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Molecular and Cellular Hallmarks of Malignant Brain Tumors

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 34245

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Special Issue Editors

Dr. Bruno M. Costa

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Guest Editor

School of Medicine, University of Minho, Braga, Portugal
Interests: brain tumors; glioblastoma; biomarkers; glioma stem cells; epigenetics

Dr. Adília Hormigo

E-Mail Website
Guest Editor

Director Neuro-Oncology Mount Sinai and Mount Sinai Health System, Professor of Neurology, Medicine and Neurosurgery, Icahn School of Medicine at Mount Sinai, The Tisch Cancer Institute, Department of Neurology, New York, NY, USA
Interests: glioblastoma; glioma, immuno-oncology; brain tumor vaccines; biomarkers; angiogenesis

Special Issue Information

Dear Colleagues,

Malignant gliomas account for the majority of primary brain tumors and are particularly serious as they rank first among all human cancer types with respect to average years of life lost. Glioblastoma, the most common and most malignant subtype, is universally fatal, and only modest progress in the clinical management of patients has been achieved in the last few decades. Critically, glioblastoma affects patients of all ages, from children to adults, further highlighting the urgent, unmet need for better and more rational precision therapies.

In the last decade, an exponential body of data has emerged on various molecular (genetic and epigenetic), metabolic, and cellular hallmarks of human brain tumors, highlighting a remarkable intra- and inter-tumor heterogeneity in particular tumor niches that hampers the development of innovative, efficient therapies. More recently, various studies have also shed light on the complex and very dynamic interactions between glioma cells and multiple immune cells and have started to explore the potential of innovative anti-tumor immunotherapies for malignant gliomas.

This Special Issue will cover the most current and pertinent lines of investigation and recent findings in the field of neuro-oncology. Some main areas of focus will include the following: i) molecular features, ii) cellular interactions in the tumor microenvironment, iii) tumor heterogeneity, iv) energetic metabolism, and v) immune responses and therapies. Studies exploring the peculiar differences between pediatric and adult gliomas will also be welcome. Ultimately, this collection of manuscripts will also have a strong emphasis on established and new putative clinically relevant biomarkers that may provide valuable therapeutic and prognostic information, potentially contributing to a more rational precision approach in the future of brain cancer care.

Dr. Bruno M. Costa
Dr. Adília Hormigo
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Brain tumors
Glioma
Glioblastoma
Biomarkers
Glioma stem cells
Epigenetics
Onco-metabolism
Immuno-oncology
Novel therapies

Published Papers (7 papers)

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Research

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22 pages, 2991 KiB

Open AccessArticle

MRI Radiomic Features to Predict IDH1 Mutation Status in Gliomas: A Machine Learning Approach using Gradient Tree Boosting

by Yu Sakai, Chen Yang, Shingo Kihira, Nadejda Tsankova, Fahad Khan, Adilia Hormigo, Albert Lai, Timothy Cloughesy and Kambiz Nael

Int. J. Mol. Sci. 2020, 21(21), 8004; https://doi.org/10.3390/ijms21218004 - 27 Oct 2020

Cited by 24 | Viewed by 3301

Abstract

In patients with gliomas, isocitrate dehydrogenase 1 (IDH1) mutation status has been studied as a prognostic indicator. Recent advances in machine learning (ML) have demonstrated promise in utilizing radiomic features to study disease processes in the brain. We investigate whether ML analysis of multiparametric radiomic features from preoperative Magnetic Resonance Imaging (MRI) can predict IDH1 mutation status in patients with glioma. This retrospective study included patients with glioma with known IDH1 status and preoperative MRI. Radiomic features were extracted from Fluid-Attenuated Inversion Recovery (FLAIR) and Diffusion-Weighted-Imaging (DWI). The dataset was split into training, validation, and testing sets by stratified sampling. Synthetic Minority Oversampling Technique (SMOTE) was applied to the training sets. eXtreme Gradient Boosting (XGBoost) classifiers were trained, and the hyperparameters were tuned. Receiver operating characteristic curve (ROC), accuracy, and f1-scores were collected. A total of 100 patients (age: 55 ± 15, M/F 60/40); with IDH1 mutant (n = 22) and IDH1 wildtype (n = 78) were included. The best performance was seen with a DWI-trained XGBoost model, which achieved ROC with Area Under the Curve (AUC) of 0.97, accuracy of 0.90, and f1-score of 0.75 on the test set. The FLAIR-trained XGBoost model achieved ROC with AUC of 0.95, accuracy of 0.90, f1-score of 0.75 on the test set. A model that was trained on combined FLAIR-DWI radiomic features did not provide incremental accuracy. The results show that a XGBoost classifier using multiparametric radiomic features derived from preoperative MRI can predict IDH1 mutation status with > 90% accuracy. Full article

(This article belongs to the Special Issue Molecular and Cellular Hallmarks of Malignant Brain Tumors)

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Review

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24 pages, 1311 KiB

Open AccessReview

Molecular Mechanisms of Treatment Resistance in Glioblastoma

by Alexander Ou, W. K. Alfred Yung and Nazanin Majd

Int. J. Mol. Sci. 2021, 22(1), 351; https://doi.org/10.3390/ijms22010351 - 31 Dec 2020

Cited by 108 | Viewed by 8651

Abstract

Glioblastoma is the most common malignant primary brain tumor in adults and is almost invariably fatal. Despite our growing understanding of the various mechanisms underlying treatment failure, the standard-of-care therapy has not changed over the last two decades, signifying a great unmet need. The challenges of treating glioblastoma are many and include inadequate drug or agent delivery across the blood–brain barrier, abundant intra- and intertumoral heterogeneity, redundant signaling pathways, and an immunosuppressive microenvironment. Here, we review the innate and adaptive molecular mechanisms underlying glioblastoma’s treatment resistance, emphasizing the intrinsic challenges therapeutic interventions must overcome—namely, the blood–brain barrier, tumoral heterogeneity, and microenvironment—and the mechanisms of resistance to conventional treatments, targeted therapy, and immunotherapy. Full article

(This article belongs to the Special Issue Molecular and Cellular Hallmarks of Malignant Brain Tumors)

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21 pages, 1693 KiB

Open AccessReview

Mechanisms of EGFR Resistance in Glioblastoma

by Peter C. Pan and Rajiv S. Magge

Int. J. Mol. Sci. 2020, 21(22), 8471; https://doi.org/10.3390/ijms21228471 - 11 Nov 2020

Cited by 34 | Viewed by 4734

Abstract

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Despite numerous efforts to target epidermal growth factor receptor (EGFR), commonly dysregulated in GBM, approaches directed against EGFR have not achieved the same degree of success as seen in other tumor types, particularly as compared to non-small cell lung cancer (NSCLC). EGFR alterations in glioblastoma lie primarily in the extracellular domain, unlike the kinase domain alterations seen in NSCLC. Small molecule inhibitors are difficult to develop for the extracellular domain. Monoclonal antibodies can be developed to target the extracellular domain but must contend with the blood brain barrier (BBB). We review the role of EGFR in GBM, the history of trialed treatments, and the potential paths forward to target the pathway that may have greater success. Full article

(This article belongs to the Special Issue Molecular and Cellular Hallmarks of Malignant Brain Tumors)

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19 pages, 929 KiB

Open AccessReview

The CNS and the Brain Tumor Microenvironment: Implications for Glioblastoma Immunotherapy

by Fiona A. Desland and Adília Hormigo

Int. J. Mol. Sci. 2020, 21(19), 7358; https://doi.org/10.3390/ijms21197358 - 05 Oct 2020

Cited by 45 | Viewed by 7763

Abstract

Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor in adults. Its aggressive nature is attributed partly to its deeply invasive margins, its molecular and cellular heterogeneity, and uniquely tolerant site of origin—the brain. The immunosuppressive central nervous system (CNS) and GBM microenvironments are significant obstacles to generating an effective and long-lasting anti-tumoral response, as evidenced by this tumor’s reduced rate of treatment response and high probability of recurrence. Immunotherapy has revolutionized patients’ outcomes across many cancers and may open new avenues for patients with GBM. There is now a range of immunotherapeutic strategies being tested in patients with GBM that target both the innate and adaptive immune compartment. These strategies include antibodies that re-educate tumor macrophages, vaccines that introduce tumor-specific dendritic cells, checkpoint molecule inhibition, engineered T cells, and proteins that help T cells engage directly with tumor cells. Despite this, there is still much ground to be gained in improving the response rates of the various immunotherapies currently being trialed. Through historical and contemporary studies, we examine the fundamentals of CNS immunity that shape how to approach immune modulation in GBM, including the now revamped concept of CNS privilege. We also discuss the preclinical models used to study GBM progression and immunity. Lastly, we discuss the immunotherapeutic strategies currently being studied to help overcome the hurdles of the blood–brain barrier and the immunosuppressive tumor microenvironment. Full article

(This article belongs to the Special Issue Molecular and Cellular Hallmarks of Malignant Brain Tumors)

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23 pages, 2712 KiB

Open AccessReview

Histone-Mutant Glioma: Molecular Mechanisms, Preclinical Models, and Implications for Therapy

by Maya S. Graham and Ingo K. Mellinghoff

Int. J. Mol. Sci. 2020, 21(19), 7193; https://doi.org/10.3390/ijms21197193 - 29 Sep 2020

Cited by 13 | Viewed by 2802

Abstract

Pediatric high-grade glioma (pHGG) is the leading cause of cancer death in children. Despite histologic similarities, it has recently become apparent that this disease is molecularly distinct from its adult counterpart. Specific hallmark oncogenic histone mutations within pediatric malignant gliomas divide these tumors into subgroups with different neuroanatomic and chronologic predilections. In this review, we will summarize the characteristic molecular alterations of pediatric high-grade gliomas, with a focus on how preclinical models of these alterations have furthered our understanding of their oncogenicity as well as their potential impact on developing targeted therapies for this devastating disease. Full article

(This article belongs to the Special Issue Molecular and Cellular Hallmarks of Malignant Brain Tumors)

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16 pages, 267 KiB

Open AccessReview

Glioblastoma: Is There Any Blood Biomarker with True Clinical Relevance?

by Paulo Linhares, Bruno Carvalho, Rui Vaz and Bruno M. Costa

Int. J. Mol. Sci. 2020, 21(16), 5809; https://doi.org/10.3390/ijms21165809 - 13 Aug 2020

Cited by 35 | Viewed by 3211

Abstract

Glioblastoma (GBM) is the most frequent malignant primary brain tumor in adults, characterized by a highly aggressive, inflammatory and angiogenic phenotype. It is a remarkably heterogeneous tumor at several levels, including histopathologically, radiographically and genetically. The 2016 update of the WHO Classification of Tumours of the Central Nervous System highlighted molecular parameters as paramount features for the diagnosis, namely IDH1/2 mutations that distinguish primary and secondary GBM. An ideal biomarker is a molecule that can be detected/quantified through simple non- or minimally invasive methods with the potential to assess cancer risk; promote early diagnosis; increase grading accuracy; and monitor disease evolution and treatment response, as well as fundamentally being restricted to one aspect. Blood-based biomarkers are particularly attractive due to their easy access and have been widely used for various cancer types. A number of serum biomarkers with multiple utilities for glioma have been reported that could classify glioma grades more precisely and provide prognostic value among these patients. At present, screening for gliomas has no clinical relevance. This is because of the low incidence, the lack of sensitive biomarkers in plasma, and the observation that gliomas may develop apparently de novo within few weeks or months. To the best of our knowledge, there is no routine use of a serum biomarker for clinical follow-up. The purpose of this paper is to review the serum biomarkers described in the literature related to glioblastoma and their possible relationship with clinical features. Full article

(This article belongs to the Special Issue Molecular and Cellular Hallmarks of Malignant Brain Tumors)

30 pages, 1136 KiB

Open AccessReview

Exploiting the Complexities of Glioblastoma Stem Cells: Insights for Cancer Initiation and Therapeutic Targeting

by Joana Vieira de Castro, Céline S. Gonçalves, Adília Hormigo and Bruno M. Costa

Int. J. Mol. Sci. 2020, 21(15), 5278; https://doi.org/10.3390/ijms21155278 - 25 Jul 2020

Cited by 22 | Viewed by 3306

Abstract

The discovery of glioblastoma stem cells (GSCs) in the 2000s revolutionized the cancer research field, raising new questions regarding the putative cell(s) of origin of this tumor type, and partly explaining the highly heterogeneous nature of glioblastoma (GBM). Increasing evidence has suggested that GSCs play critical roles in tumor initiation, progression, and resistance to conventional therapies. The remarkable oncogenic features of GSCs have generated significant interest in better defining and characterizing these cells and determining novel pathways driving GBM that could constitute attractive key therapeutic targets. While exciting breakthroughs have been achieved in the field, the characterization of GSCs is a challenge and the cell of origin of GBM remains controversial. For example, the use of several cell-surface molecular markers to identify and isolate GSCs has been a challenge. It is now widely accepted that none of these markers is, per se, sufficiently robust to distinguish GSCs from normal stem cells. Finding new strategies that are able to more efficiently and specifically target these niches could also prove invaluable against this devastating and therapy-insensitive tumor. In this review paper, we summarize the most relevant findings and discuss emerging concepts and open questions in the field of GSCs, some of which are, to some extent, pertinent to other cancer stem cells. Full article

(This article belongs to the Special Issue Molecular and Cellular Hallmarks of Malignant Brain Tumors)

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