title: Dedifferentiation of patient-derived glioblastoma multiforme cell lines results in a cancer stem cell-like state with mitogen-independent growth.
abstract: Emerging evidence shows that glioblastoma multiforme (GBM) originates from cancer stem cells (CSCs). Characterization of CSC-specific signalling pathways would help identify new therapeutic targets and perhaps lead to the development of more efficient therapies selectively targeting CSCs. Here; we successfully dedifferentiated two patient-derived GBM cell lines into CSC-like cells (induced glioma stem cells, iGSCs) through expression of Oct4, Sox2 and Nanog transcription factors. Transformed cells exhibited significant suppression of epidermal growth factor receptor and its downstream pathways. Compared with parental GBM cells, iGSCs formed large neurospheres even in the absence of exogenous mitogens; they exhibited significant sensitivity to salinomycin and chemoresistance to temozolomide. Further characterization of iGSCs revealed induction of NOTCH1 and Wnt/β-catenin signalling and expression of CD133, CD44 and ALDH1A1. Our results indicate that iGSCs may help us understand CSC physiology and lead to development of potential therapeutic interventions aimed at differentiating tumour cells to render them more sensitive to chemotherapy or other standard agents.
authors: Department of Neurology, Vanderbilt University, Nashville, TN, USA.
authors: Inan
authors: I
authors: Olmez
authors: Department of Neurology, Vanderbilt University, Nashville, TN, USA.
authors: Wangzhen
authors: W
authors: Shen
authors: Department of Biochemistry, Vanderbilt University, Nashville, TN, USA.
authors: Hayes
authors: H
authors: McDonald
authors: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Non-Coding RNA Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Bulent
authors: B
authors: Ozpolat
mesh_terms: D015153:Blotting, Western; D054337:Cell Dedifferentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics*; D000067470:Cellular Reprogramming Techniques / Q000379:methods; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology; D008934:Mitogens / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D051881:Receptor, Notch1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D000077204:Temozolomide; D051176:beta Catenin / Q000378:metabolism
chemical_list: D008934:Mitogens; D051881:Receptor, Notch1; D051176:beta Catenin; D003606:Dacarbazine; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077204:Temozolomide
keywords: EphB4; Nanog; Oct4; Sox2; cancer stem cells; epidermal growth factor receptor; glioblastoma multiforme; salinomycin