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Cells
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Molecular Basis of Brain Tumors
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Molecular Basis of Brain Tumors

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (1 June 2021) | Viewed by 53053

Special Issue Editors

Dr. Chun Zhang Yang

E-Mail Website
Guest Editor
Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
Interests: glioma; isocitrate dehydrogenase; chemotherapy; metabolism; DNA repair
Dr. Prashant Chittiboina

E-Mail Website
Guest Editor
National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, MD, USA
Interests: metabolic reprogramming; pituitary adenoma; Cushing’s disease; hemangioblastoma; schwannoma

Special Issue Information

Dear Colleagues,

Brain tumors, the neoplastic disease derived from the central nervous system (CNS), are highly heterogeneous diseases, reflected by their diversified genetics, morphology, and disease outcome. Primary brain tumors are derived from a variety of cellular origins in the CNS, which exhibit distinctive phenotypes, ranging from benign tumors (e.g. pituitary adenoma and hemangioblastoma) to highly aggressive cancers (e.g. glioblastoma, gliosarcoma, and diffuse intrinsic pontine glioma). Advances in cancer genetics, cancer metabolomics and biomarker studies of brain tumors have led improved understanding of brain tumors. The recent WHO classification of brain tumors (2016) reflects this new understanding of the molecular basis of brain tumors. The molecular classification also facilitates development of experimental therapeutics based on an in-depth understanding in brain tumor biology. The latest advances in brain tumor research inevitably shed light on the translational medicine and potential novel therapeutic approaches.

This Special Issue will cover the critical aspects of the molecular biology of brain tumors, including the conceptual advances in biochemistry, cancer biology, epigenetics, tumor microenvironment, and immuno-oncology. Original research articles and systemic reviews to these topics are cordially encouraged to comment on the cutting edges in brain tumor research and future directions.

Dr. Chun Zhang Yang
Dr. Prashant Chittiboina
Guest Editors

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Keywords

  • brain tumor
  • tumor microenvironment
  • chemotherapy
  • hypoxia
  • cancer metabolism
  • pituitary adenoma

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Published Papers (8 papers)

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Research

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14 pages, 1137 KiB  
Article
Association of TP53 Alteration with Tissue Specificity and Patient Outcome of IDH1-Mutant Glioma
by Balazs Murnyak and L. Eric Huang
Cells 2021, 10(8), 2116; https://doi.org/10.3390/cells10082116 - 17 Aug 2021
Cited by 9 | Viewed by 3251
Abstract
Since the initial discovery of recurrent isocitrate dehydrogenase 1 (IDH1) mutations at Arg132 in glioma, IDH1 hotspot mutations have been identified in cholangiocarcinoma, chondrosarcoma, leukemia, and various other types of cancer of sporadic incidence. Studies in glioma and leukemia have helped promote [...] Read more.
Since the initial discovery of recurrent isocitrate dehydrogenase 1 (IDH1) mutations at Arg132 in glioma, IDH1 hotspot mutations have been identified in cholangiocarcinoma, chondrosarcoma, leukemia, and various other types of cancer of sporadic incidence. Studies in glioma and leukemia have helped promote the theory that IDH1 mutations are an oncogenic event that drives tumorigenesis in general. Through bioinformatic analysis of more than 45,000 human pan-cancer samples from three independent datasets, we show here that IDH1 mutations are rare events in human cancer but are exclusively prevalent in WHO grade II and grade III (lower-grade) glioma. Interestingly, alterations in the tumor-suppressor gene TP53 (tumor protein p53) co-occur significantly with IDH1 mutations and show a tendency of exclusivity to IDH2 mutations. The co-occurrence of IDH1 mutation and TP53 alteration is widespread in glioma, particularly in those harboring IDH1R132H, IDH1R132G, and IDH1R132S, whereas co-occurrence of IDH1R132C and TP53 alteration can be found sporadically in other cancer types. In keeping with the importance of p53 in tumor suppression, TP53 status is an independent predictor of overall survival irrespective of histological and molecular subgroups in lower-grade glioma. Together, these results indicate tissue specificity of IDH1 hotspot mutation and TP53 alteration and the importance of TP53 status as a predictor of patient outcome in lower-grade glioma. Full article
(This article belongs to the Special Issue Molecular Basis of Brain Tumors)
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Review

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24 pages, 4071 KiB  
Review
Canonical and Non-Canonical Roles of PFKFB3 in Brain Tumors
by Reinier Alvarez, Debjani Mandal and Prashant Chittiboina
Cells 2021, 10(11), 2913; https://doi.org/10.3390/cells10112913 - 27 Oct 2021
Cited by 11 | Viewed by 4360
Abstract
PFKFB3 is a bifunctional enzyme that modulates and maintains the intracellular concentrations of fructose-2,6-bisphosphate (F2,6-P2), essentially controlling the rate of glycolysis. PFKFB3 is a known activator of glycolytic rewiring in neoplastic cells, including central nervous system (CNS) neoplastic cells. The pathologic regulation of [...] Read more.
PFKFB3 is a bifunctional enzyme that modulates and maintains the intracellular concentrations of fructose-2,6-bisphosphate (F2,6-P2), essentially controlling the rate of glycolysis. PFKFB3 is a known activator of glycolytic rewiring in neoplastic cells, including central nervous system (CNS) neoplastic cells. The pathologic regulation of PFKFB3 is invoked via various microenvironmental stimuli and oncogenic signals. Hypoxia is a primary inducer of PFKFB3 transcription via HIF-1alpha. In addition, translational modifications of PFKFB3 are driven by various intracellular signaling pathways that allow PFKFB3 to respond to varying stimuli. PFKFB3 synthesizes F2,6P2 through the phosphorylation of F6P with a donated PO4 group from ATP and has the highest kinase activity of all PFKFB isoenzymes. The intracellular concentration of F2,6P2 in cancers is maintained primarily by PFKFB3 allowing cancer cells to evade glycolytic suppression. PFKFB3 is a primary enzyme responsible for glycolytic tumor metabolic reprogramming. PFKFB3 protein levels are significantly higher in high-grade glioma than in non-pathologic brain tissue or lower grade gliomas, but without relative upregulation of transcript levels. High PFKFB3 expression is linked to poor survival in brain tumors. Solitary or concomitant PFKFB3 inhibition has additionally shown great potential in restoring chemosensitivity and radiosensitivity in treatment-resistant brain tumors. An improved understanding of canonical and non-canonical functions of PFKFB3 could allow for the development of effective combinatorial targeted therapies for brain tumors. Full article
(This article belongs to the Special Issue Molecular Basis of Brain Tumors)
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19 pages, 1305 KiB  
Review
D-2-Hydroxyglutarate in Glioma Biology
by Fu-Ju Chou, Yang Liu, Fengchao Lang and Chunzhang Yang
Cells 2021, 10(9), 2345; https://doi.org/10.3390/cells10092345 - 7 Sep 2021
Cited by 31 | Viewed by 8830
Abstract
Isocitrate dehydrogenase (IDH) mutations are common genetic abnormalities in glioma, which result in the accumulation of an “oncometabolite”, D-2-hydroxyglutarate (D-2-HG). Abnormally elevated D-2-HG levels result in a distinctive pattern in cancer biology, through competitively inhibiting α-ketoglutarate (α-KG)/Fe(II)-dependent dioxgenases (α-KGDDs). Recent studies have revealed [...] Read more.
Isocitrate dehydrogenase (IDH) mutations are common genetic abnormalities in glioma, which result in the accumulation of an “oncometabolite”, D-2-hydroxyglutarate (D-2-HG). Abnormally elevated D-2-HG levels result in a distinctive pattern in cancer biology, through competitively inhibiting α-ketoglutarate (α-KG)/Fe(II)-dependent dioxgenases (α-KGDDs). Recent studies have revealed that D-2-HG affects DNA/histone methylation, hypoxia signaling, DNA repair, and redox homeostasis, which impacts the oncogenesis of IDH-mutated cancers. In this review, we will discuss the current understanding of D-2-HG in cancer biology, as well as the emerging opportunities in therapeutics in IDH-mutated glioma. Full article
(This article belongs to the Special Issue Molecular Basis of Brain Tumors)
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23 pages, 1737 KiB  
Review
The Role of NKT Cells in Glioblastoma
by Emily E. S. Brettschneider and Masaki Terabe
Cells 2021, 10(7), 1641; https://doi.org/10.3390/cells10071641 - 30 Jun 2021
Cited by 13 | Viewed by 5622
Abstract
Glioblastoma is an aggressive and deadly cancer, but to date, immunotherapies have failed to make significant strides in improving prognoses for glioblastoma patients. One of the current challenges to developing immunological interventions for glioblastoma is our incomplete understanding of the numerous immunoregulatory mechanisms [...] Read more.
Glioblastoma is an aggressive and deadly cancer, but to date, immunotherapies have failed to make significant strides in improving prognoses for glioblastoma patients. One of the current challenges to developing immunological interventions for glioblastoma is our incomplete understanding of the numerous immunoregulatory mechanisms at play in the glioblastoma tumor microenvironment. We propose that Natural Killer T (NKT) cells, which are unconventional T lymphocytes that recognize lipid antigens presented by CD1d molecules, may play a key immunoregulatory role in glioblastoma. For example, evidence suggests that the activation of type I NKT cells can facilitate anti-glioblastoma immune responses. On the other hand, type II NKT cells are known to play an immunosuppressive role in other cancers, as well as to cross-regulate type I NKT cell activity, although their specific role in glioblastoma remains largely unclear. This review provides a summary of our current understanding of NKT cells in the immunoregulation of glioblastoma as well as highlights the involvement of NKT cells in other cancers and central nervous system diseases. Full article
(This article belongs to the Special Issue Molecular Basis of Brain Tumors)
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23 pages, 2150 KiB  
Review
From Laboratory Studies to Clinical Trials: Temozolomide Use in IDH-Mutant Gliomas
by Xueyuan Sun and Sevin Turcan
Cells 2021, 10(5), 1225; https://doi.org/10.3390/cells10051225 - 17 May 2021
Cited by 22 | Viewed by 5365
Abstract
In this review, we discuss the use of the alkylating agent temozolomide (TMZ) in the treatment of IDH-mutant gliomas. We describe the challenges associated with TMZ in clinical (drug resistance and tumor recurrence) and preclinical settings (variabilities associated with in vitro models) in [...] Read more.
In this review, we discuss the use of the alkylating agent temozolomide (TMZ) in the treatment of IDH-mutant gliomas. We describe the challenges associated with TMZ in clinical (drug resistance and tumor recurrence) and preclinical settings (variabilities associated with in vitro models) in treating IDH-mutant glioma. Lastly, we summarize the emerging therapeutic targets that can potentially be used in combination with TMZ. Full article
(This article belongs to the Special Issue Molecular Basis of Brain Tumors)
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18 pages, 739 KiB  
Review
Contemporary Mouse Models in Glioma Research
by William H. Hicks, Cylaina E. Bird, Jeffrey I. Traylor, Diana D. Shi, Tarek Y. El Ahmadieh, Timothy E. Richardson, Samuel K. McBrayer and Kalil G. Abdullah
Cells 2021, 10(3), 712; https://doi.org/10.3390/cells10030712 - 23 Mar 2021
Cited by 28 | Viewed by 12818
Abstract
Despite advances in understanding of the molecular pathogenesis of glioma, outcomes remain dismal. Developing successful treatments for glioma requires faithful in vivo disease modeling and rigorous preclinical testing. Murine models, including xenograft, syngeneic, and genetically engineered models, are used to study glioma-genesis, identify [...] Read more.
Despite advances in understanding of the molecular pathogenesis of glioma, outcomes remain dismal. Developing successful treatments for glioma requires faithful in vivo disease modeling and rigorous preclinical testing. Murine models, including xenograft, syngeneic, and genetically engineered models, are used to study glioma-genesis, identify methods of tumor progression, and test novel treatment strategies. Since the discovery of highly recurrent isocitrate dehydrogenase (IDH) mutations in lower-grade gliomas, there is increasing emphasis on effective modeling of IDH mutant brain tumors. Improvements in preclinical models that capture the phenotypic and molecular heterogeneity of gliomas are critical for the development of effective new therapies. Herein, we explore the current status, advancements, and challenges with contemporary murine glioma models. Full article
(This article belongs to the Special Issue Molecular Basis of Brain Tumors)
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21 pages, 1014 KiB  
Review
The Many Facets of Therapy Resistance and Tumor Recurrence in Glioblastoma
by Anshika Goenka, Deanna Tiek, Xiao Song, Tianzhi Huang, Bo Hu and Shi-Yuan Cheng
Cells 2021, 10(3), 484; https://doi.org/10.3390/cells10030484 - 24 Feb 2021
Cited by 84 | Viewed by 6516
Abstract
Glioblastoma (GBM) is the most lethal type of primary brain cancer. Standard care using chemo- and radio-therapy modestly increases the overall survival of patients; however, recurrence is inevitable, due to treatment resistance and lack of response to targeted therapies. GBM therapy resistance has [...] Read more.
Glioblastoma (GBM) is the most lethal type of primary brain cancer. Standard care using chemo- and radio-therapy modestly increases the overall survival of patients; however, recurrence is inevitable, due to treatment resistance and lack of response to targeted therapies. GBM therapy resistance has been attributed to several extrinsic and intrinsic factors which affect the dynamics of tumor evolution and physiology thus creating clinical challenges. Tumor-intrinsic factors such as tumor heterogeneity, hypermutation, altered metabolomics and oncologically activated alternative splicing pathways change the tumor landscape to facilitate therapy failure and tumor progression. Moreover, tumor-extrinsic factors such as hypoxia and an immune-suppressive tumor microenvironment (TME) are the chief causes of immunotherapy failure in GBM. Amid the success of immunotherapy in other cancers, GBM has occurred as a model of resistance, thus focusing current efforts on not only alleviating the immunotolerance but also evading the escape mechanisms of tumor cells to therapy, caused by inter- and intra-tumoral heterogeneity. Here we review the various mechanisms of therapy resistance in GBM, caused by the continuously evolving tumor dynamics as well as the complex TME, which cumulatively contribute to GBM malignancy and therapy failure; in an attempt to understand and identify effective therapies for recurrent GBM. Full article
(This article belongs to the Special Issue Molecular Basis of Brain Tumors)
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21 pages, 1209 KiB  
Review
Arginine Methylation in Brain Tumors: Tumor Biology and Therapeutic Strategies
by Jean-Paul Bryant, John Heiss and Yeshavanth Kumar Banasavadi-Siddegowda
Cells 2021, 10(1), 124; https://doi.org/10.3390/cells10010124 - 11 Jan 2021
Cited by 17 | Viewed by 4882
Abstract
Protein arginine methylation is a common post-translational modification that plays a pivotal role in cellular regulation. Protein arginine methyltransferases (PRMTs) catalyze the modification of target proteins by adding methyl groups to the guanidino nitrogen atoms of arginine residues. Protein arginine methylation takes part [...] Read more.
Protein arginine methylation is a common post-translational modification that plays a pivotal role in cellular regulation. Protein arginine methyltransferases (PRMTs) catalyze the modification of target proteins by adding methyl groups to the guanidino nitrogen atoms of arginine residues. Protein arginine methylation takes part in epigenetic and cellular regulation and has been linked to neurodegenerative diseases, metabolic diseases, and tumor progression. Aberrant expression of PRMTs is associated with the development of brain tumors such as glioblastoma and medulloblastoma. Identifying PRMTs as plausible contributors to tumorigenesis has led to preclinical and clinical investigations of PRMT inhibitors for glioblastoma and medulloblastoma therapy. In this review, we discuss the role of arginine methylation in cancer biology and provide an update on the use of small molecule inhibitors of PRMTs to treat glioblastoma, medulloblastoma, and other cancers. Full article
(This article belongs to the Special Issue Molecular Basis of Brain Tumors)
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