Aberrant mesenchymal differentiation of glioma stem-like cells: implications for therapeutic targeting
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Veerakumar Balasubramaniyan1,4,9,*, Brian Vaillant1,4,*, Shuzhen Wang1,4, Joy Gumin3,4, M. Elena Butalid2, Ke Sai1,4, Farah Mukheef2, Se Hoon Kim2,4, H.W.G.M. Boddeke5, Frederick Lang3,4, Kenneth Aldape6, Erik P. Sulman4,7, Krishna P. Bhat2,4 and Howard Colman1,4,8
1 Department of Neuro-Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
2 Department of Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
3 Department of Neurosurgery, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
4 Brain Tumor Center, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
5 Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
6 Department of Pathology, Toronto General Hospital/Princess Margaret Cancer Centre, Toronto, Ontario
7 Department of Radiation Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
8 Department of Neurosurgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
9 Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
* These authors have contributed equally to this work
Krishna P. Bhat, email:
Howard Colman, email:
Keywords: glioblastoma, glioma stem-like cells, serum differentiation, mesenchymal, tumorigenicity
Received: June 10, 2014 Accepted: August 08, 2015 Published: August 19, 2015
Differentiation has been proposed as a therapeutic strategy for glioblastoma (GBM) in part due to observations of stem-like cells in GBM that have been shown to undergo terminal differentiation in response to growth factor withdrawal and BMP activation. However, the effects of long term exposure to serum culture conditions on glioma sphere cultures/glioma stem-like cells (GSCs) have not been examined. Here we show that GSCs retained both neurosphere formation and tumor initiation abilities after short or long term serum exposure. Under these conditions, GSCs expressed both neural lineage and stem cell markers, highlighting the aberrant pseudo-differentiation state. GSCs maintained under adherent serum cultured conditions continued to proliferate and initiate tumor formation with efficiencies similar to GSCs maintained under proliferating (neurosphere) conditions. Proneural (PN) GSCs under serum exposure showed an induction of mesenchymal (MES) gene expression signatures. Our data indicate that exposure to serum containing media result in aberrant differentiation (e.g. toward MES lineage) and activation of alternative oncogenic pathways in GSCs.
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