Glioma

Weller, Michael; Wick, Wolfgang; Aldape, Ken; Brada, Michael; Berger, Mitchell S.; Pfister, Stefan M.; Nishikawa, Ryo; Rosenthal, Mark; Wen, Patrick Y.; Stupp, Roger; Reifenberger, Guido

doi:10.1038/nrdp.2015.17

“…In spite of decades of intense research, GBM continues to be associated with extremely poor outcomes, with a median survival after diagnosis of less than 15 months [1]. The main reason for this dismal course is the high rate of tumour recurrence, which is associated with both the extremely infiltrative nature of glioblastoma growth and a frequently occurring resistance to conventional treatments, such as chemoradiation therapy [2]. …”

Section: Introductionmentioning

confidence: 99%

“…While GBMs share certain pathognomonic histological hallmarks, such as high vascularity, pseudopalisading necrosis and infiltrative growth patterns, these tumours are otherwise highly heterogeneous at the molecular and cellular levels [2,3]. This diversity is underscored by a broad spectrum of recurrent oncogenic driver mutations, including amplification of the epidermal growth factor receptor (EGFR), EGFR variant III mutation (EGFRvIII), isocitrate dehydrogenase 1 R132C (IDH1 R132C) mutation and multiple other changes [4].…”

Section: Introductionmentioning

confidence: 99%

Molecular subtypes and differentiation programmes of glioma stem cells as determinants of extracellular vesicle profiles and endothelial cell‐stimulating activities

Spinelli

¹

,

Montermini

²

,

Meehan

³

et al. 2018

J of Extracellular Vesicle

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We have previously uncovered the impact of oncogenic and differentiation processes on extracellular vesicles (EVs) in cancer. This is of interested in the context of glioma stem cells (GSC) that are responsible for recurrent nature of glioblastoma multiforme (GBM), while retaining the potential to undergo differentiation and self renewal. GSCs reside in vascular niches where they interact with endothelial cells through a number of mediators including bioactive cargo of EVs. GSCs can be classified as proneural (PN) or mesenchymal (MES) subtypes on the basis of their gene expression profiles and distinct biological characteristics. In the present study we investigated how GSC diversity and differentiation programmes influence their EV-mediated communication potentials. Indeed, molecular subtypes of GBMs and GSCs differ with respect to their expression of EV-related genes (vesiculome) and GSCs with PN or MES phenotypes produce EVs with markedly different characteristics, marker profiles, proteomes and endothelial stimulating activities. For example, while EVs of PN GSC are largely devoid of exosomal markers their counterparts from MES GSCs express ample CD9, CD63 and CD81 tetraspanins. In both GSC subtypes serum-induced differentiation results in profound, but distinct changes of cellular phenotypes including the enhanced EV production, reconfiguration of their proteomes and the related functional pathways. Notably, the EV uptake was a function of both subtype and differentiation state of donor cells. Thus, while, EVs produced by differentiated MES GSCs were internalized less efficiently than those from undifferentiated cells they exhibited an increased stimulatory potential for human brain endothelial cells. Such stimulating activity was also observed for EVs derived from differentiated PN GSCs, despite their even weaker uptake by endothelial cells. These findings suggest that the role of EVs as biological mediators and biomarkers in GBM may depend on the molecular subtype and functional state of donor cancer cells, including cancer stem cells.Abbreviations: CryoTEM: cryo-transmission electron microscopy; DIFF: differentiated GSCs; EGF: epidermal growth factor; DUC: differential ultracentrifugation; EV: extracellular vesicle; FGF: fibroblast growth factor; GBM: glioblastoma multiforme; GFAP: glial fibrillary acidic protein; GO: gene ontology; GSC: glioma stem cells; HBEC-5i: human brain endothelial cells; MES: mesenchymal cells; MTS - [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; PMT1: proneural-to-mesenchyman transition cell line 1; PN: proneural cells; TEM: transmission electron microscopy; WB: western blotting

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“…Glioblastomas recurr nearly inevitably after (or even during) standard therapy with tumour recurrence after the initial treatment being the ultimate cause of death [19]. For recGB, there is no standard treatment.…”

Section: Glioblastoma: General Factsmentioning

confidence: 99%

“…Immunotherapeutic approaches based on autologous vaccination with dendritic cells have yielded some encouraging preliminary results in both ndGB and recGBs in a series of Phase I/II trials [21,22] but their confirmation in Phase III is still awaited. A comprehensive discussion of the outcomes of all completed trials on recGB has been covered in several recent reviews [5,19,20].…”

Section: Glioblastoma: General Factsmentioning

confidence: 99%

Assessment of Anti-Proliferative Activities of Selected Medicinal Plant Extracts Used for Management of Diseases around Lake Victoria Basin

Swaya¹,

Aduma²,

Chelimo³

et al. 2017

J Carcinog Mutagen

2

0

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Glioblastoma is the most common and most malignant type of intrinsic brain tumor in adults. The standard of care for glioblastoma consists of surgical debulking followed by combined radiochemotherapy. The clinical efficacy of standard therapies for newly diagnosed glioblastomas is rather modest with the highest survival rate at 5-years being less than 10%. Inevitable recurrence after cytotoxic therapies poses the major challenge in the clinical management of high grade gliomas. For recurrent glioblastomas, there is no standard therapy with lack of level one evidence for treatment efficacy. Recent evidence indicates that post-therapy recurrence in gliomas is a consequence of a plethora of molecular and cellular factors including intratumoural heterogeneity, functional hierarchy of distinct types of glioma cells, dynamic changes in the molecular landscapes and cellular composition of the tumour during therapy and the impact of particular treatment modalities. There is an emerging consensus that molecular distinctions within and between individual tumours is an important factor determining clinical outcomes. Consequently, integrated approaches based on the combination of molecular profiling with traditional methods such as immunohistochemical phenotyping, karyotyping and/or non-quantitative methylation-specific PCR have emerged as a promising venue towards increasing the predictive value of diagnostics for malignant brain tumors. The high level of inter-and intra-tumoural molecular diversity in gliomas underscores the need of integrating high throughput molecular profiling and pharmacogenomics into a diagnostic paradigm for gliomas and raises the possibility that molecular-instructed personalized treatments may provide clinical benefit to patients with glioblastoma, particularly in the setting of post-treatment recurrence. Here we discuss potential prospects and challenges of patient-tailored diagnostics and personalized treatment strategies for recurrent glioblastomas.

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“…For recGB, there is no standard treatment. Despite intensive efforts in the past decade to define therapeutically effective treatments for recGB none of the regimens tested yielded significant results [5,19,20]. Most of investigational therapies tested so far in recGBs have been based on a hypothesistesting approach aiming at addressing the following possibilities 1) Improving clinical outcomes through repeated application of the principle modules of standard unspecific therapy (surgery, RT or TMZ) in recGBs 2) Improving clinical outcomes through targetoriented treatments interfering with intrinsic (angiogenesis, invasion/ adhesion/ECM remodelling, proliferation) or extrinsic (tumourassociated immunosupression) mechanisms in recGB.…”

Section: Glioblastoma: General Factsmentioning

confidence: 99%

Perspectives and Challenges in Molecular-Based Diagnostics and Personalized Treatment for Recurrent High-Grade Gliomas

Kalasauskas¹,

Renovanz²,

Bikar³

et al. 2017

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Glioblastoma is the most common and most malignant type of intrinsic brain tumor in adults. The standard of care for glioblastoma consists of surgical debulking followed by combined radiochemotherapy. The clinical efficacy of standard therapies for newly diagnosed glioblastomas is rather modest with the highest survival rate at 5-years being less than 10%. Inevitable recurrence after cytotoxic therapies poses the major challenge in the clinical management of high grade gliomas. For recurrent glioblastomas, there is no standard therapy with lack of level one evidence for treatment efficacy. Recent evidence indicates that post-therapy recurrence in gliomas is a consequence of a plethora of molecular and cellular factors including intratumoural heterogeneity, functional hierarchy of distinct types of glioma cells, dynamic changes in the molecular landscapes and cellular composition of the tumour during therapy and the impact of particular treatment modalities. There is an emerging consensus that molecular distinctions within and between individual tumours is an important factor determining clinical outcomes. Consequently, integrated approaches based on the combination of molecular profiling with traditional methods such as immunohistochemical phenotyping, karyotyping and/or non-quantitative methylation-specific PCR have emerged as a promising venue towards increasing the predictive value of diagnostics for malignant brain tumors. The high level of inter-and intra-tumoural molecular diversity in gliomas underscores the need of integrating high throughput molecular profiling and pharmacogenomics into a diagnostic paradigm for gliomas and raises the possibility that molecular-instructed personalized treatments may provide clinical benefit to patients with glioblastoma, particularly in the setting of post-treatment recurrence. Here we discuss potential prospects and challenges of patient-tailored diagnostics and personalized treatment strategies for recurrent glioblastomas.

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Glioma

Cited by 859 publications

References 183 publications

Molecular subtypes and differentiation programmes of glioma stem cells as determinants of extracellular vesicle profiles and endothelial cell‐stimulating activities

Molecular subtypes and differentiation programmes of glioma stem cells as determinants of extracellular vesicle profiles and endothelial cell‐stimulating activities

Assessment of Anti-Proliferative Activities of Selected Medicinal Plant Extracts Used for Management of Diseases around Lake Victoria Basin

Perspectives and Challenges in Molecular-Based Diagnostics and Personalized Treatment for Recurrent High-Grade Gliomas

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