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Frontiers in Bioscience (Landmark... Jan 2017Glioblastoma (GBM) is the most malignant and aggressive among primary brain tumors, characterized by very low life expectancy. In vivo, glioma and glioblastoma in... (Review)
Review
Glioblastoma (GBM) is the most malignant and aggressive among primary brain tumors, characterized by very low life expectancy. In vivo, glioma and glioblastoma in particular contain large numbers of immune cells (myeloid cells) such as microglia and tumour-infiltrating macrophages (or glioma associated macrophages). These glioma-infiltrating myeloid cells comprise up to 30% of total tumor mass and have been suggested to play several roles in glioma progression including proliferation, survival, motility and immunosuppression. Although tumor microglia and macrophages can acquire proinflammatory (M1) phenotype being capable of releasing proinflammatory cytokines, phagocytosing and presenting antigens, their effector immune function in gliomas appears to be suppressed by the acquisition of an anti-inflammatory (M2) phenotype. In the present work we review the microglia-glioma interactions to highlight the close relationship between the two cell types and the factors that can influence their properties (chemokines, cytokines, S100B protein). A future therapeutic possibility might be to simultaneously targeting, for example with nanomedicine, glioma cells and microglia to push the microglia towards an antitumor phenotype (M1) and/or prevent glioma cells from "conditioning" by microglia.
Topics: Biomarkers, Tumor; Brain Neoplasms; Cell Communication; Glioma; Humans; Immune Tolerance; Microglia; Myeloid-Derived Suppressor Cells; Neoplastic Stem Cells; Phenotype; Tumor Microenvironment
PubMed: 27814616
DOI: 10.2741/4486 -
Stem Cell Research & Therapy Aug 2018Glioma, which accounts for more than 30% of primary central nervous system tumours, is characterised by symptoms such as headaches, epilepsy, and blurred vision.... (Review)
Review
Glioma, which accounts for more than 30% of primary central nervous system tumours, is characterised by symptoms such as headaches, epilepsy, and blurred vision. Glioblastoma multiforme is the most aggressive, malignant, and lethal brain tumour in adults. Even with progressive combination treatment with surgery, radiotherapy, and chemotherapy, the prognosis for glioma patients is still extremely poor. Compared with the poor outcome and slowly developing technologies for surgery and radiotherapy, the application of targeted chemotherapy with a new mechanism has become a research focus in this field.Moreover, targeted therapy is promising for most solid tumours. The tumour-tropic ability of stem cells, including neural stem cells and mesenchymal stem cells, provides an alternative therapeutic approach. Thus, mesenchymal stem cell-based therapy is based on a tumour-selective capacity and has been thought to be an effective anti-tumour option over the past decades. An increasing number of basic studies on mesenchymal stem cell-based therapy for gliomas has yielded complex outcomes.In this review, we summarise the biological characteristics of human mesenchymal stem cells, and the current status and potential challenges of mesenchymal stem cell-based therapy in patients with malignant gliomas.
Topics: Angiogenesis Inhibitors; Animals; Biomarkers, Tumor; Brain Neoplasms; Combined Modality Therapy; Genes, Transgenic, Suicide; Genetic Therapy; Glioma; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Molecular Targeted Therapy; Neural Stem Cells; Oncolytic Virotherapy; Signal Transduction
PubMed: 30143053
DOI: 10.1186/s13287-018-0977-z -
Frontiers in Bioscience (Landmark... Jan 2014Malignant gliomas, the most common type of primary brain tumor, account for 80% of malignant tumors in the central nervous system (CNS). There are three principal types... (Review)
Review
Malignant gliomas, the most common type of primary brain tumor, account for 80% of malignant tumors in the central nervous system (CNS). There are three principal types of glioma: astrocytomas, oligodendrogliomas, and oligoastrocytomas. Glioma stem cells (GSCs) have been found in all types; however, many fundamental questions about GSCs remain unanswered. This review will examine the current state of knowledge regarding GSC origin and the signaling pathways implicated in GSC tumorigenesis. The outstanding challenges for the study of GSCs in the context of glioma progression will also be discussed.
Topics: Biomarkers, Tumor; Brain Neoplasms; Carcinogenesis; Glioma; Humans; Neoplastic Stem Cells; Signal Transduction
PubMed: 24389226
DOI: 10.2741/4249 -
Journal of Neuro-oncology Oct 2017Diagnosis of a pediatric high grade brain stem glioma is devastating with dismal outcomes. This systematic review and meta-analysis was undertaken to determine the... (Meta-Analysis)
Meta-Analysis Review
Diagnosis of a pediatric high grade brain stem glioma is devastating with dismal outcomes. This systematic review and meta-analysis was undertaken to determine the survival rates and assess potential prognostic factors including selected interventions. Studies included involved pediatric participants with high grade brain stem gliomas diagnosed by magnetic resonance imaging or biopsy reporting overall survival rates. Meta-analysis was undertaken using a binomial random effects model. Sixty-five studies (2336 participants) were included. Meta-analysis showed 1 year overall survival (OS) of 41% (95% confidence interval (CI) 38-44%, I-sq 52%, 2083 participants), 2 year OS of 15.3% (95% confidence interval 12-20%, I-sq 73.1%, 1329 participants) and 3 year OS of 7.3% (95% confidence interval 5.2-10%, I-sq 26%, 584 participants). Meta-analyses of median overall survival results was not possible due to the lack of reported measures of variance. Subgroup analysis comparing date of study, classification of tumor, use of temozolomide, non-standard interventions or phase 1/2 versus other studies demonstrated no difference in survival outcomes. There was insufficient data to undertake subgroup meta-analysis of patient age, duration of symptoms, K27M histone mutations and AVCR1 mutations. Survival outcomes of high grade brain stem gliomas have remained very poor, and do not clearly vary according to classification, phase of study or use of different therapeutic interventions. Future studies should harmonize outcome and prognostic variable reporting to enable accurate meta-analysis and better exploration of prognosis.
Topics: Brain Stem Neoplasms; Child; Glioma; Humans; Neoplasm Grading; Prognosis; Survival Rate
PubMed: 28681244
DOI: 10.1007/s11060-017-2546-1 -
Frontiers in Immunology 2020Gliomas, particularly high-grade gliomas including glioblastoma (GBM), represent the most common and malignant types of primary brain cancer in adults, and carry a poor... (Review)
Review
Gliomas, particularly high-grade gliomas including glioblastoma (GBM), represent the most common and malignant types of primary brain cancer in adults, and carry a poor prognosis. GBM has been classified into distinct subgroups over the years based on cellular morphology, clinical characteristics, biomarkers, and neuroimaging findings. Based on these classifications, differences in therapeutic response and patient outcomes have been established. Recently, the identification of complex molecular signatures of GBM has led to the development of diverse targeted therapeutic regimens and translation into multiple clinical trials. Chemical-, peptide-, antibody-, and nanoparticle-based probes have been designed to target specific molecules in gliomas and then be visualized with multimodality molecular imaging (MI) techniques including positron emission tomography (PET), single-photon emission computed tomography (SPECT), near-infrared fluorescence (NIRF), bioluminescence imaging (BLI), and magnetic resonance imaging (MRI). Thus, multiple molecules of interest can now be noninvasively imaged to guide targeted therapies with a potential survival benefit. Here, we review developments in molecular-targeted diagnosis and therapy in glioma, MI of these targets, and MI monitoring of treatment response, with a focus on the biological mechanisms of these advanced molecular probes. MI probes have the potential to noninvasively demonstrate the pathophysiologic features of glioma for diagnostic, treatment, and response assessment considerations for various targeted therapies, including immunotherapy. However, most MI tracers are in preclinical development, with only integrin αβ and isocitrate dehydrogenase (IDH)-mutant MI tracers having been translated to patients. Expanded international collaborations would accelerate translational research in the field of glioma MI.
Topics: Animals; Biomarkers, Tumor; Brain Neoplasms; Clinical Trials as Topic; Disease Susceptibility; Glioma; Humans; Magnetic Resonance Imaging; Molecular Imaging; Molecular Targeted Therapy; Multimodal Imaging; Mutation; Neoplastic Stem Cells; Positron-Emission Tomography; Receptors, Platelet-Derived Growth Factor; src-Family Kinases
PubMed: 33193439
DOI: 10.3389/fimmu.2020.592389 -
Diagnostic and Interventional Imaging Oct 2014The traditional approach in neuro-oncology is to study the tumor in great detail and ultimately give little consideration to the brain itself. Choosing the best... (Review)
Review
The traditional approach in neuro-oncology is to study the tumor in great detail and ultimately give little consideration to the brain itself. Choosing the best treatment strategy for each patient with a diffuse low-grade glioma, in other words optimizing the oncologic and functional balance, implies not only a full knowledge of the natural history of this chronic disease, but also an understanding of the adaptation of the brain in response to growth and spread of the glioma. The aim of this review is to examine the mechanisms underlying this neuroplasticity, allowing functional compensation when the tumor progresses, and opening the way to new treatments with the principle of shifting towards "functional personalized neuro-oncology", improving both median survival and quality of life.
Topics: Brain; Brain Neoplasms; Disease Progression; Glioma; Humans; Neuronal Plasticity; Precision Medicine; Quality of Life; Survival Rate
PubMed: 25218490
DOI: 10.1016/j.diii.2014.08.001 -
Genetic, cellular, and connectomic characterization of the brain regions commonly plagued by glioma.Brain : a Journal of Neurology Dec 2020For decades, it has been known that gliomas follow a non-random spatial distribution, appearing more often in some brain regions (e.g. the insula) compared to others...
For decades, it has been known that gliomas follow a non-random spatial distribution, appearing more often in some brain regions (e.g. the insula) compared to others (e.g. the occipital lobe). A better understanding of the localization patterns of gliomas could provide clues to the origins of these types of tumours, and consequently inform treatment targets. Following hypotheses derived from prior research into neuropsychiatric disease and cancer, gliomas may be expected to localize to brain regions characterized by functional hubness, stem-like cells, and transcription of genetic drivers of gliomagenesis. We combined neuroimaging data from 335 adult patients with high- and low-grade glioma to form a replicable tumour frequency map. Using this map, we demonstrated that glioma frequency is elevated in association cortex and correlated with multiple graph-theoretical metrics of high functional connectedness. Brain regions populated with putative cells of origin for glioma, neural stem cells and oligodendrocyte precursor cells, exhibited a high glioma frequency. Leveraging a human brain atlas of post-mortem gene expression, we found that gliomas were localized to brain regions enriched with expression of genes associated with chromatin organization and synaptic signalling. A set of glioma proto-oncogenes was enriched among the transcriptomic correlates of glioma distribution. Finally, a regression model incorporating connectomic, cellular, and genetic factors explained 58% of the variance in glioma frequency. These results add to previous literature reporting the vulnerability of hub regions to neurological disease, as well as provide support for cancer stem cell theories of glioma. Our findings illustrate how factors of diverse scale, from genetic to connectomic, can independently influence the anatomic localization of brain dysfunction.
Topics: Algorithms; Atlases as Topic; Brain; Brain Mapping; Brain Neoplasms; Cerebral Cortex; Chromatin; Connectome; Gene Expression Regulation, Neoplastic; Glioma; Humans; Neoplastic Stem Cells; Neural Stem Cells; Neuroimaging; Oligodendrocyte Precursor Cells; Postmortem Changes; Synapses
PubMed: 33278823
DOI: 10.1093/brain/awaa277 -
Cell Mar 2012Eighty percent of malignant tumors that develop in the central nervous system are malignant gliomas, which are essentially incurable. Here, we discuss how recent... (Review)
Review
Eighty percent of malignant tumors that develop in the central nervous system are malignant gliomas, which are essentially incurable. Here, we discuss how recent sequencing studies are identifying unexpected drivers of gliomagenesis, including mutations in isocitrate dehydrogenase 1 and the NF-κB pathway, and how genome-wide analyses are reshaping the classification schemes for tumors and enhancing prognostic value of molecular markers. We discuss the controversies surrounding glioma stem cells and explore how the integration of new molecular data allows for the generation of more informative animal models to advance our knowledge of glioma's origin, progression, and treatment.
Topics: Animals; Brain Neoplasms; Disease Models, Animal; Glioma; Humans; Mice; NF-kappa B; Neoplastic Stem Cells; Signal Transduction
PubMed: 22464322
DOI: 10.1016/j.cell.2012.03.009 -
Cell Cycle (Georgetown, Tex.) Sep 2017Glioblastoma (GBM) is the most prevalent and malignant brain tumor, displaying notorious resistance to conventional therapy, partially due to molecular and genetic... (Review)
Review
Glioblastoma (GBM) is the most prevalent and malignant brain tumor, displaying notorious resistance to conventional therapy, partially due to molecular and genetic heterogeneity. Understanding the mechanisms for gliomagenesis, tumor stem/progenitor cell propagation and phenotypic diversity is critical for devising effective and targeted therapy for this lethal disease. The basic helix-loop-helix transcription factor OLIG2, which is universally expressed in gliomas, has emerged as an important player in GBM cell reprogramming, genotoxic resistance, and tumor phenotype plasticity. In an animal model of proneural GBM, elimination of mitotic OLIG2 progenitors blocks tumor growth, suggesting that these progenitors are a seeding source for glioma propagation. OLIG2 deletion reduces tumor growth and causes an oligodendrocytic to astrocytic phenotype shift, with PDGFRα downregulation and reciprocal EGFR signaling upregulation, underlying alternative pathways in tumor recurrence. In patient-derived glioma stem cells (GSC), knockdown of OLIG2 leads to downregulation of PDGFRα, while OLIG2 silencing results in a shift from proneural-to-classical gene expression pattern or a proneural-to-mesenchymal transition in distinct GSC cell lines, where OLIG2 appears to regulate EGFR expression in a context-dependent manner. In addition, post-translational modifications such as phosphorylation by a series of protein kinases regulates OLIG2 activity in glioma cell growth and invasive behaviors. In this perspective, we will review the role of OLIG2 in tumor initiation, proliferation and phenotypic plasticity in animal models of gliomas and human GSC cell lines, and discuss the underlying mechanisms in the control of tumor growth and potential therapeutic strategies to target OLIG2 in malignant gliomas.
Topics: Animals; Brain Neoplasms; Carcinogenesis; Disease Models, Animal; Glioma; Humans; Oligodendrocyte Transcription Factor 2; Signal Transduction
PubMed: 28806136
DOI: 10.1080/15384101.2017.1361062 -
Annual Review of Genomics and Human... Aug 2019High-grade gliomas, particularly glioblastomas (grade IV), are devastating diseases with dismal prognoses; afflicted patients seldom live longer than 15 months, and... (Review)
Review
High-grade gliomas, particularly glioblastomas (grade IV), are devastating diseases with dismal prognoses; afflicted patients seldom live longer than 15 months, and their quality of life suffers immensely. Our current standard-of-care therapy has remained essentially unchanged for almost 15 years, with little new therapeutic progress. We desperately need a better biologic understanding of these complicated tumors in a complicated organ. One area of rejuvenated study relates to extracellular vesicles (EVs)-membrane-enclosed nano- or microsized particles that originate from the endosomal system or are shed from the plasma membrane. EVs contribute to tumor heterogeneity (including the maintenance of glioma stem cells or their differentiation), the impacts of hypoxia (angiogenesis and coagulopathies), interactions amid the tumor microenvironment (concerning the survival of astrocytes, neurons, endothelial cells, blood vessels, the blood-brain barrier, and the ensuing inflammation), and influences on the immune system (both stimulatory and suppressive). This article reviews glioma EVs and the ways that EVs manifest themselves as autocrine, paracrine, and endocrine factors in proximal and distal intra- and intercellular communications. The reader should note that there is much controversy, and indeed confusion, in the field over the exact roles for EVs in many biological processes, and we will engage some of these difficulties herein.
Topics: Animals; Astrocytes; Brain Neoplasms; Extracellular Vesicles; Glioma; Humans; Immune System; Inflammation; Tumor Microenvironment
PubMed: 30978305
DOI: 10.1146/annurev-genom-083118-015324