Development of Ewing's Sarcoma from Primary Bone Marrow–Derived Mesenchymal Progenitor Cells

Abstract

Ewing's sarcoma is a member of Ewing's family tumors (EFTs) 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 5V segment of the EWS gene with the 3V segment of the ETS family gene FLI-1. The EWS-FLI-1 fusion protein behaves as an aberrant transcriptional activator and is believed to contribute to EFT development. However, EWS-FLI-1 induces growth arrest and apoptosis in normal fibroblasts, and primary cells that are permissive for its putative oncogenic properties have not been discovered, hampering basic understanding of EFT biology. Here, we show that EWS-FLI-1 alone can transform primary bone marrow-derived mesenchymal progenitor cells and generate tumors that display hallmarks of Ewing's sarcoma, including a small round cell phenotype, expression of EFTassociated markers, insulin like growth factor-I dependence, and induction or repression of numerous EWS-FLI-1 target genes. These observations provide the first identification of candidate primary cells from which EFTs originate and suggest that EWS-FLI-1 expression may constitute the initiating event in EFT pathogenesis. (Cancer Res 2005; 65(24): 11459-68)

Angiomatoid Fibrous Histiocytoma: The Current Status of Pathology and Genetics

“…11 Another theory has been of origin from fibroblastic reticulum cells that provide a structural supporting function in the stroma of lymph nodes, a subset of cells that have been shown to express desmin. 25 Pluripotent mesenchymal stem cells have been postulated as potential originating cells for several sarcoma types, [26][27][28][29][30][31] and the same suggestion was made for AFH by some authors in the 1980s. 5 Further to the characterization of the recurrent chromosomal rearrangements that result in the EWSR1-CREB1, t(12;22)(q13;q12) EWSR1-ATF1, and t(12;16)(q13;p11) FUS-ATF1 gene fusions, AFH is of course now established as a translocation-associated neoplasm.…”

Modeling sarcomagenesis using multipotent mesenchymal stem cells

“…mMSCs Two different groups have reported that the expression of EWS-FLI-1 in BM-mMSCs resulted in cell transformation and sarcoma development when implanted into immunodeficient mice [54,55]. These tumors shared some features with Ewing's sarcoma, including cell surface markers and cell morphology.…”

“…These tumors shared some features with Ewing's sarcoma, including cell surface markers and cell morphology. Interestingly, the expression of EWS-FLI-1 was able to transform mMSCs on its own in one of the studies [55] while secondary hits acquired in culture (i.e. p53 mutation) were required in another study [54].…”

Inducible Expression of Chimeric EWS/ETS Proteins Confers Ewing's Family Tumor-Like Phenotypes to Human Mesenchymal Progenitor Cells

“…As described above, ectopic expression of EWS/FLI1 results in dramatic changes in morphology and the formation of EFT-like tumors in murine primary bone marrow-derived MPCs but not in murine embryonic stem cells (6,45,52), supporting the notion that MPCs are a plausible cell origin of EFT (45). However, others argue that MPCs cannot be considered progenitors of EFT without further evidence of similarity between human EFT and MPC-EWS/FLI1-induced tumors in mice (29,46).…”

“…The products of these chimeric genes behave as aberrant transcriptional regulators and are believed to play a crucial role in the onset and progression of EFT (3,36). Indeed, recent studies have revealed that the induction of EWS/FLI1 proteins can trigger transformation in certain cell types, including NIH 3T3 cells (36), C2C12 myoblasts (12), and murine primary bone marrow-derived mesenchymal progenitor cells (MPCs) (6,45,52). However, studies have also indicated that overexpression of EWS/ FLI1 provokes apoptosis and growth arrest in mouse normal embryonic fibroblasts and primary human fibroblasts (10,31), hence hampering understanding of the precise role of EWS/ ETS proteins in the development of EFT.…”