Cancer stem cells in glioblastoma

Lathia, Justin D.; Mack, Stephen C.; Mulkearns-Hubert, Erin E.; Valentim, Carolina C S; Rich, Jeremy

doi:10.1101/gad.261982.115

Cited by 1,370 publications

(1,354 citation statements)

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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%

“…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.…”

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confidence: 99%

“…6,7 The potent capacity of GSCs in promoting tumor progression may be a result of their extensive potential to maintain cell proliferation and to support malignant behaviors such as cancer invasion, tumor angiogenesis, vascular pericyte generation and immune evasion. 5,8 GSCs have been found to be enriched in GBMs after radiation and chemotherapy, and contribute to therapeutic resistance and tumor re-initiation. 3,9 The pivotal role of GSCs in promoting malignant progression and tumor recurrence in GBMs indicate that targeting GSCs may significantly improve GBM treatment and overcome the therapeutic resistance.…”

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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%

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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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“…Indeed, GSCs are endowed with several growth properties typical of neural stem cells, including self-renewal by symmetric and asymmetric division dependent upon several factors, including the functional interplay with surrounding tumor and tumor-associated cells [10]. In comparison to the highly proliferating cells from the tumor bulk, this rare quiescent cell population is able to reconstitute the tumor mass and spread into the brain.…”

Section: Introductionmentioning

confidence: 99%

A combined microRNA-based targeted therapeutic approach to eradicate glioblastoma stem-like cells

Esposito

Nuzzo

Kumar

et al. 2016

Journal of Controlled Release

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Release, 238 . pp. 43 57. ISSN 0168 3659 It is advisable to refer to the publisher's version if you intend to cite from the work.http://dx.doi.org/10. 1016/j.jconrel.2016.07.032 For more information about UCLan's research in this area go to http://www.uclan.ac.uk/researchgroups/ and search for . This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT

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“…RNAi targeting drivers of tumorigenesis shows strong potential to supplement the development of traditional small-molecule pharmaceutics (6). However, delivery remains a key obstacle for efficient RNAi against tumor drivers (5,7,8). RNA-sequencing analysis of patient tissue combined with histology and in situ hybridization (Ivy Glioblastoma Atlas Project; SI Appendix, Fig.…”

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Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Khan

Suvà

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

112

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Brain tumor-initiating cells (BTICs) have been identified as key contributors to therapy resistance, recurrence, and progression of diffuse gliomas, particularly glioblastoma (GBM). BTICs are elusive therapeutic targets that reside across the blood-brain barrier, underscoring the urgent need to develop novel therapeutic strategies. Additionally, intratumoral heterogeneity and adaptations to therapeutic pressure by BTICs impede the discovery of effective anti-BTIC therapies and limit the efficacy of individual gene targeting. Recent discoveries in the genetic and epigenetic determinants of BTIC tumorigenesis offer novel opportunities for RNAi-mediated targeting of BTICs. Here we show that BTIC growth arrest in vitro and in vivo is accomplished via concurrent siRNA knockdown of four transcription factors (SOX2, OLIG2, SALL2, and POU3F2) that drive the proneural BTIC phenotype delivered by multiplexed siRNA encapsulation in the lipopolymeric nanoparticle 7C1. Importantly, we demonstrate that 7C1 nano-encapsulation of multiplexed RNAi is a viable BTICtargeting strategy when delivered directly in vivo in an established mouse brain tumor. Therapeutic potential was most evident via a convection-enhanced delivery method, which shows significant extension of median survival in two patient-derived BTIC xenograft mouse models of GBM. Our study suggests that there is potential advantage in multiplexed targeting strategies for BTICs and establishes a flexible nonviral gene therapy platform with the capacity to channel multiplexed RNAi schemes to address the challenges posed by tumor heterogeneity.siRNA | lipopolymeric nanoparticle | glioblastoma transcription factor | brain tumor-initiating cells | convection-enhanced delivery G lioblastoma (GBM) is one of the most challenging tumors to treat (1, 2). Despite decades of research and maximal clinical combination therapy encompassing surgical resection, chemotherapy, and radiation, the median life expectancy of patients has not been extended beyond 2 y after diagnosis (2). Increasing evidence suggests that the genetic, epigenetic, and signaling heterogeneity of GBM underlies the ineffectiveness of currently available therapeutics (1, 2). Additionally, therapeutic schemes devised to challenge brain tumor cells are frequently thwarted by insufficient delivery caused by pharmacokinetics, the blood-brain barrier (BBB), and an altered tumor microenvironment in which tumor-derived signaling recruits immunomodulatory cells and induces extracellular matrix remodeling to build safe harbors of tumorigenic niches (3-5). These obstacles call for tailored therapeutic strategies to counter tumor heterogeneity and overcome roadblocks in delivery. RNAi targeting drivers of tumorigenesis shows strong potential to supplement the development of traditional small-molecule pharmaceutics (6). However, delivery remains a key obstacle for efficient RNAi against tumor drivers (5,7,8). RNA-sequencing analysis of patient tissue combined with histology and in situ hybridization (Ivy Glioblastoma Atlas Pro...

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Cancer stem cells in glioblastoma

Cited by 1,370 publications

References 151 publications

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

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

A combined microRNA-based targeted therapeutic approach to eradicate glioblastoma stem-like cells

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

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