Cancer Stem Cells and Immunosuppressive Microenvironment in Glioma

Ma, Qianquan; Long, Wenyong; Xing, Changsheng; Chu, Jianping; Luo, Mei; Wang, Helen Yicheng; Liu, Qing; Wang, Rongfu

doi:10.3389/fimmu.2018.02924

Cited by 182 publications

(168 citation statements)

References 194 publications

(208 reference statements)

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“…Unfortunately, immune cells in the high grade glioblastoma (GBM) microenvironment generally assume tumor-promoting roles (47)(48)(49)(50)(51). Under the influence of GBM, microglia/macrophages are immunosuppressed and may even contribute to GBM invasion (52)(53)(54). BTICs are thought to help enforce immunosuppression (11,12,(55)(56)(57)(58).…”

Section: Discussionmentioning

confidence: 99%

Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes

Sarkar

Mirzaei

et al. 2020

Front. Immunol.

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Myeloid cells that infiltrate into brain tumors are deactivated or exploited by the tumor cells. We previously demonstrated that compromised microglia, monocytes, and macrophages in malignant gliomas could be reactivated by amphotericin-B to contain the growth of brain tumorinitiating cells (BTICs). We identified meclocycline as another activator of microglia, so we sought to test whether its better-tolerated derivative, demeclocycline, also stimulates monocytes to restrict BTIC growth. Monocytes were selected for study as they would be exposed to demeclocycline in the circulation prior to entry into brain tumors to become macrophages. We found that demeclocycline increased the activity of monocytes in culture, as determined by tumor necrosis factor-α production and chemotactic capacity. The conditioned medium of demeclocycline-stimulated monocytes attenuated the growth of BTICs generated from human glioblastoma resections, as evaluated using neurosphere and alamarBlue assays, and cell counts. Demeclocycline also had direct effects in reducing BTIC growth. A global gene expression screen identified several genes, such as DNA damage inducible transcript 4, frizzled class receptor 5 and reactive oxygen species modulator 1, as potential regulators of demeclocycline-mediated BTIC growth reduction. Amongst several tetracycline derivatives, only demeclocycline directly reduced BTIC growth. In summary, we have identified demeclocycline as a novel inhibitor of the growth of BTICs, through direct effect and through indirect stimulation of monocytes. Demeclocycline is a candidate to reactivate compromised immune cells to improve the prognosis of patients with gliomas.

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Section: Discussionmentioning

confidence: 99%

Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes

Sarkar

Mirzaei

et al. 2020

Front. Immunol.

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“…The orchestrated immunological interactions within glioma TME have received increased focus and harnessing the immune system is becoming a hotspot in the eld of oncology. Various components of glioma TME, such as immune cells, cytokines and markers are coordinately interact with each other to establish the immunosuppressive phenotype and promote the development of glioma [5]. From this perspective, advanced clinical practices by targeting speci c immunotherapies have already showed profound outcomes compared to conventional therapy against glioma.…”

Section: Discussionmentioning

confidence: 99%

“…Patients with GBM still have dismal prognosis, with median overall survival time less than 17 months [3]. The tolerance against multiple treatments and invariably relapse of gliomas are extensively studied as consequences of molecular or chromosomal subtypes, oncogenic activations and distinct metabolic immunosuppressive tumor microenvironment (TME) [3][4][5][6]. Pursuing better understanding of molecular landscape in gliomas, novel markers are successively detected with important clinical signi cance.…”

Section: Introductionmentioning

confidence: 99%

PDIA4 correlates with poor prognosis and is a potential biomarker in glioma

Liu

Xiao

et al. 2020

Preprint

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Background: Gliomas, characterized by aggressiveness and invasiveness, remain incurable after conventional therapies. The molecular mechanisms driving the progression and maintenance of glioma are still poorly understood.Methods: PDIA4 expression was analyzed via Gene Expression Profiling Interactive Analysis (GEPIA) which data were from TCGA and GTEx databases. We estimated the prognostic value of PDIA4 using Kaplan–Meier survival analysis and the Cox proportional hazard model. The functional enrichment analysis was done by using cluster Profiler package in R language, including gene ontology (GO) analysis comprised of cellular component (CC), molecular function (MF), and biological process (BP), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. In addition, correlation between PDIA4 and immunity were analyzed by Protein-protein interaction (PPI) analysis, RNA extraction and Real-time RT-PCR.Results: In this study, we identified PDIA4 was highly expressed in gliomas and closely correlated with poor prognosis. The association with IDH1 and different patterns of gliomas also indicates the potential biological processes that PDIA4 involves in the development of tumor. Mechanistically, PDIA4 interacts with multiple immunological components to promote an immunosuppressive tumor microenvironment (TME).Conclusions: Our results confirm PDIA4 is an efficient biomarker of gliomas, with implications for prognosis and therapeutic strategies.

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“…This pattern of relapse and progression suggests the presence of a subpopulation of cancer cells within the initial tumor that is able to survive cytotoxic therapies and drive tumor recurrence. Data from multiple studies have supported a hypothesis that the cells responsible for GBM recurrence are cancer stem cells (CSCs) (Singh et al 2004;Sanai et al 2005;Gimple et al 2019;Ma et al 2018;Lathia and Mack 2015).…”

Section: Introductionmentioning

confidence: 99%

CASCADES, a novelSOX2super-enhancer associated long noncoding RNA, regulates cancer stem cell specification and differentiation in glioblastoma multiforme

Shahzad

Johnston

et al. 2020

Preprint

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Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults, with a median survival of just over one year. The failure of available treatments to achieve remission in patients with GBM has been attributed to the presence of cancer stem cells (CSCs), which are thought to play a central role in tumor development and progression and serve as a treatment-resistant cell repository capable of driving tumor recurrence; in fact, the property of "stemness" itself may be responsible for treatment resistance. In this study, we identify a novel lncRNA, Cancer stem cell associated distal enhancer of SOX2 (CASCADES) that functions as an epigenetic regulator in glioma CSCs (GSCs). CASCADES is expressed in IDH-wild type GBM and significantly enriched in GSCs. Knockdown of CASCADES in GSCs results in differentiation towards a neuronal lineage in a cell- and cancer-specific manner. Bioinformatics analysis reveals that CASCADES functions as a super-enhancer associated lncRNA epigenetic regulator of SOX2. Our findings identify CASCADES as a critical regulator of stemness in GSCs and represent a novel epigenetic and therapeutic target for disrupting the cancer stem cell compartment in GBM.

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Cancer Stem Cells and Immunosuppressive Microenvironment in Glioma

Cited by 182 publications

References 194 publications

Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes

Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes

PDIA4 correlates with poor prognosis and is a potential biomarker in glioma

CASCADES, a novelSOX2super-enhancer associated long noncoding RNA, regulates cancer stem cell specification and differentiation in glioblastoma multiforme

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