title: Serum-Induced Differentiation of Glioblastoma Neurospheres Leads to Enhanced Migration/Invasion Capacity That Is Associated with Increased MMP9.
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.
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Justin V
authors.initials: JV
authors.lastname: Joseph
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|Department of Pharmacy, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Ingrid A M
authors.initials: IA
authors.lastname: van Roosmalen
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Busschers
authors.affiliation: Department of Gynecologic Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Tushar
authors.initials: T
authors.lastname: Tomar
authors.affiliation: Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Conroy
authors.affiliation: Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Ellie
authors.initials: E
authors.lastname: Eggens-Meijer
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Natalia
authors.initials: N
authors.lastname: Peñaranda Fajardo
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Milind M
authors.initials: MM
authors.lastname: Pore
authors.affiliation: Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Veerakumar
authors.initials: V
authors.lastname: Balasubramanyian
authors.affiliation: Department of Neuro-surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: Wagemakers
authors.affiliation: Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Sjef
authors.initials: S
authors.lastname: Copray
authors.affiliation: Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Wilfred F A
authors.initials: WF
authors.lastname: den Dunnen
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Frank A E
authors.initials: FA
authors.lastname: Kruyt
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D044967:Serum / Q000737:chemistry
chemical_list: D020780:Matrix Metalloproteinase 9