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EWS/ETS
Fusion Genes Induce Epithelial and Neuroectodermal Differentiation in NIH
3T3 Fibroblasts |
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Michael A. Teitell,
Andrew D. Thompson, Poul H.B. Sorensen, Hiroyuki Shimada, Timothy J. Triche,
and Christopher T. Denny |
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Department
of Pathology (MAT), Pediatrics (CTD), Jonsson Comprehensive Cancer Center
(MAT, ADT, CTD), and Molecular Biology Institute (MAT, ADT), University
of California at Los Angeles, Los Angeles, California; Department of Pathology
(PHBS), British Columbia's Children's Hospital, Vancouver, British Columbia,
Canada; and Department of Pathology (MAT, HS, TJT), Children's Hospital
Los Angeles and University of Southern California School of Medicine, Los
Angeles, California |
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SUMMARY: Ewing's sarcoma
is the least differentiated member of the peripheral primitive neuroectodermal
(pPNET) tumor family. Chromosomal translocations involving the EWS
gene and five different Ets family transcription factor genes create
fusion genes encoding aberrant transcription factors and are implicated
in the vast majority of Ewing's sarcoma cases. Here, NIH 3T3 fibroblasts
were infected with control (tk-neo or RAS) and two different EWS/ETS-expressing
retroviruses. In vitro studies of established polyclonal lines expressing
the two EWS/ETS genes, either EWS/FLI1 or EWS/ETV1,
showed induction of cytokeratin 15 gene expression. Both fusion genes
also caused characteristic gross morphologic, histologic, and ultrastructural
changes in NIH 3T3 cells when transformed cell lines were injected into
CB-17-scid mice. Native NIH 3T3 cells with a spindled cell morphology
were converted to polygonal cells with high nucleo-cytoplasmic ratios that
continued to express abundant cytokeratin. Extracellular collagen deposition
was abolished, rough endoplasmic reticulum was markedly diminished, and
rudimentary cell-cell attachments appeared. Most strikingly, neurosecretory-type
dense core granules like those seen in pPNET were now evident. This murine
model, created in mesenchyme-derived NIH 3T3 cells, demonstrated new characteristics
of both neuroectodermal and epithelial differentiation and resembled small
round cell tumors microscopically.
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