Mesenchymal Stem Cells and the Origin of Ewing's Sarcoma

Abstract

The origin of Ewing's sarcoma is a subject of much debate. Once thought to be derived from primitive neuroectodermal cells, many now believe it to arise from a mesenchymal stem cell (MSC). Expression of the EWS-FLI1 fusion gene in MSCs changes cell morphology to resemble Ewing's sarcoma and induces expression of neuroectodermal markers. In murine cells, transformation to sarcomas can occur. In knockdown experiments, Ewing's sarcoma cells develop characteristics of MSCs and the ability to differentiate into mesodermal lineages. However, it cannot be concluded that MSCs are the cell of origin. The concept of an MSC still needs to be rigorously defined, and there may be different subpopulations of mesenchymal pluripotential cells. Furthermore, EWS-FLI1 by itself does not transform human cells, and cooperating mutations appear to be necessary. Therefore, while it is possible that Ewing's sarcoma may originate from a primitive mesenchymal cell, the idea needs to be refined further.

Figure 1

Cooperative mutations in the development of Ewing's sarcoma. (a) A t(11;22) reciprocal translocation produces the EWS-FLI1 gene, but this tends to cause growth arrest in normal cells. (b) A mutation randomly occurring prior to the t(11;22) translocation might cooperate with EWS-FLI1 to permit escape from growth arrest (or even promote cell proliferation) and subsequent transformation to Ewing's sarcoma. (c) The cooperative mutation may occur after the t(11;22) translocation; this would necessarily imply a mechanism for continued cell growth after EWS-FLI1 is expressed.