Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • Chlortetracycline HCl structure br Molecular genetics Based

    2019-07-11


    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 EWS-FLI-1 fusion gene (Fig. 2) [3]. In another 10--15% of cases the translocation t(21;12)(22;12) generates the EWS-ERG fusion, whereas the remaining 1--5% of cases may harbor one of several possible translocations, each resulting in a fusion gene containing a portion of the EWS gene and a member of the ets family of transcription factors (Table 1). In addition to providing the key to understanding the biology of Ewing sarcoma, these translocations constitute its most reliable diagnostic criterion.
    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 haematopoietic Chlortetracycline HCl structure can initiate T-cell lymphomas [29]. The invertor knock-in strategy used to generate these tumors offers hope for the development of transgenic mouse models for bone and soft tissue tumors by circumventing transgene toxicity [30]. There are currently two animal models of sarcoma associated with specific chromosomal translocations that recapitulate many of the features of their human counterparts. They include the conditional PAX3-FKHR knock-in model of alveolar rhabdomyosarcoma, where the fusion gene is expressed in terminally differentiated skeletal muscle cells [31], and the TLS/FUS-CHOP transgenic model of myxoid liposarcoma, where the ubiquitous expression of the TLS/FUS-CHOP transgene resulted in the exclusive generation of myxoid liposarcoma-like tumors in their classical anatomical locations [32]. In the absence of adequate transgenic mouse models, two major approaches have been used to address the potential role of EWS-FLI-1 in the pathogenesis of Ewing sarcoma: exogenous expression of the translocation in different cell types and downregulation of EWS-FLI-1 in Ewing sarcoma cell lines. Expression of EWS-FLI-1 in murine NIH-3T3 cells resulted in anchorage independent growth and accelerated tumorigenesis in immunocompromized mice with a tumor phenotype reminiscent of that of human Ewing sarcoma [33], [34]. These observations are consistent with the notion that EWS-FLI-1 can enhance oncogenesis and that it is largely responsible for the histological characteristics associated with ESFT. Moreover, expression of EWS-FLI-1 in non-ESFT tumor cells, including neuroblastoma and alveolar rhabdomyosarcoma cells, resulted in transdifferentiation with the appearance of Ewing sarcoma features, including neural marker expression [35], [36], [37]. By contrast, the same approach using Rat-1 cells [33], mouse embryonic fibroblasts (MEFs) [38] and human primary fibroblasts [39] not only failed to induce transformation but resulted in growth arrest and apoptosis, underscoring the importance of the cellular environment for EWS-FLI-1-mediated oncogenesis. Growth inhibitory effects of dominant negative FLI-1 on Ewing sarcoma cell lines support the notion that EWS-FLI-1 is implicated in ESFT development [40]. Studies by several groups have also shown that antisense EWS-FLI-1 and EWS-FLI-1 siRNA expression in human Ewing sarcoma cell lines result in decreased cell growth in vitro and tumorigenicity in vivo[41].