TY - JOUR
T1 - Serum-Induced Differentiation of Glioblastoma Neurospheres Leads to Enhanced Migration/Invasion Capacity That Is Associated with Increased MMP9
AU - Vareecal Joseph, Justin
AU - van Roosmalen, Ingrid A. M.
AU - Busschers, Ellen
AU - Tomar, Tushar
AU - Conroy, Siobhan
AU - Eggens-Meijer, Ellie
AU - Fajardo, Natalia Penaranda
AU - Pore, Milind M.
AU - Balasubramaniyan, Veerakumar
AU - Wagemakers, Michiel
AU - Copray, Sjef
AU - den Dunnen, Wilfred F. A.
AU - Kruyt, Frank A. E.
PY - 2015/12/23
Y1 - 2015/12/23
N2 - 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.
AB - 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.
KW - CANCER STEM-CELLS
KW - EPITHELIAL-MESENCHYMAL TRANSITION
KW - HUMAN BRAIN
KW - MATRIX METALLOPROTEINASES
KW - METASTATIC COLONIZATION
KW - SIGNALING PATHWAY
KW - GLIOMA INVASION
KW - TRANSDIFFERENTIATION
KW - IDENTIFICATION
KW - ASTROCYTES
U2 - 10.1371/journal.pone.0145393
DO - 10.1371/journal.pone.0145393
M3 - Article
C2 - 26700636
VL - 10
JO - PLOS-One
JF - PLOS-One
SN - 1932-6203
IS - 12
M1 - e0145393
ER -