Glioma stem cells and their roles within the hypoxic tumor microenvironment

Boyd, Nathaniel H.; Tran, Anh; Bernstock, Joshua D.; Etminan, Tina; Jones, Amber; Gillespie, G. Yancey; Friedman, Gregory K.; Hjelmeland, Anita B.

doi:10.7150/thno.41692

Cited by 121 publications

(101 citation statements)

References 135 publications

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“…Besides, we established that high IER5 expression was linked to the KRAS signaling pathway, MTORC1 signaling pathway, hypoxia and angiogenesis by GSEA. These pathways and pathological processes are related to glioblastoma pathogenesis (Pachow et al, 2015;Boyd et al, 2021;Hajj et al, 2021). However, this is the first report of the association of IER5 expression with the KRAS signaling pathway, MTORC1 signaling pathway, hypoxia and angiogenesis.…”

Section: Discussionmentioning

confidence: 83%

High IER5 Gene Expression Is Associated With Poor Prognosis in Glioma Patients

Wang

Zeng

et al. 2021

Front. Cell Dev. Biol.

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ObjectiveImmediate early response 5 (IER5) plays a core role in cell cycle and response to irradiation. However, its role in glioma remains unclear. We aimed to evaluate its prognostic significance in glioma based on The Cancer Genome Atlas data resource.MethodsThe Kruskal–Wallis test, Wilcoxon signed-rank test, and logistic regression were employed to explore the relationship between IER5 expression and clinicopathological features. Kaplan–Meier and Cox regression analyses were implemented to investigate the relationship of IER5 with prognosis. A nomogram to estimate the impact of IER5 on prognosis was created based on the Cox multivariate data. We performed gene set enrichment analysis (GSEA) to determine the key signaling cascades associated with IER5. Immunohistochemistry was performed to examine IER5 expression in a tissue microarray (TMA) of glioma samples.ResultsImmediate early response 5 gene expression was elevated in glioma patients. The level of IER5 was significantly correlated with WHO grade [OR = 6.71 (4.34–10.68) for G4 vs. G2 and G3], IDH (isocitrate dehydrogenase enzyme) status [OR = 13.35 (8.92–20.46) for wild-type (WT) vs. mutated (Mut)], epidermal growth factor receptor status [OR = 8.42 (4.32–18.43) for Mut vs. WT], age [OR = 0.27 (0.18–0.41) for ≤ 60 years vs. >60 years], and histological type [OR = 7.13 (4.63–11.31] for glioblastoma vs. astrocytoma, oligoastrocytoma, and oligodendroglioma). Univariate analyses revealed that high IER5 expression was linked to short overall survival (OS) [hazard ratio (HR): 3.747; 95% confidence interval (CI): 2.847–4.933; and P < 0.001]. High IER5 expression was linked to poor OS in multivariate analyses (HR: 2.474; 95% CI: 1.552–3.943; and P < 0.001). TMA results showed that high IER5 protein levels were related to short OS (HR: 1.84; 95% CI: 1.10–3.07; and P = 0.021) and poor disease-specific survival (HR: 1.82; 95% CI: 1.09–3.04; and P = 0.023). GSEA showed that many tumor related pathways were enriched differentially in the IER5-high expression group. The C-index and calibration plots of the nomogram showed an effective estimation performance in glioma patients.ConclusionHerein, we established that IER5 plays a critical role in glioma progression and prognosis, which might be an important biomarker for the prognosis of glioma patients.

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Section: Discussionmentioning

confidence: 83%

High IER5 Gene Expression Is Associated With Poor Prognosis in Glioma Patients

Wang

Zeng

et al. 2021

Front. Cell Dev. Biol.

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“…GSCs were among the first CSCs identified in solid tumors[ 132 ]. GSCs are one of the major contributors to GBM heterogeneity; these cells exhibit a high proliferation rate and self-renewal capacity (reviewed in[ 71 ]), an ability to differentiate into diverse cell types, the ability to recapitulate a whole tumor (reviewed in[ 133 ]), enhanced invasive capacity, increased angiogenic potential[ 134 ] and an ability to initiate tumor growth and progression shortly after the surgical removal of the primary GBM tumor (reviewed in[ 92 ]). GSCs usually express specific markers, such as CD133 (Prominin 1), CD44, NANOG, SOX2, OCT4, POU class 3 homeobox 2 (POU3F2), MYC proto-oncogene (c-Myc), Spalt Like TF 2 (SALL2) and KAT8 regulatory NSL complex subunit 2[ 135 , 136 ].…”

Section: Gscsmentioning

confidence: 99%

“…Cells expressing molecular markers of both hypoxia and GSCs ( e.g. , SOX2, NANOG, CD133) are largely found in perinecrotic niches (reviewed in[ 134 ]).…”

Section: Gscsmentioning

confidence: 99%

SOX transcription factors and glioma stem cells: Choosing between stemness and differentiation

Stevanović

Kovacevic-Grujicic

Mojsin

et al. 2021

WJSC

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Glioblastoma (GBM) is the most common, most aggressive and deadliest brain tumor. Recently, remarkable progress has been made towards understanding the cellular and molecular biology of gliomas. GBM tumor initiation, progression and relapse as well as resistance to treatments are associated with glioma stem cells (GSCs). GSCs exhibit a high proliferation rate and self-renewal capacity and the ability to differentiate into diverse cell types, generating a range of distinct cell types within the tumor, leading to cellular heterogeneity. GBM tumors may contain different subsets of GSCs, and some of them may adopt a quiescent state that protects them against chemotherapy and radiotherapy. GSCs enriched in recurrent gliomas acquire more aggressive and therapy-resistant properties, making them more malignant, able to rapidly spread. The impact of SOX transcription factors (TFs) on brain tumors has been extensively studied in the last decade. Almost all SOX genes are expressed in GBM, and their expression levels are associated with patient prognosis and survival. Numerous SOX TFs are involved in the maintenance of the stemness of GSCs or play a role in the initiation of GSC differentiation. The fine-tuning of SOX gene expression levels controls the balance between cell stemness and differentiation. Therefore, innovative therapies targeting SOX TFs are emerging as promising tools for combatting GBM. Combatting GBM has been a demanding and challenging goal for decades. The current therapeutic strategies have not yet provided a cure for GBM and have only resulted in a slight improvement in patient survival. Novel approaches will require the fine adjustment of multimodal therapeutic strategies that simultaneously target numerous hallmarks of cancer cells to win the battle against GBM.

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“…Besides perivascular niches, the brain TME includes hypoxic areas [ 166 ], which result from inadequate vasculature and/or rapidly dividing cells that outstrip the local supply of oxygen and nutrients living behind many dying cells. Hypoxic areas are often acidic [ 167 ], although acidosis can also occur independently from hypoxia [ 168 ].…”

Section: Determinants Of Ithmentioning

confidence: 99%

Cell-of-Origin and Genetic, Epigenetic, and Microenvironmental Factors Contribute to the Intra-Tumoral Heterogeneity of Pediatric Intracranial Ependymoma

Servidei

Lucchetti

Navarra

et al. 2021

Cancers

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Intra-tumoral heterogeneity (ITH) is a complex multifaceted phenomenon that posits major challenges for the clinical management of cancer patients. Genetic, epigenetic, and microenvironmental factors are concurrent drivers of diversity among the distinct populations of cancer cells. ITH may also be installed by cancer stem cells (CSCs), that foster unidirectional hierarchy of cellular phenotypes or, alternatively, shift dynamically between distinct cellular states. Ependymoma (EPN), a molecularly heterogeneous group of tumors, shows a specific spatiotemporal distribution that suggests a link between ependymomagenesis and alterations of the biological processes involved in embryonic brain development. In children, EPN most often arises intra-cranially and is associated with an adverse outcome. Emerging evidence shows that EPN displays large intra-patient heterogeneity. In this review, after touching on EPN inter-tumoral heterogeneity, we focus on the sources of ITH in pediatric intra-cranial EPN in the framework of the CSC paradigm. We also examine how single-cell technology has shed new light on the complexity and developmental origins of EPN and the potential impact that this understanding may have on the therapeutic strategies against this deadly pediatric malignancy.

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Glioma stem cells and their roles within the hypoxic tumor microenvironment

Cited by 121 publications

References 135 publications

High IER5 Gene Expression Is Associated With Poor Prognosis in Glioma Patients

High IER5 Gene Expression Is Associated With Poor Prognosis in Glioma Patients

SOX transcription factors and glioma stem cells: Choosing between stemness and differentiation

Cell-of-Origin and Genetic, Epigenetic, and Microenvironmental Factors Contribute to the Intra-Tumoral Heterogeneity of Pediatric Intracranial Ependymoma

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