Abstract
One of the most detrimental hallmarks of glioblastoma multiforme (GBM) is cellular invasiveness, which is considered a potential cause of tumor recurrence. Infiltrated GBM cells are difficult to completely eradicate surgically and with local therapeutic modalities. Although much effort has focused on understanding the various mechanisms controlling GBM invasiveness, its nature remains poorly understood. In this study, we established highly serial intracranial transplantation. U87R4 cells were highly invasive and displayed stem cell-like properties, as compared to noninvasive but proliferative U87L4 cells. Microarray analysis during serial transplantation revealed that apoptosis-inducing genes (caspase3 and PDCD4) were downregulated whereas several cancer stem cell-relevant genes [Frizzled 4 (FZD4) and CD44] were upregulated in more invasive cells. U87R4 cells were resistant to anticancer drug-induced cell death, partly due to downregulation of caspase3 and PDCD4, and they retained activated Wnt/β-catenin signaling due to upregulation of Frizzled 4, which was sufficient to control neurosphere formation. We also found that FZD4 promoted expression of the epithelial to mesenchymal transition regulator SNAI1, along with acquisition of a mesenchymal phenotype. Taken together, our results argue that Frizzled 4 is a member of the Wnt signaling family that governs both stemness and invasiveness of glioma stem cells, and that it may be a major cause of GBM recurrence and poor prognosis.
Highlights
Glioblastoma multiforme (GBM; WHO grade IV) is one of the most common and malignant central nervous system tumors in humans, with an estimated median survival time of less than 1 year [1]
We demonstrated that increased expression of the signaling regulator Frizzled 4 (FZD4), upregulated Wnt signaling, and decreased caspase3 and PDCD4 expression in U87R4 cells were responsible for acquisition of glioma stem cells (GSC)-like properties and resistance to apoptosis
We examined GSC markers, such as CD133 and nestin [15] in neurospheres derived from U87L4 and U87R4 cells using immunofluorescence and found that U87R4-derived neurospheres showed increased nestin and decreased CD133 expression compared to U87L4-derived neurospheres (Fig. 2D), suggesting that neurospheres derived from U87R4 and U87L4 cells may contain different types of glioma stem-like cells
Summary
Glioblastoma multiforme (GBM; WHO grade IV) is one of the most common and malignant central nervous system tumors in humans, with an estimated median survival time of less than 1 year [1]. Much information about the clinicopathological roles of various causal factors for GBM. Authors' Affiliations: 1School of Life Sciences and Biotechnology, Korea University; 2Department of Anatomy, Seoul National University College of Medicine; 3Cancer Stem Cell Research Center and 4Department of Neurosurgery, Sungkyunkwan University School of Medicine; 5National Research Laboratory of Animal Cell Biotechnology, School of Agricultural Biotechnology, Seoul National University; and 6Genomic Medicine Institute, Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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