Abstract
Glioblastoma (GBM) is a highly infiltrative brain tumor in which cells with properties of stem cells, called glioblastoma stem cells (GSCs), have been identified. In general, the dominant view is that GSCs are responsible for the initiation, progression, invasion and recurrence of this tumor. In this study, we addressed the question whether the differentiation status of GBM cells is associated with their invasive capacity. For this, several primary GBM cell lines were used, cultured either as neurospheres known to enrich for GSCs or in medium supplemented with 10% FCS that promotes differentiation. The differentiation state of the cells was confirmed by determining the expression of stem cell and differentiation markers. The migration/invasion potential of these cells was tested using in vitro assays and intracranial mouse models. Interestingly, we found that serum-induced differentiation enhanced the invasive potential of GBM cells, which was associated with enhanced MMP9 expression. Chemical inhibition of MMP9 significantly reduced the invasive potential of differentiated cells in vitro. Furthermore, the serum-differentiated cells could revert back to an undifferentiated/stem cell state that were able to form neurospheres, although with a reduced efficiency as compared to non-differentiated counterparts. We propose a model in which activation of the differentiation program in GBM cells enhances their infiltrative potential and that depending on microenvironmental cues a significant portion of these cells are able to revert back to an undifferentiated state with enhanced tumorigenic potential. Thus, effective therapy should target both GSCs and differentiated offspring and targeting of differentiation-associated pathways may offer therapeutic opportunities to reduce invasive growth of GBM.
Highlights
Glioblastoma (GBM) is an extremely aggressive and clinically difficult to treat cancer that is in part caused by its highly invasive nature [1, 2]
Like normal neuronal stem cells (NSCs), which can differentiate into neurons, astrocytes and oligodendrocytes [9, 10], glioblastoma stem cells (GSCs) can differentiate into similar cell lineages [11]
The material was obtained after approval and following the ethical guidelines of the Medical Ethics Review Committee (METC) of the University Medical Center Groningen (UMCG).The animal experiments described in this manuscript were approved by the Animal Ethical Committee (DEC) and conducted in compliance with the Animal Welfare Act Regulations
Summary
Glioblastoma (GBM) is an extremely aggressive and clinically difficult to treat cancer that is in part caused by its highly invasive nature [1, 2]. In GBM, tumor initiating stem cells or cancer stem cells (CSCs) have been identified and are commonly referred to as glioblastoma stem cells (GSCs) [3,4,5]. In vitro GSCs are known to be enriched in spherical floating structures, named neurospheres, when cultured in serum-free medium containing bFGF and EGF, which maintains these cells in a largely stem cell or undifferentiated state [6,7,8]. GSCs have been shown to be highly resistant to chemo- and radiotherapy indicating that these cells may be responsible for tumor relapse after therapy [12, 13]
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