Dedifferentiation of patient-derived glioblastoma multiforme cell lines results in a cancer stem cell-like state with mitogen-independent growth.

Inan Olmez,Bulent Ozpolat,Wangzhen Shen,Hayes Mcdonald

doi:10.1111/jcmm.12479

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.

Highlights

Glioblastoma multiforme (GBM) is the most common primary brain tumour and contains a heterogeneous population of cells, including cancer stem cells (CSCs) [1]
As a confirmation of successful transfection, induced glioma stem cells (iGSCs) were tested for transcription factors such as Oct4, Nanog and Sox2 (Fig. 1B)
We found that NOTCH1 and b-catenin were activated in iGSCs compared with GBM cells (Fig. 6A)

Summary

Introduction

Glioblastoma multiforme (GBM) is the most common primary brain tumour and contains a heterogeneous population of cells, including cancer stem cells (CSCs) [1]. There is growing evidence that anaplastic gliomas and GBMs originate from CSCs that eventually differentiate into a phenotypically diverse cell population [1,2,3]. For glioma stem cells (GSCs), several markers have been proposed including CD133, CD44, L1CAM and SSEA-1 [5,6,7]. As in neural stem cells, these pathways are believed to be responsible for regulation of maintenance and differentiation of GSCs and to promote tumour growth [10, 11] and confer resistance to cancer therapy [12, 13]

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Results

Conclusion