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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Article numbere0145393
Number of pages19
JournalPLoS ONE
Volume10
Issue number12
DOIs
Publication statusPublished - 23-Dec-2015

Keywords

  • CANCER STEM-CELLS
  • EPITHELIAL-MESENCHYMAL TRANSITION
  • HUMAN BRAIN
  • MATRIX METALLOPROTEINASES
  • METASTATIC COLONIZATION
  • SIGNALING PATHWAY
  • GLIOMA INVASION
  • TRANSDIFFERENTIATION
  • IDENTIFICATION
  • ASTROCYTES

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