Serum-Induced Differentiation of Glioblastoma Neurospheres Leads to Enhanced Migration/Invasion Capacity That Is Associated with Increased MMP9

Justin Vareecal Joseph, Ingrid A. M. van Roosmalen, Ellen Busschers, Tushar Tomar, Siobhan Conroy, Ellie Eggens-Meijer, Natalia Penaranda Fajardo, Milind M. Pore, Veerakumar Balasubramaniyan, Michiel Wagemakers, Sjef Copray, Wilfred F. A. den Dunnen, Frank A. E. Kruyt*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

23 Citaten (Scopus)
435 Downloads (Pure)


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.

Originele taal-2English
Aantal pagina's19
TijdschriftPLoS ONE
Nummer van het tijdschrift12
StatusPublished - 23-dec.-2015

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