EWS/FLI-1 oncoprotein subtypes impose different requirements for transformation and metastatic activity in a murine model.

摘要: Ewing sarcoma/primitive neuroectodermal tumors (EWS/PNET) are characterized by specific chromosomal translocations most often generating a chimeric EWS/FLI-1 gene. Depending on the number of juxtaposed exons assembled, several fusion types have been described with different incidences and prognoses. To assess impact each type phenotypic, tumorigenic, metastatic features EWS/PNET, we developed an amenable system using murine mesenchymal multipotent C3H10T1/2 cell line. Upon transduction EWS/FLI-1, cells acquired dramatic morphological changes in vitro, including smaller size "neurite-like" membrane elongations. Chimeric proteins conferred oncogenic properties anchorage-independent growth increased rate proliferation. Furthermore, expression blocked mineralization, concomitant repression osteoblastic genes, induced adipocytic differentiation program. Moreover, promoted aberrant neural phenotype de novo genes. The intramuscular injection transduced led to tumor development induction overt osteolytic lesions. Analogously, what was observed human tumors, 2 formed primary immunodeficient mice higher incidence lower latency than bearing 1 3 fusions. By contrast, expressing fusions showed activity macroscopic metastases soft tissues lesions limbs as compared type-1-expressing cells. Therefore, structure oncoprotein strongly influenced its tumorigenicity metastagenicity. Thus, this model provides basis for understanding genetic determinants involved represents cellular analyze other oncoproteins sarcomagenesis.