewing sarcoma family of tumors (ESFT) as a second malignant neoplasm (SMN) following treatment of a primary malignant neoplasm (PMN) during childhood. Proc Annu Meet Am Soc Clin Oncol 2004; 22:808 (abstract). 4 Torchia EC, Jaishankar S, Baker SJ. Ewing tumor fusion proteins block the differentiation of pluripotent marrow stromal cells. Cancer Res 2003; 63:3464-3468. 5de Alava E, Gerald WL. Molecular biology of the Ewing's sarcoma/primitive neuroectodermal tumor family. J Clin Oncol 2000; 18:204-213. 6 Delattre O, Zucman J, Melot T, Sastre Garau X, Zucker J-M, Lenoir GM et al.