Salient features of mesenchymal stem cells—implications for Ewing sarcoma modeling

Michael J Monument,Nicholas M Bernthal,R Lor Randall

doi:10.3389/fonc.2013.00024

Abstract

Despite a heightened appreciation of the many defining molecular aberrations in Ewing sarcoma, the cooperative genetic environment and permissive cell of origin essential for EWS/ETS-mediated oncogenesis remain elusive. Consequently, inducible animal and in vitro models of Ewing sarcoma from a native cellular context are unable to fully recapitulate malignant transformation. Despite these shortcomings, human, and murine mesenchymal stem cells (MSCs) are the closest working in vitro systems available. MSCs are tolerant of ectopic EWS/FLI expression, which is accompanied by a molecular signature most similar to Ewing sarcoma. Whether MSCs are the elusive cell of origin or simply a tolerant platform of the EWS/FLI transcriptome, these cells have become an excellent molecular tool to investigate and manipulate oncogenesis in Ewing sarcoma. Our understanding of the biological complexity and heterogeneity of human MSCs (hMSCs) has increased substantially over time and as such, appreciation and utilization of these salient complexities may greatly enhance the efficient use of these cells as surrogate models for Ewing sarcoma tumorigenesis.

Highlights

Ewing sarcoma is an aggressive translocation-derived malignancy primarily affecting adolescents and young adults
These data interestingly demonstrate phenotypic differences in adult and pediatric human mesenchymal stromal cells” (MSC) (hMSCs) populations expressing EWS/FLI, suggestive that cells from pediatric sources have a greater proliferative ability, have a EWS/FLI-mediated transcriptome most similar to Ewing sarcoma tumors and cells lines and are more likely to show evidence of genetic reprogramming toward a more pluripotent, stem cell phenotype
For the purposes of in vitro modeling of Ewing sarcoma, immortalization of hMSCs can be achieved, is unlikely to affect transformation under 100 PDs and may greatly increase the window of opportunity to select a homogenous population of MSCs without losing the stem cell phenotype

Summary

INTRODUCTION

Ewing sarcoma is an aggressive translocation-derived malignancy primarily affecting adolescents and young adults. A global skepticism of these aforementioned cell progenitor models of Ewing sarcoma is that ectopic EWS/FLI expression in either mesenchymal or neural crest progenitors has been unable to consistently recapitulate the full phenotypic spectrum of oncogenic transformation This maturing evidence suggests a mere permissive cell environment may be insufficient for transformation, prompting speculation that in addition to EWS/ETS gene fusions, other mutations, epigenetic phenomena, or cell cycle modifications are cooperatively necessary in Ewing sarcoma. The cultured BM-MSC came from INK4A/ARF deficient mice and no phenotypic assays of transformation were assessed such as proliferation assays, anchorage independent growth or xenograft tumor formation These initial results importantly demonstrated tolerable EWS/FLI expression in murine MSCs and the capability of EWS/FLI to repress lineage-specific differentiation. Human cells are generally regarded as more challenging to transform than their mouse counterparts, which are transformed and produce seemingly more aggressive tumors (Akagi, 2004)

HUMAN MSC MODELS

MESENCHYMAL STEM CELL BASICS

Findings

Self renewal potential Unspecified