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4 pages, 178 KiB

Open AccessEditorial

Tumors of the Central Nervous System: An Update

by Carla Mucignat-Caretta

Cancers 2020, 12(9), 2507; https://doi.org/10.3390/cancers12092507 - 3 Sep 2020

Cited by 1 | Viewed by 1564

Abstract

The brain may be affected by a variety of tumors of different grade, which originate from different cell types at distinct locations, thus impacting on the brain structure and function [...] Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

Research

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11 pages, 2559 KiB

Open AccessArticle

Predicting Glioblastoma Recurrence from Preoperative MR Scans Using Fractional-Anisotropy Maps with Free-Water Suppression

by Marie-Christin Metz, Miguel Molina-Romero, Jana Lipkova, Jens Gempt, Friederike Liesche-Starnecker, Paul Eichinger, Lioba Grundl, Bjoern Menze, Stephanie E. Combs, Claus Zimmer and Benedikt Wiestler

Cancers 2020, 12(3), 728; https://doi.org/10.3390/cancers12030728 - 19 Mar 2020

Cited by 26 | Viewed by 4280

Abstract

Diffusion tensor imaging (DTI), and fractional-anisotropy (FA) maps in particular, have shown promise in predicting areas of tumor recurrence in glioblastoma. However, analysis of peritumoral edema, where most recurrences occur, is impeded by free-water contamination. In this study, we evaluated the benefits of [...] Read more.

Diffusion tensor imaging (DTI), and fractional-anisotropy (FA) maps in particular, have shown promise in predicting areas of tumor recurrence in glioblastoma. However, analysis of peritumoral edema, where most recurrences occur, is impeded by free-water contamination. In this study, we evaluated the benefits of a novel, deep-learning-based approach for the free-water correction (FWC) of DTI data for prediction of later recurrence. We investigated 35 glioblastoma cases from our prospective glioma cohort. A preoperative MR image and the first MR scan showing tumor recurrence were semiautomatically segmented into areas of contrast-enhancing tumor, edema, or recurrence of the tumor. The 10th, 50th and 90th percentiles and mean of FA and mean-diffusivity (MD) values (both for the original and FWC–DTI data) were collected for areas with and without recurrence in the peritumoral edema. We found significant differences in the FWC–FA maps between areas of recurrence-free edema and areas with later tumor recurrence, where differences in noncorrected FA maps were less pronounced. Consequently, a generalized mixed-effect model had a significantly higher area under the curve when using FWC–FA maps (AUC = 0.9) compared to noncorrected maps (AUC = 0.77, p < 0.001). This may reflect tumor infiltration that is not visible in conventional imaging, and may therefore reveal important information for personalized treatment decisions. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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18 pages, 4675 KiB

Open AccessArticle

Diversity of Clinically Relevant Outcomes Resulting from Hypofractionated Radiation in Human Glioma Stem Cells Mirrors Distinct Patterns of Transcriptomic Changes

by Darius Kalasauskas, Maxim Sorokin, Bettina Sprang, Alhassan Elmasri, Sina Viehweg, Gabriela Salinas, Lennart Opitz, Margret Rave-Fraenk, Walter Schulz-Schaeffer, Sven Reiner Kantelhardt, Alf Giese, Anton Buzdin and Ella L. Kim

Cancers 2020, 12(3), 570; https://doi.org/10.3390/cancers12030570 - 1 Mar 2020

Cited by 11 | Viewed by 2838

Abstract

Hypofractionated radiotherapy is the mainstay of the current treatment for glioblastoma. However, the efficacy of radiotherapy is hindered by the high degree of radioresistance associated with glioma stem cells comprising a heterogeneous compartment of cell lineages differing in their phenotypic characteristics, molecular signatures, [...] Read more.

Hypofractionated radiotherapy is the mainstay of the current treatment for glioblastoma. However, the efficacy of radiotherapy is hindered by the high degree of radioresistance associated with glioma stem cells comprising a heterogeneous compartment of cell lineages differing in their phenotypic characteristics, molecular signatures, and biological responses to external signals. Reconstruction of radiation responses in glioma stem cells is necessary for understanding the biological and molecular determinants of glioblastoma radioresistance. To date, there is a paucity of information on the longitudinal outcomes of hypofractionated radiation in glioma stem cells. This study addresses long-term outcomes of hypofractionated radiation in human glioma stem cells by using a combinatorial approach integrating parallel assessments of the tumor-propagating capacity, stemness-associated properties, and array-based profiling of gene expression. The study reveals a broad spectrum of changes in the tumor-propagating capacity of glioma stem cells after radiation and finds association with proliferative changes at the onset of differentiation. Evidence is provided that parallel transcriptomic patterns and a cumulative impact of pathways involved in the regulation of apoptosis, neural differentiation, and cell proliferation underly similarities in tumorigenicity changes after radiation. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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14 pages, 1573 KiB

Open AccessArticle

The IL-1 Antagonist Anakinra Attenuates Glioblastoma Aggressiveness by Dampening Tumor-Associated Inflammation

by Max Hübner, David Effinger, Tingting Wu, Gabriele Strauß, Kristin Pogoda, Friedrich-Wilhelm Kreth and Simone Kreth

Cancers 2020, 12(2), 433; https://doi.org/10.3390/cancers12020433 - 13 Feb 2020

Cited by 15 | Viewed by 3798

Abstract

Background: The recombinant IL-1 receptor antagonist anakinra—currently approved for the treatment of autoinflammatory diseases—blocks IL-1β-mediated inflammatory signaling. As inflammation is a major driver of cancer, we hypothesized that anakinra might be able to mitigate glioblastoma (GBM) aggressiveness. Methods: Primary GBM or T98G cells [...] Read more.

Background: The recombinant IL-1 receptor antagonist anakinra—currently approved for the treatment of autoinflammatory diseases—blocks IL-1β-mediated inflammatory signaling. As inflammation is a major driver of cancer, we hypothesized that anakinra might be able to mitigate glioblastoma (GBM) aggressiveness. Methods: Primary GBM or T98G cells were incubated alone or with peripheral blood mononuclear cells (PBMCs) and were subsequently treated with IL-1β and/or anakinra. T cells were obtained by magnetic bead isolation. Protein and mRNA expression were quantified by SDS-PAGE, qRT-PCR, and ELISA, respectively. Cell proliferation and apoptosis were analyzed via flow cytometry. Chemotaxis was studied via time-lapse microscopy. Results: Upon IL-1β stimulation, anakinra attenuated proinflammatory gene expression in both GBM cells and PBMCs, and mitigated tumor migration and proliferation. In a more lifelike model replacing IL-1β stimulation by GBM–PBMC co-culture, sole presence of PBMCs proved sufficient to induce a proinflammatory phenotype in GBM cells with enhanced proliferation and migration rates and attenuated apoptosis. Anakinra antagonized these pro-tumorigenic effects and, moreover, reduced inflammatory signaling in T cells without compromising anti-tumor effector molecules. Conclusion: By dampening the inflammatory crosstalk between GBM and immune cells, anakinra mitigated GBM aggressiveness. Hence, counteracting IL-1β-mediated inflammation might be a promising strategy to pursue. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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16 pages, 4784 KiB

Open AccessArticle

The RNA-Binding Ubiquitin Ligase MEX3A Affects Glioblastoma Tumorigenesis by Inducing Ubiquitylation and Degradation of RIG-I

by Francesca Bufalieri, Miriam Caimano, Ludovica Lospinoso Severini, Irene Basili, Francesco Paglia, Luigi Sampirisi, Elena Loricchio, Marialaura Petroni, Gianluca Canettieri, Antonio Santoro, Luca D’Angelo, Paola Infante and Lucia Di Marcotullio

Cancers 2020, 12(2), 321; https://doi.org/10.3390/cancers12020321 - 30 Jan 2020

Cited by 41 | Viewed by 5423

Abstract

Glioblastoma multiforme (GB) is the most malignant primary brain tumor in humans, with an overall survival of approximatively 15 months. The molecular heterogeneity of GB, as well as its rapid progression, invasiveness and the occurrence of drug-resistant cancer stem cells, limits the efficacy [...] Read more.

Glioblastoma multiforme (GB) is the most malignant primary brain tumor in humans, with an overall survival of approximatively 15 months. The molecular heterogeneity of GB, as well as its rapid progression, invasiveness and the occurrence of drug-resistant cancer stem cells, limits the efficacy of the current treatments. In order to develop an innovative therapeutic strategy, it is mandatory to identify and characterize new molecular players responsible for the GB malignant phenotype. In this study, the RNA-binding ubiquitin ligase MEX3A was selected from a gene expression analysis performed on publicly available datasets, to assess its biological and still-unknown activity in GB tumorigenesis. We find that MEX3A is strongly up-regulated in GB specimens, and this correlates with very low protein levels of RIG-I, a tumor suppressor involved in differentiation, apoptosis and innate immune response. We demonstrate that MEX3A binds RIG-I and induces its ubiquitylation and proteasome-dependent degradation. Further, the genetic depletion of MEX3A leads to an increase of RIG-I protein levels and results in the suppression of GB cell growth. Our findings unveil a novel molecular mechanism involved in GB tumorigenesis and suggest MEX3A and RIG-I as promising therapeutic targets in GB. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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17 pages, 2889 KiB

Open AccessArticle

The EGFR-TMEM167A-p53 Axis Defines the Aggressiveness of Gliomas

by Berta Segura-Collar, Ricardo Gargini, Elena Tovar-Ambel, Esther Hernández-SanMiguel, Carolina Epifano, Ignacio Pérez de Castro, Aurelio Hernández-Laín, Sergio Casas-Tintó and Pilar Sánchez-Gómez

Cancers 2020, 12(1), 208; https://doi.org/10.3390/cancers12010208 - 14 Jan 2020

Cited by 13 | Viewed by 3783

Abstract

Despite the high frequency of EGFR and TP53 genetic alterations in gliomas, little is known about their crosstalk during tumor progression. Here, we described a mutually exclusive distribution between mutations in these two genes. We found that wild-type p53 gliomas are more aggressive [...] Read more.

Despite the high frequency of EGFR and TP53 genetic alterations in gliomas, little is known about their crosstalk during tumor progression. Here, we described a mutually exclusive distribution between mutations in these two genes. We found that wild-type p53 gliomas are more aggressive than their mutant counterparts, probably because the former accumulate amplifications and/or mutations in EGFR and show a stronger activation of this receptor. In addition, we identified a series of genes associated with vesicular trafficking of EGFR in p53 wild-type gliomas. Among these genes, TMEM167A showed the strongest implication in overall survival in this group of tumors. In agreement with this observation, inhibition of TMEM167A expression impaired the subcutaneous and the intracranial growth of wild-type p53 gliomas, regardless of the presence of EGFR mutations. In the absence of p53 mutations, TMEM167A knockdown reduced the acidification of intracellular vesicles, affecting the autophagy process and impairing EGFR trafficking and signaling. This effect was mimicked by an inhibitor of the vacuolar ATPase. We propose that the increased aggressiveness of wild-type p53 gliomas might be due to the increase in growth factor signaling activity, which depends on the regulation of vesicular trafficking by TMEM167A. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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10 pages, 624 KiB

Open AccessArticle

BRAF V600E Detection in Liquid Biopsies from Pediatric Central Nervous System Tumors

by Noemi García-Romero, Josefa Carrión-Navarro, Pilar Areal-Hidalgo, Ana Ortiz de Mendivil, Adriá Asensi-Puig, Rodrigo Madurga, Rocio Núñez-Torres, Anna González-Neira, Cristobal Belda-Iniesta, Victor González-Rumayor, Blanca López-Ibor and Angel Ayuso-Sacido

Cancers 2020, 12(1), 66; https://doi.org/10.3390/cancers12010066 - 25 Dec 2019

Cited by 34 | Viewed by 3386

Abstract

Pediatric Central Nervous System (CNS) tumors are the most fatal cancer diseases in childhood. Due to their localization and infiltrative nature, some tumor resections or biopsies are not feasible. In those cases, the use of minimally invasive methods as diagnostic, molecular marker detection, [...] Read more.

Pediatric Central Nervous System (CNS) tumors are the most fatal cancer diseases in childhood. Due to their localization and infiltrative nature, some tumor resections or biopsies are not feasible. In those cases, the use of minimally invasive methods as diagnostic, molecular marker detection, prognostic or monitoring therapies are emerging. The analysis of liquid biopsies which contain genetic information from the tumor has been much more widely explored in adults than in children. We compare the detection of BRAF V600E targetable mutation by digital-PCR from cell-free-DNA and EV-derived DNA (ctDNA) in serum, plasma and cerebrospinal fluid (CSF) isolated from a cohort of 29 CNS pediatric patients. Here we demonstrate that ctDNA isolated from serum and plasma could be successfully analyzed to obtain tumor genetic information which could be used to guide critical treatment decisions. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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19 pages, 2538 KiB

Open AccessArticle

Implementing Patient-Derived Xenografts to Assess the Effectiveness of Cyclin-Dependent Kinase Inhibitors in Glioblastoma

by Janis J. Noonan, Monika Jarzabek, Frank A. Lincoln, Brenton L. Cavanagh, Arhona R. Pariag, Viktorija Juric, Leonie S. Young, Keith L. Ligon, Hanne Jahns, Daniella Zheleva, Jochen H. M. Prehn, Markus Rehm, Annette T. Byrne and Brona M. Murphy

Cancers 2019, 11(12), 2005; https://doi.org/10.3390/cancers11122005 - 12 Dec 2019

Cited by 10 | Viewed by 4338

Abstract

Glioblastoma (GBM) is the most common primary brain tumor with no available cure. As previously described, seliciclib, a first-generation cyclin-dependent kinase (CDK) inhibitor, down-regulates the anti-apoptotic protein, Mcl-1, in GBM, thereby sensitizing GBM cells to the apoptosis-inducing effects of the death receptor ligand, [...] Read more.

Glioblastoma (GBM) is the most common primary brain tumor with no available cure. As previously described, seliciclib, a first-generation cyclin-dependent kinase (CDK) inhibitor, down-regulates the anti-apoptotic protein, Mcl-1, in GBM, thereby sensitizing GBM cells to the apoptosis-inducing effects of the death receptor ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, we have assessed the efficacy of seliciclib when delivered in combination with the antibody against human death receptor 5, drozitumab, in clinically relevant patient-derived xenograft (PDX) models of GBM. A reduction in viability and significant levels of apoptosis were observed in vitro in human GBM neurospheres following treatment with seliciclib plus drozitumab. While the co-treatment strategy induced a similar effect in PDX models, the dosing regimen required to observe seliciclib-targeted responses in the brain, resulted in lethal toxicity in 45% of animals. Additional studies showed that the second-generation CDK inhibitor, CYC065, with improved potency in comparison to seliciclib, induced a significant decrease in the size of human GBM neurospheres in vitro and was well tolerated in vivo, upon administration at clinically relevant doses. This study highlights the continued need for robust pre-clinical assessment of promising treatment approaches using clinically relevant models. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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12 pages, 1467 KiB

Open AccessArticle

Cerebrospinal Fluid MicroRNA Signatures as Diagnostic Biomarkers in Brain Tumors

by Alena Kopkova, Jiri Sana, Tana Machackova, Marek Vecera, Lenka Radova, Karolina Trachtova, Vaclav Vybihal, Martin Smrcka, Tomas Kazda, Ondrej Slaby and Pavel Fadrus

Cancers 2019, 11(10), 1546; https://doi.org/10.3390/cancers11101546 - 12 Oct 2019

Cited by 50 | Viewed by 5160

Abstract

Central nervous system (CNS) malignancies include primary tumors that originate within the CNS as well as secondary tumors that develop as a result of metastatic spread. Circulating microRNAs (miRNAs) were found in almost all human body fluids including cerebrospinal fluid (CSF), and they [...] Read more.

Central nervous system (CNS) malignancies include primary tumors that originate within the CNS as well as secondary tumors that develop as a result of metastatic spread. Circulating microRNAs (miRNAs) were found in almost all human body fluids including cerebrospinal fluid (CSF), and they seem to be highly stable and resistant to even extreme conditions. The overall aim of our study was to identify specific CSF miRNA patterns that could differentiate among brain tumors. These new biomarkers could potentially aid borderline or uncertain imaging results onto diagnosis of CNS malignancies, avoiding most invasive procedures such as stereotactic biopsy or biopsy. In total, 175 brain tumor patients (glioblastomas, low-grade gliomas, meningiomas and brain metastases), and 40 non-tumor patients with hydrocephalus as controls were included in this prospective monocentric study. Firstly, we performed high-throughput miRNA profiling (Illumina small RNA sequencing) on a discovery cohort of 70 patients and 19 controls and identified specific miRNA signatures of all brain tumor types tested. Secondly, validation of 9 candidate miRNAs was carried out on an independent cohort of 105 brain tumor patients and 21 controls using qRT-PCR. Based on the successful results of validation and various combination patterns of only 5 miRNA levels (miR-30e, miR-140, let-7b, mR-10a and miR-21-3p) we proposed CSF-diagnostic scores for each tumor type which enabled to distinguish them from healthy donors and other tumor types tested. In addition to this primary diagnostic tool, we described the prognostic potential of the combination of miR-10b and miR-196b levels in CSF of glioblastoma patients. In conclusion, we performed the largest study so far focused on CSF miRNA profiling in patients with brain tumors, and we believe that this new class of biomarkers have a strong potential as a diagnostic and prognostic tool in these patients. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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12 pages, 837 KiB

Open AccessArticle

Validation of the Comprehensive Geriatric Assessment as a Predictor of Mortality in Elderly Glioblastoma Patients

by Giuseppe Lombardi, Eleonora Bergo, Mario Caccese, Marta Padovan, Luisa Bellu, Antonella Brunello and Vittorina Zagonel

Cancers 2019, 11(10), 1509; https://doi.org/10.3390/cancers11101509 - 9 Oct 2019

Cited by 24 | Viewed by 2681

Abstract

Background: Treatment of elderly glioblastoma patients (EGP) is a challenge in neuro-oncology. The comprehensive geriatric assessment (CGA) is currently used to assess geriatric oncological patients with other types of tumors. We performed a large retrospective study to analyze its predictive role in EGP. [...] Read more.

Background: Treatment of elderly glioblastoma patients (EGP) is a challenge in neuro-oncology. The comprehensive geriatric assessment (CGA) is currently used to assess geriatric oncological patients with other types of tumors. We performed a large retrospective study to analyze its predictive role in EGP. Methods: Patients aged ≥65 years with histologically confirmed diagnosis of glioblastoma were enrolled. CGA included the following tests: the Cumulative Illness Rating Scale-Comorbidity and Severity Index, Activities of Daily Living, Instrumental Activities of Daily Living, the Mini Mental State Examination, and the Geriatric Depression Scale. Based on CGA results, each patient was categorized as fit, vulnerable, or frail. Results: We enrolled 113 patients. According to the CGA scores, 35% of patients were categorized as “fit”, 30% as “vulnerable”, and 35% as “frail” patients. Median overall survival was 16.5, 12.1, and 10.3 months in fit, vulnerable, and frail patients (p = 0.1), respectively. On multivariate analysis, the CGA score resulted an independent predictor of survival; indeed, vulnerable and frail patients had a hazard ratio of 1.5 and 2.2, respectively, compared to fit patients (p = 0.04). No association between CGA and progression-free survival (PFS) was demonstrated. Conclusions: The CGA score proved to be a significant predictor of mortality in EGP, and it could be a useful treatment decision tool. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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17 pages, 5953 KiB

Open AccessFeature PaperArticle

Ultra-Mutation in IDH Wild-Type Glioblastomas of Patients Younger than 55 Years is Associated with Defective Mismatch Repair, Microsatellite Instability, and Giant Cell Enrichment

by Valeria Barresi, Michele Simbolo, Andrea Mafficini, Maria Liliana Piredda, Maria Caffo, Salvatore Massimiliano Cardali, Antonino Germanò, Sara Cingarlini, Claudio Ghimenton and Aldo Scarpa

Cancers 2019, 11(9), 1279; https://doi.org/10.3390/cancers11091279 - 30 Aug 2019

Cited by 26 | Viewed by 4411

Abstract

Background: Glioblastomas (GBMs) are classified into isocitrate dehydrogenase (IDH) mutants and IDH wild-types (IDH-wt). This study aimed at identifying the mutational assets of IDH-wt GBMs in patients aged 18–54 years for which limited data are available. Methods: Sixteen IDH [...] Read more.

Background: Glioblastomas (GBMs) are classified into isocitrate dehydrogenase (IDH) mutants and IDH wild-types (IDH-wt). This study aimed at identifying the mutational assets of IDH-wt GBMs in patients aged 18–54 years for which limited data are available. Methods: Sixteen IDH-wt GBMs from adults < 55 years old were explored for mutations, copy number variations, tumour mutational load (TML), and mutational spectrum by a 409 genes TML panel. Results: Eight (50%) IDH-wt GBMs were hypermutated (TML > 9 mutations/Mb) and two (12.5%) were ultra-mutated (TML > 100 mutations/Mb). One ultra-mutated GBM had microsatellite instability (MSI), a somatic MSH6 mutation, and a germline POLE mutation. The other ultra-mutated GBMs had MSI and two somatic mutations in MSH2. Both ultra-mutated GBMs featured at least 25% giant cells. The overall survival of eight patients with hypermutated GBMs was significantly longer than that of patients with non-hypermutated GBMs (p = 0.04). Conclusions: We identified a hyper-mutated subgroup among IDH-wt GBMs in adults < 55 years that had improved prognosis. Two cases were ultra-mutated and characterized by the presence of at least 25% giant cells, MMR mutations, and MSI. Since high TML has been associated with response to immune checkpoint inhibition in paediatric gliomas, the identification of a subtype of ultra-mutated IDH-wt GBM may have implications for immunotherapy. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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15 pages, 946 KiB

Open AccessArticle

Extent of Resection, MGMT Promoter Methylation Status and Tumor Location Independently Predict Progression-Free Survival in Adult Sporadic Pilocytic Astrocytoma

by Christine Jungk, Annekathrin Reinhardt, Rolf Warta, David Capper, Andreas von Deimling, Christel Herold-Mende and Andreas Unterberg

Cancers 2019, 11(8), 1072; https://doi.org/10.3390/cancers11081072 - 29 Jul 2019

Cited by 15 | Viewed by 3105

Abstract

In adults, pilocytic astrocytomas (PA) account for less than 2% of gliomas, resulting in uncertainty regarding the clinical course and optimal treatment, particularly in cases where gross total resection (GTR) could not be achieved. Moreover, information on molecular markers and their prognostic impact [...] Read more.

In adults, pilocytic astrocytomas (PA) account for less than 2% of gliomas, resulting in uncertainty regarding the clinical course and optimal treatment, particularly in cases where gross total resection (GTR) could not be achieved. Moreover, information on molecular markers and their prognostic impact is sparse. In order to improve risk stratification, we analyzed our institutional series of 58 patients aged 17 years and older with histology-proven intracranial PA World Health Organization grade I for clinical and molecular prognosticators. Anaplastic and NF1-associated tumors were excluded. O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was determined by pyrosequencing or 450k/850k DNA methylation array. A univariate log-rank test and multivariate StepAIC were applied to identify prognostic factors. The median age was 30 years (range 17–66). Tumors were located in the cerebral/cerebellar hemispheres, midline structures and cerebello-pontine angle in 53%, 38% and 9%. MGMT promoter methylation was present in eight patients (14%). GTR (39/58 patients) significantly reduced the likelihood of tumor recurrence (p = 0.0001). Tumor relapse occurred in 16 patients (28%) after a median progression-free survival (PFS) of 135 months (range 6–153 months); there was one tumor-related death. PFS at 5 and 10 years was 67% and 53%. In multivariate analysis, PFS was significantly prolonged in patients with GTR (HR 0.1; CI 0.03–0.37; p < 0.001), unmethylated MGMT promoter (HR 0.18; CI 0.05–0.64; p = 0.009) and midline tumors (HR 0.21; CI 0.06–0.78; p = 0.02). In conclusion, MGMT promoter methylation status and tumor location were identified as novel prognostic factors in adult PAs, pointing at distinct molecular subtypes and detecting patients in need of close observance and intensified treatment. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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20 pages, 3258 KiB

Open AccessArticle

A New Strategy for Glioblastoma Treatment: In Vitro and In Vivo Preclinical Characterization of Si306, a Pyrazolo[3,4-d]Pyrimidine Dual Src/P-Glycoprotein Inhibitor

by Anna Lucia Fallacara, Claudio Zamperini, Ana Podolski-Renić, Jelena Dinić, Tijana Stanković, Marija Stepanović, Arianna Mancini, Enrico Rango, Giulia Iovenitti, Alessio Molinari, Francesca Bugli, Maurizio Sanguinetti, Riccardo Torelli, Maurizio Martini, Laura Maccari, Massimo Valoti, Elena Dreassi, Maurizio Botta, Milica Pešić and Silvia Schenone

Cancers 2019, 11(6), 848; https://doi.org/10.3390/cancers11060848 - 19 Jun 2019

Cited by 35 | Viewed by 5459

Abstract

Overexpression of P-glycoprotein (P-gp) and other ATP-binding cassette (ABC) transporters in multidrug resistant (MDR) cancer cells is responsible for the reduction of intracellular drug accumulation, thus decreasing the efficacy of chemotherapeutics. P-gp is also found at endothelial cells’ membrane of the blood-brain barrier, [...] Read more.

Overexpression of P-glycoprotein (P-gp) and other ATP-binding cassette (ABC) transporters in multidrug resistant (MDR) cancer cells is responsible for the reduction of intracellular drug accumulation, thus decreasing the efficacy of chemotherapeutics. P-gp is also found at endothelial cells’ membrane of the blood-brain barrier, where it limits drug delivery to central nervous system (CNS) tumors. We have previously developed a set of pyrazolo[3,4-d]pyrimidines and their prodrugs as novel Src tyrosine kinase inhibitors (TKIs), showing a significant activity against CNS tumors in in vivo. Here we investigated the interaction of the most promising pair of drug/prodrug with P-gp at the cellular level. The tested compounds were found to increase the intracellular accumulation of Rho 123, and to enhance the efficacy of paclitaxel in P-gp overexpressing cells. Encouraging pharmacokinetics properties and tolerability in vivo were also observed. Our findings revealed a novel role of pyrazolo[3,4-d]pyrimidines which may be useful for developing a new effective therapy in MDR cancer treatment, particularly against glioblastoma. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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13 pages, 811 KiB

Open AccessArticle

Circulating MACC1 Transcripts in Glioblastoma Patients Predict Prognosis and Treatment Response

by Carsten Hagemann, Nikolas Neuhaus, Mathias Dahlmann, Almuth F. Kessler, Dennis Kobelt, Pia Herrmann, Matthias Eyrich, Benjamin Freitag, Thomas Linsenmann, Camelia M. Monoranu, Ralf-Ingo Ernestus, Mario Löhr and Ulrike Stein

Cancers 2019, 11(6), 825; https://doi.org/10.3390/cancers11060825 - 13 Jun 2019

Cited by 8 | Viewed by 4123

Abstract

Glioblastoma multiforme is the most aggressive primary brain tumor of adults, but lacks reliable and liquid biomarkers. We evaluated circulating plasma transcripts of metastasis-associated in colon cancer-1 (MACC1), a prognostic biomarker for solid cancer entities, for prediction of clinical outcome and therapy response [...] Read more.

Glioblastoma multiforme is the most aggressive primary brain tumor of adults, but lacks reliable and liquid biomarkers. We evaluated circulating plasma transcripts of metastasis-associated in colon cancer-1 (MACC1), a prognostic biomarker for solid cancer entities, for prediction of clinical outcome and therapy response in glioblastomas. MACC1 transcripts were significantly higher in patients compared to controls. Low MACC1 levels clustered together with other prognostically favorable markers. It was associated with patients’ prognosis in conjunction with the isocitrate dehydrogenase (IDH) mutation status: IDH1 R132H mutation and low MACC1 was most favorable (median overall survival (OS) not yet reached), IDH1 wildtype and high MACC1 was worst (median OS 8.1 months), while IDH1 wildtype and low MACC1 was intermediate (median OS 9.1 months). No patients displayed IDH1 R132H mutation and high MACC1. Patients with low MACC1 levels receiving standard therapy survived longer (median OS 22.6 months) than patients with high MACC1 levels (median OS 8.1 months). Patients not receiving the standard regimen showed the worst prognosis, independent of MACC1 levels (low: 6.8 months, high: 4.4 months). Addition of circulating MACC1 transcript levels to the existing prognostic workup may improve the accuracy of outcome prediction and help define more precise risk categories of glioblastoma patients. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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20 pages, 2352 KiB

Open AccessArticle

Semaphorin-7A on Exosomes: A Promigratory Signal in the Glioma Microenvironment

by Ivana Manini, Maria Elisabetta Ruaro, Riccardo Sgarra, Anna Bartolini, Federica Caponnetto, Tamara Ius, Miran Skrap, Carla Di Loreto, Antonio Paolo Beltrami, Guidalberto Manfioletti and Daniela Cesselli

Cancers 2019, 11(6), 758; https://doi.org/10.3390/cancers11060758 - 30 May 2019

Cited by 20 | Viewed by 4318

Abstract

Exosomes are one of the most important mediators of the cross talk occurring between glioma stem cells (GSCs) and the surrounding microenvironment. We have previously shown that exosomes released by patient-derived glioma-associated stem cells (GASC) are able to increase, in vitro, the aggressiveness [...] Read more.

Exosomes are one of the most important mediators of the cross talk occurring between glioma stem cells (GSCs) and the surrounding microenvironment. We have previously shown that exosomes released by patient-derived glioma-associated stem cells (GASC) are able to increase, in vitro, the aggressiveness of both GSC and glioblastoma cell lines. To understand which molecules are responsible for this tumour-supporting function, we performed a descriptive proteomic analysis of GASC-exosomes and identified, among the others, Semaphorin7A (SEMA7A). SEMA7A was described as a promigratory cue in physiological and pathological conditions, and we hypothesised that it could modulate GSC migratory properties. Here, we described that SEMA7A is exposed on GASC-exosomes’ surface and signals to GSC through Integrin β1. This interaction activates focal adhesion kinase into GSC and increases their motility, in our patient-based in vitro model. Our findings suggest SEMA7A-β1-integrin as a new target to disrupt the communication between GSCs and the supporting microenvironment. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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Review

Jump to: Editorial, Research

28 pages, 1355 KiB

Open AccessEditor’s ChoiceReview

Glioblastoma: Pathogenesis and Current Status of Chemotherapy and Other Novel Treatments

by Vilashini Rajaratnam, Mohammad Mohiminul Islam, Maixee Yang, Rachel Slaby, Hilda Martinez Ramirez and Shama Parveen Mirza

Cancers 2020, 12(4), 937; https://doi.org/10.3390/cancers12040937 - 10 Apr 2020

Cited by 87 | Viewed by 10961

Abstract

Glioblastoma is one of the most common and detrimental forms of solid brain tumor, with over 10,000 new cases reported every year in the United States. Despite aggressive multimodal treatment approaches, the overall survival period is reported to be less than 15 months [...] Read more.

Glioblastoma is one of the most common and detrimental forms of solid brain tumor, with over 10,000 new cases reported every year in the United States. Despite aggressive multimodal treatment approaches, the overall survival period is reported to be less than 15 months after diagnosis. A widely used approach for the treatment of glioblastoma is surgical removal of the tumor, followed by radiotherapy and chemotherapy. While there are several drugs available that are approved by the Food and Drug Administration (FDA), significant efforts have been made in recent years to develop new chemotherapeutic agents for the treatment of glioblastoma. This review describes the molecular targets and pathogenesis as well as the current progress in chemotherapeutic development and other novel therapies in the clinical setting for the treatment of glioblastoma. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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21 pages, 1936 KiB

Open AccessReview

Tunneling Nanotubes and Tumor Microtubes in Cancer

by Cora Roehlecke and Mirko H. H. Schmidt

Cancers 2020, 12(4), 857; https://doi.org/10.3390/cancers12040857 - 1 Apr 2020

Cited by 78 | Viewed by 8604

Abstract

Intercellular communication among cancer cells and their microenvironment is crucial to disease progression. The mechanisms by which communication occurs between distant cells in a tumor matrix remain poorly understood. In the last two decades, experimental evidence from different groups proved the existence of [...] Read more.

Intercellular communication among cancer cells and their microenvironment is crucial to disease progression. The mechanisms by which communication occurs between distant cells in a tumor matrix remain poorly understood. In the last two decades, experimental evidence from different groups proved the existence of thin membranous tubes that interconnect cells, named tunneling nanotubes, tumor microtubes, cytonemes or membrane bridges. These highly dynamic membrane protrusions are conduits for direct cell-to-cell communication, particularly for intercellular signaling and transport of cellular cargo over long distances. Tunneling nanotubes and tumor microtubes may play an important role in the pathogenesis of cancer. They may contribute to the resistance of tumor cells against treatments such as surgery, radio- and chemotherapy. In this review, we present the current knowledge about the structure and function of tunneling nanotubes and tumor microtubes in cancer and discuss the therapeutic potential of membrane tubes in cancer treatment. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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20 pages, 2286 KiB

Open AccessReview

Autophagy in the Immunosuppressive Perivascular Microenvironment of Glioblastoma

by Maria L. Molina, David García-Bernal, Salvador Martinez and Rut Valdor

Cancers 2020, 12(1), 102; https://doi.org/10.3390/cancers12010102 - 31 Dec 2019

Cited by 22 | Viewed by 5143

Abstract

Glioblastoma (GB) has been shown to up-regulate autophagy with anti- or pro-oncogenic effects. Recently, our group has shown how GB cells aberrantly up-regulate chaperone-mediated autophagy (CMA) in pericytes of peritumoral areas to modulate their immune function through cell-cell interaction and in the tumor’s [...] Read more.

Glioblastoma (GB) has been shown to up-regulate autophagy with anti- or pro-oncogenic effects. Recently, our group has shown how GB cells aberrantly up-regulate chaperone-mediated autophagy (CMA) in pericytes of peritumoral areas to modulate their immune function through cell-cell interaction and in the tumor’s own benefit. Thus, to understand GB progression, the effect that GB cells could have on autophagy of immune cells that surround the tumor needs to be deeply explored. In this review, we summarize all the latest evidence of several molecular and cellular immunosuppressive mechanisms in the perivascular tumor microenvironment. This immunosuppression has been reported to facilitate GB progression and may be differently modulated by several types of autophagy as a critical point to be considered for therapeutic interventions. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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13 pages, 609 KiB

Open AccessReview

The Genetic Architecture of Gliomagenesis–Genetic Risk Variants Linked to Specific Molecular Subtypes

by Wendy Yi-Ying Wu, Gunnar Johansson, Carl Wibom, Thomas Brännström, Annika Malmström, Roger Henriksson, Irina Golovleva, Melissa L. Bondy, Ulrika Andersson, Anna M. Dahlin and Beatrice Melin

Cancers 2019, 11(12), 2001; https://doi.org/10.3390/cancers11122001 - 12 Dec 2019

Cited by 12 | Viewed by 3775

Abstract

Genome-wide association studies have identified 25 germline genetic loci that increase the risk of glioma. The somatic tumor molecular alterations, including IDH-mutation status and 1p/19q co-deletion, have been included into the WHO 2016 classification system for glioma. To investigate how the germline [...] Read more.

Genome-wide association studies have identified 25 germline genetic loci that increase the risk of glioma. The somatic tumor molecular alterations, including IDH-mutation status and 1p/19q co-deletion, have been included into the WHO 2016 classification system for glioma. To investigate how the germline genetic risk variants correlate with the somatic molecular subtypes put forward by WHO, we performed a meta-analysis that combined findings from 330 Swedish cases and 876 controls with two other recent studies. In total, 5,103 cases and 10,915 controls were included. Three categories of associations were found. First, variants in TERT and TP53 were associated with increased risk of all glioma subtypes. Second, variants in CDKN2B-AS1, EGFR, and RTEL1 were associated with IDH-wildtype glioma. Third, variants in CCDC26 (the 8q24 locus), C2orf80 (close to IDH), LRIG1, PHLDB1, ETFA, MAML2 and ZBTB16 were associated with IDH-mutant glioma. We therefore propose three etiopathological pathways in gliomagenesis based on germline variants for future guidance of diagnosis and potential functional targets for therapies. Future prospective clinical trials of patients with suspicion of glioma diagnoses, using the genetic variants as biomarkers, are necessary to disentangle how strongly they can predict glioma diagnosis. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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14 pages, 1514 KiB

Open AccessReview

Changes of O⁶-Methylguanine DNA Methyltransferase (MGMT) Promoter Methylation in Glioblastoma Relapse—A Meta-Analysis Type Literature Review

by Jonas Feldheim, Almuth F. Kessler, Camelia M. Monoranu, Ralf-Ingo Ernestus, Mario Löhr and Carsten Hagemann

Cancers 2019, 11(12), 1837; https://doi.org/10.3390/cancers11121837 - 21 Nov 2019

Cited by 39 | Viewed by 4742

Abstract

Methylation of the O⁶-methylguanine DNA methyltransferase (MGMT) promoter has emerged as strong prognostic factor in the therapy of glioblastoma multiforme. It is associated with an improved response to chemotherapy with temozolomide and longer overall survival. MGMT promoter methylation has implications for [...] Read more.

Methylation of the O⁶-methylguanine DNA methyltransferase (MGMT) promoter has emerged as strong prognostic factor in the therapy of glioblastoma multiforme. It is associated with an improved response to chemotherapy with temozolomide and longer overall survival. MGMT promoter methylation has implications for the clinical course of patients. In recent years, there have been observations of patients changing their MGMT promoter methylation from primary tumor to relapse. Still, data on this topic are scarce. Studies often consist of only few patients and provide rather contrasting results, making it hard to draw a clear conclusion on clinical implications. Here, we summarize the previous publications on this topic, add new cases of changing MGMT status in relapse and finally combine all reports of more than ten patients in a statistical analysis based on the Wilson score interval. MGMT promoter methylation changes are seen in 115 of 476 analyzed patients (24%; CI: 0.21–0.28). We discuss potential reasons like technical issues, intratumoral heterogeneity and selective pressure of therapy. The clinical implications are still ambiguous and do not yet support a change in clinical practice. However, retesting MGMT methylation might be useful for future treatment decisions and we encourage clinical studies to address this topic. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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17 pages, 1497 KiB

Open AccessReview

Genetically Engineered Mouse Models of Gliomas: Technological Developments for Translational Discoveries

by Imran Noorani

Cancers 2019, 11(9), 1335; https://doi.org/10.3390/cancers11091335 - 9 Sep 2019

Cited by 30 | Viewed by 5217

Abstract

The most common brain tumours, gliomas, have significant morbidity. Detailed biological and genetic understanding of these tumours is needed in order to devise effective, rational therapies. In an era generating unprecedented quantities of genomic sequencing data from human cancers, complementary methods of deciphering [...] Read more.

The most common brain tumours, gliomas, have significant morbidity. Detailed biological and genetic understanding of these tumours is needed in order to devise effective, rational therapies. In an era generating unprecedented quantities of genomic sequencing data from human cancers, complementary methods of deciphering the underlying functional cancer genes and mechanisms are becoming even more important. Genetically engineered mouse models of gliomas have provided a platform for investigating the molecular underpinning of this complex disease, and new tools for such models are emerging that are enabling us to answer the most important questions in the field. Here, I discuss improvements to genome engineering technologies that have led to more faithful mouse models resembling human gliomas, including new cre/LoxP transgenic lines that allow more accurate cell targeting of genetic recombination, Sleeping Beauty and piggyBac transposons for the integration of transgenes and genetic screens, and CRISPR-cas9 for generating genetic knockout and functional screens. Applications of these technologies are providing novel insights into the functional genetic drivers of gliomagenesis, how these genes cooperate with one another, and the potential cells-of-origin of gliomas, knowledge of which is critical to the development of targeted treatments for patients in the clinic. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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14 pages, 4548 KiB

Open AccessReview

Optimizing Neuro-Oncology Imaging: A Review of Deep Learning Approaches for Glioma Imaging

by Madeleine M. Shaver, Paul A. Kohanteb, Catherine Chiou, Michelle D. Bardis, Chanon Chantaduly, Daniela Bota, Christopher G. Filippi, Brent Weinberg, Jack Grinband, Daniel S. Chow and Peter D. Chang

Cancers 2019, 11(6), 829; https://doi.org/10.3390/cancers11060829 - 14 Jun 2019

Cited by 75 | Viewed by 7984

Abstract

Radiographic assessment with magnetic resonance imaging (MRI) is widely used to characterize gliomas, which represent 80% of all primary malignant brain tumors. Unfortunately, glioma biology is marked by heterogeneous angiogenesis, cellular proliferation, cellular invasion, and apoptosis. This translates into varying degrees of enhancement, [...] Read more.

Radiographic assessment with magnetic resonance imaging (MRI) is widely used to characterize gliomas, which represent 80% of all primary malignant brain tumors. Unfortunately, glioma biology is marked by heterogeneous angiogenesis, cellular proliferation, cellular invasion, and apoptosis. This translates into varying degrees of enhancement, edema, and necrosis, making reliable imaging assessment challenging. Deep learning, a subset of machine learning artificial intelligence, has gained traction as a method, which has seen effective employment in solving image-based problems, including those in medical imaging. This review seeks to summarize current deep learning applications used in the field of glioma detection and outcome prediction and will focus on (1) pre- and post-operative tumor segmentation, (2) genetic characterization of tissue, and (3) prognostication. We demonstrate that deep learning methods of segmenting, characterizing, grading, and predicting survival in gliomas are promising opportunities that may enhance both research and clinical activities. Full article

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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