A Hierarchy of Self-Renewing Tumor-Initiating Cell Types in Glioblastoma

Chen, Ruihuan; Nishimura, Merry; Bumbaca, Stephanie M.; Kharbanda, Samir; Forrest, William F.; Kasman, Ian; Greve, Joan M.; Soriano, Robert; Gilmour, Laurie L.; Rivers, Celina Sanchez; Modrušan, Zora; Nacu, Şerban; Guerrero, Steve; Edgar, Kyle A.; Wallin, Jeffrey J.; Lamszus, Katrin; Westphal, Manfred; Heim, Susanne; James, C. David; VandenBerg, Scott R.; Costello, J; Moorefield, Scott; Cowdrey, Cynthia; Prados, Michael D.; Phillips, Heidi S.

doi:10.1016/j.ccr.2009.12.049

Cited by 500 publications

(467 citation statements)

References 35 publications

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“…As CD133 was originally described as the NSC (Uchida et al, 2000) and BTIC (Singh et al, 2004) marker, its ability to exclusively isolate tumor-initiating cells has been debated in the literature, especially in adult glioblastoma. In this heterogeneous tumor, CD133À cells in long-term culture were found to be capable of tumor initiation in mice (Chen et al, 2010), although many recent publications maintain that not only is the CD133 þ fraction enriched in BTIC capacity Yan et al, 2011), but the features of 'stemness' marked by CD133 are associated with increasing malignancy and poor patient outcome (Bao et al, 2006;Thon et al, 2008;McCord et al, 2009;Pallini et al, 2010). In medulloblastoma, evidence more uniformly supports the application of CD133 as a BTIC marker, as CD133 þ multipotent NSCs were described in the postnatal cerebellum (Lee et al, 2005), and further studies showed that CD133 enriched for brain tumor-initiating capacity and radioresistance in primary and Daoy medulloblastoma-derived tumors (Fan et al, 2006;Blazek et al, 2007;Annabi et al, 2008Annabi et al, , 2010Pistollato et al, 2010;Yu et al, 2010).…”

Section: Shh Regulates Bmi1 In Medulloblastoma Bticsmentioning

confidence: 94%

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

et al. 2011

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Bmi1 is a key stem cell regulatory gene implicated in the pathogenesis of many aggressive cancers, including medulloblastoma. Overexpression of Bmi1 promotes cell proliferation and is required for hedgehog (Hh) pathwaydriven tumorigenesis. This study aimed to determine if Sonic hedgehog (Shh) modulates the key stem cell regulatory gene Bmi1 in childhood medulloblastoma brain tumor-initiating cells (BTICs). Although current literature suggests that there is a correlation between Shh pathway genes and Bmi1 expression, it is unclear whether there is indeed a direct regulatory mechanism. To address whether Shh induces expression of Bmi1, stem cell-enriched populations from medulloblastoma cell lines and primary samples were treated with Shh ligand and KAAD-cyclopamine (Shh antagonist). Our data indicate that Bmi1 expression positively correlates with increasing Shh ligand concentrations. Chromatin immunoprecipitation reveals that Gli1 preferentially binds to the Bmi1 promoter, and Bmi1 transcript levels are increased and decreased by Gli1 overexpression and downregulation, respectively. Knockdown experiments of Bmi1 in vitro and in vivo demonstrate that Hh signaling not only drives Bmi1 expression, but a feedback mechanism exists wherein downstream effectors of Bmi1 may, in turn, activate Hh pathway genes. These findings implicate Bmi1 and Hh as mutually indispensable pathways in medulloblastoma BTIC maintenance. Recent molecular characterization of medulloblastoma also reveals that Bmi1 is overexpressed across all subgroups of medulloblastoma, particularly in the most aggressive subtypes. Lastly, despite recent identification of BTIC markers, the molecular characterization of these cell populations remains unclear. In this work, we propose that the BTIC marker CD133 may segregate a cell population with a Hh-receptor phenotype, thus demonstrating a cell-cell interaction between the CD133 þ Hh receptor cells and the CD133À Hh-secreting cells.

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Section: Shh Regulates Bmi1 In Medulloblastoma Bticsmentioning

confidence: 94%

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

et al. 2011

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“…In the conditional knockout of the CD133 animal model, glioma can be formed from the cell population without CD133 expression (Nishide et al, 2009). In addition, both CD133-positive and CD133-negative human glioma-derived stem cell clones exhibit tumor formation ability (Chen et al, 2010). Some embryonic stem cell markers associated with glioma identification and aggressiveness, such as Oct4, Nanog, and Sox2, have been used for the guidance of glioma therapeutic selection (Ben-Porath et al, 2008;Holmberg et al, 2011;Shats et al, 2011).…”

Section: Molecular Markers Of Glioma Stem Cellsmentioning

confidence: 99%

Neuronal stem cells in the central nervous system and in human diseases

Wang

2012

Protein Cell

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The process of cortical expansion in the central nervous system is a key step of mammalian brain development to ensure its physiological function. Radial glial (RG) cells are a glial cell type contributing to this progress as intermediate neural progenitor cells responsible for an increase in the number of cortical neurons. In this review, we discuss the current understanding of RG cells during neurogenesis and provide further information on the mechanisms of neurodevelopmental diseases and stem cell-related brain tumorigenesis. Knowledge of neuronal stem cell and relative diseases will bridge benchmark research through translational studies to clinical therapeutic treatments of these diseases.

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“…Growing evidence supported that a subset of cancer cells, referred to as glioma stem cells (GSCs) or tumor initiating cells, are responsible for tumor propagation and recurrence in GBMs. [3][4][5] Although the cellular origin of GSCs remains controversial, 6 these cells have been demonstrated to share several typical features of embryonic or somatic stem cells (i.e., self-renewal capacity and multi-lineage differentiation potential). GSCs are privileged to drive tumor initiation and malignant progression.…”

mentioning

confidence: 99%

Tetraspanin CD9 stabilizes gp130 by preventing its ubiquitin-dependent lysosomal degradation to promote STAT3 activation in glioma stem cells

et al. 2016

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Glioblastoma (GBM) is the most malignant and lethal brain tumor harboring glioma stem cells (GSCs) that promote tumor propagation and therapeutic resistance. GSCs preferentially express several critical cell surface molecules that regulate the prosurvival signaling for maintaining the stem cell-like phenotype. Tetraspanin CD9 has recently been reported as a GSC biomarker that is relevant to the GSC maintenance. However, the underlying molecular mechanisms of CD9 in maintaining GSC property remain elusive. Herein, we report that CD9 stabilizes the IL-6 receptor glycoprotein 130 (gp130) by preventing its ubiquitindependent lysosomal degradation to facilitate the STAT3 activation in GSCs. CD9 is preferentially expressed in GSCs of human GBM tumors. Mass spectrometry analysis identified gp130 as an interacting protein of CD9 in GSCs, which was confirmed by immunoprecipitation and immunofluorescent analyses. Disrupting CD9 or gp130 by shRNA significantly inhibited the self-renewal and promoted the differentiation of GSCs. Moreover, CD9 disruption markedly reduced gp130 protein levels and STAT3 activating phosphorylation in GSCs. CD9 stabilized gp130 by preventing its ubiquitin-dependent lysosomal degradation to promote the BMX-STAT3 signaling in GSCs. Importantly, targeting CD9 potently inhibited GSC tumor growth in vivo, while ectopic expression of the constitutively activated STAT3 (STAT3-C) restored the tumor growth impaired by CD9 disruption. Collectively, we uncovered a critical regulatory mechanism mediated by tetraspanin CD9 to maintain the stem cell-like property and tumorigenic potential of GSCs.

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A Hierarchy of Self-Renewing Tumor-Initiating Cell Types in Glioblastoma

Cited by 500 publications

References 35 publications

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

Neuronal stem cells in the central nervous system and in human diseases

Tetraspanin CD9 stabilizes gp130 by preventing its ubiquitin-dependent lysosomal degradation to promote STAT3 activation in glioma stem cells

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