Molecular subtypes, stem cells and heterogeneity: Implications for personalised therapy in glioma

Morokoff, Andrew; Ng, Wayne; Gogos, Andrew; Kaye, Andrew H.

doi:10.1016/j.jocn.2015.02.008

Cited by 46 publications

(45 citation statements)

References 111 publications

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“…2 GSCs are critical cancer cells that contribute to malignant progression, therapeutic resistance and tumor recurrence in GBM. 5,32 As STAT3 signaling is commonly activated in GSCs, and the BMX-mediated STAT3 activation is required for maintaining the self-renewal and tumorigenic potential of GSCs, 21,22,23 disrupting STAT3 signaling pathway may potently disrupt GSCs and have therapeutic potential. However, targeting STAT3 transcription factor itself is not clinically achievable, as STAT3 is required for other functions in normal cells.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…However, it is known that histologically identical tumours may have a very different outcome and response to treatment. Therefore cancer heterogeneity, both on a genetic and epigenetic level, has implications for therapy and shows challenges for the rational design of effective treatment rules [43]. Molecular markers with both diagnostic and prognostic potential contribute valuable tools by redefining tumour subtypes within each grade.…”

Section: Brain Gliomasmentioning

confidence: 99%

MicroRNAs as efficient biomarkers in high-grade gliomas

Barciszewska¹

2016

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“…Мультиформная глиобластома является одной из первых патологий, чей геномный профиль был отражен в проекте TCGA (The Cancer Genome Atlas), она характеризуется гете-рогенной клеточной популяцией с различными био-логическими свойствами и генетическими изменениями [2,3]. Выделяют 4 молекулярных подтипа глиобластом: пронейральный, нейральный, классический и мезен-химальный [1,3].…”

Section: обзорные статьиunclassified

“…Выделяют 4 молекулярных подтипа глиобластом: пронейральный, нейральный, классический и мезен-химальный [1,3]. Данная опухоль представляет собой гетерогенную клеточную популяцию с различными биологическими свойствами и генетическими изме-нениями [2]. В настоящее время, несмотря на прогресс в терапии (химио-, лучевая терапия), прогноз для боль-ных глиобластомой -один из самых неблагоприятных в онкологии [3,4].…”

Section: обзорные статьиunclassified