Cancer Letters

Cancer Letters

Volume 254, Issue 1, 28 August 2007, Pages 1-10
Cancer Letters

Mini-review
The Biology of Ewing sarcoma

https://doi.org/10.1016/j.canlet.2006.12.009Get rights and content

Abstract

Sarcomas account for less than 10% of all human malignancies that are believed to originate from as yet poorly defined mesenchymal progenitor cells. They constitute some of the most aggressive adult and childhood cancers in that they have a high metastatic proclivity and are typically refractory to conventional chemo- and radiation therapy. Ewing’s sarcoma is a member of Ewing’s family tumors (ESFT) and the second most common solid bone and soft tissue malignancy of children and young adults. It is associated in 85% of cases with the t(11;22)(q24:q12) chromosomal translocation that generates fusion of the 5′ segment of the EWS gene with the 3′ segment of the ETS family gene FLI-1. The resulting EWS-FLI-1 fusion protein is believed to behave as an aberrant transcriptional activator that contributes to ESFT development by altering the expression of its target genes in a permissive cellular environment. Although ESFTs are among the best studied sarcomas, the mechanisms involved in EWS-FLI-1-induced transformation require further elucidation and the primary cells from which ESFTs originate need to be identified. This review will highlight some of the most recent discoveries in the field of Ewing sarcoma biology and origins.

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.

References (74)

  • C.S. Mitsiades et al.

    Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors

    Cancer Cell

    (2004)
  • J.A. Toretsky et al.

    The insulin-like growth factor-I receptor is required for EWS/FLI-1 transformation of fibroblasts

    J. Biol. Chem.

    (1997)
  • S. Ushigome, R. Machinami, P.H. Sorensen, Ewing sarcoma/primitive neuroectodermal tumor, in: C.D.M. Fletcher, K.K....
  • E. Dejana

    Endothelial cell–cell junctions: happy together

    Nat. Rev. Mol. Cell. Biol.

    (2004)
  • O. Delattre et al.

    Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours

    Nature

    (1992)
  • L.J. Helman et al.

    Mechanisms of sarcoma development

    Nat. Rev. Cancer

    (2003)
  • A. Bertolotti et al.

    hTAF(II)68, a novel RNA/ssDNA-binding protein with homology to the pro-oncoproteins TLS/FUS and EWS is associated with both TFIID and RNA polymerase II

    EMBO J.

    (1996)
  • A. Arvand et al.

    Biology of EWS/ETS fusions in Ewing’s family tumors

    Oncogene

    (2001)
  • T. Ohno et al.

    The EWS gene, involved in Ewing family of tumors, malignant melanoma of soft parts and desmoplastic small round cell tumors, codes for an RNA binding protein with novel regulatory domains

    Oncogene

    (1994)
  • A. Bertolotti et al.

    EWS, but not EWS-FLI-1, is associated with both TFIID and RNA polymerase II: interactions between two members of the TET family, EWS and hTAFII68, and subunits of TFIID and RNA polymerase II complexes

    Mol. Cell. Biol.

    (1998)
  • J.S. Felsch et al.

    Tyrosine kinase Pyk2 mediates G-protein-coupled receptor regulation of the Ewing sarcoma RNA-binding protein EWS

    Curr. Biol.

    (1999)
  • D. Perrotti et al.

    BCR-ABL prevents c-jun-mediated and proteasome-dependent FUS (TLS) proteolysis through a protein kinase CbetaII-dependent pathway

    Mol. Cell. Biol.

    (2000)
  • G.G. Hicks et al.

    Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death

    Nat. Genet.

    (2000)
  • M. Kuroda et al.

    Male sterility and enhanced radiation sensitivity in TLS(−/−) mice

    EMBO J.

    (2000)
  • K. Shimizu et al.

    An ets-related gene, ERG, is rearranged in human myeloid leukemia with t(16;21) chromosomal translocation

    Proc. Natl. Acad. Sci. USA

    (1993)
  • Y. Ben-David et al.

    Erythroleukemia induction by Friend murine leukemia virus: insertional activation of a new member of the ets gene family, Fli-1, closely linked to c-ets-1

    Genes. Dev.

    (1991)
  • D.G. Blair et al.

    Ets and retroviruses - transduction and activation of members of the Ets oncogene family in viral oncogenesis

    Oncogene

    (2000)
  • V.N. Rao et al.

    Analysis of the DNA-binding and transcriptional activation functions of human Fli-1 protein

    Oncogene

    (1993)
  • A.H. Truong et al.

    The role of Fli-1 in normal cell function and malignant transformation

    Oncogene

    (2000)
  • F. Melet et al.

    Generation of a novel Fli-1 protein by gene targeting leads to a defect in thymus development and a delay in Friend virus-induced erythroleukemia

    Mol. Cell. Biol.

    (1996)
  • D.D. Spyropoulos et al.

    Hemorrhage, impaired hematopoiesis, and lethality in mouse embryos carrying a targeted disruption of the Fli1 transcription factor

    Mol. Cell. Biol.

    (2000)
  • L. Zhang et al.

    An immunological renal disease in transgenic mice that overexpress Fli-1, a member of the ets family of transcription factor genes

    Mol. Cell. Biol.

    (1995)
  • J.C. Howard et al.

    Temporal order and functional analysis of mutations within the Fli-1 and p53 genes during the erythroleukemias induced by F-MuLV

    Oncogene

    (1993)
  • R. Pereira et al.

    FLI-1 inhibits differentiation and induces proliferation of primary erythroblasts

    Oncogene

    (1999)
  • A. Tamir et al.

    Fli-1, an Ets-related transcription factor, regulates erythropoietin-induced erythroid proliferation and differentiation: evidence for direct transcriptional repression of the Rb gene during differentiation

    Mol. Cell. Biol.

    (1999)
  • R. Codrington et al.

    The Ews-ERG fusion protein can initiate neoplasia from lineage-committed haematopoietic cells

    PLoS Biol.

    (2005)
  • A. Forster et al.

    The invertor knock-in conditional chromosomal translocation mimic

    Nat. Methods

    (2005)
  • Cited by (0)

    View full text