title: Aberrant mesenchymal differentiation of glioma stem-like cells: implications for therapeutic targeting.
abstract: 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.
authors: Department of Neuro-Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.|Brain Tumor Center, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.|Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Veerakumar
authors: V
authors: Balasubramaniyan
authors: Department of Neuro-Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.|Brain Tumor Center, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors: Brian
authors: B
authors: Vaillant
authors: Department of Neuro-Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.|Brain Tumor Center, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors: Shuzhen
authors: S
authors: Wang
authors: Department of Neurosurgery, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.|Brain Tumor Center, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors: Joy
authors: J
authors: Gumin
authors: Department of Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors: M Elena
authors: ME
authors: Butalid
authors: Department of Neuro-Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.|Brain Tumor Center, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors: Ke
authors: K
authors: Sai
authors: Department of Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors: Farah
authors: F
authors: Mukheef
authors: Department of Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.|Brain Tumor Center, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors: Se Hoon
authors: SH
authors: Kim
authors: Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: H W G M
authors: HW
authors: Boddeke
authors: Department of Neurosurgery, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.|Brain Tumor Center, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors: Frederick
authors: F
authors: Lang
authors: Department of Pathology, Toronto General Hospital/Princess Margaret Cancer Centre, Toronto, Ontario.
authors: Kenneth
authors: K
authors: Aldape
authors: Brain Tumor Center, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.|Department of Radiation Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors: Erik P
authors: EP
authors: Sulman
authors: Department of Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.|Brain Tumor Center, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors: Krishna P
authors: KP
authors: Bhat
authors: Department of Neuro-Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.|Brain Tumor Center, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.|Department of Neurosurgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
authors: Howard
authors: H
authors: Colman
mesh_terms: D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D012333:RNA, Messenger
keywords: glioblastoma; glioma stem-like cells; mesenchymal; serum differentiation; tumorigenicity