Glioblastoma: State of the Art and Future Perspectives

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 December 2018) | Viewed by 245028

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Special Issue Editors

1. Department of Neurology & Interdisciplinary Neuro-Oncology, Hertie Institute for Clinical Brain Research, Center for Neuro-Oncology, Comprehensive Cancer Center, University Hospital Tübingen, Eberhard Karls University Tubingen, 72072 Tubingen, Germany
2. German Translational Cancer Consortium (DKTK), DKFZ Partner Site, 72072 Tubingen, Germany
3. Cluster of Excellence iFIT (EXC 2180) “Image Guided and Functionally Instructed Tumor Therapies”, Eberhard Karls University, 72072 Tubingen, Germany
Interests: tumors of the nervous system; acquired resistance to therapy; tumor-associated microenvironment; experimental glioma models; early phase clinical trials
Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02215, USA
Interests: neuro-oncology; glioblastoma; meningioma; oncolytic virus; herpes simplex virus; gene therapy
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Special Issue Information

Dear Colleagues,

Glioblastoma is one of the most common types of primary cancer in the central nervous system. Median overall survival is in the range of 1.5 years even in selected clinical trials populations. Many features contribute to this therapeutic challenge including high intratumoral and intertumoral heterogeneity, resistance to therapy, migration and invasion, immunosuppression. With the entry of novel highthroughput technologies, significant progress has been made to understand molecular and immunological signatures underlying the pathology of glioblastoma. Clinical trial designs have shifted from investigating broad “one-for-all” treatment approaches to precision oncology designs.

Here, we aim at updating researchers and clinicians to provide a systemic view on glioblastoma by highlighting the progress made in basic, preclinical and clinical research and outlining future challenges. To this end, we welcome articles on basic, preclinical and clinical research in glioblastoma. In addition, we will present invited review articles on the topics of neurosurgical approaches, neuropathology and genetics, preclinical research and mouse models of glioblastoma, imaging, radiation therapy and tumor-treating fields, alkylating chemotherapy, immunotherapy, investigational therapies and precision oncology trials in glioblastoma.

Prof. Dr. Ghazaleh Tabatabai
Dr. Hiroaki Wakimoto
Guest Editors

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Keywords

  • neurosurgical approaches
  • neuropathology and genetics
  • preclinical research in glioblastoma
  • mouse models of glioblastoma
  • imaging, radiation therapy of glioblastoma
  • tumor-treating fields
  • alkylating chemotherapy
  • immunotherapy
  • investigational therapies
  • precision oncology trials

Published Papers (45 papers)

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Editorial

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4 pages, 206 KiB  
Editorial
Glioblastoma: State of the Art and Future Perspectives
by Ghazaleh Tabatabai and Hiroaki Wakimoto
Cancers 2019, 11(8), 1091; https://doi.org/10.3390/cancers11081091 - 31 Jul 2019
Cited by 8 | Viewed by 3006
Abstract
This special issue is dedicated to glioblastoma and elucidates this disease from different perspectives [...] Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)

Research

Jump to: Editorial, Review, Other

13 pages, 2928 KiB  
Article
Glioma Stem-Like Cells Can Be Targeted in Boron Neutron Capture Therapy with Boronophenylalanine
by Natsuko Kondo, Masaki Hikida, Mitsutoshi Nakada, Yoshinori Sakurai, Eishu Hirata, Satoshi Takeno and Minoru Suzuki
Cancers 2020, 12(10), 3040; https://doi.org/10.3390/cancers12103040 - 19 Oct 2020
Cited by 10 | Viewed by 2970
Abstract
As glioma stem cells are chemo- and radio-resistant, they could be the origins of recurrent malignant glioma. Boron neutron capture therapy (BNCT) is a tumor-selective particle radiation therapy. 10B(n,α)7Li capture reaction produces alpha particles whose short paths (5–9 µm) lead [...] Read more.
As glioma stem cells are chemo- and radio-resistant, they could be the origins of recurrent malignant glioma. Boron neutron capture therapy (BNCT) is a tumor-selective particle radiation therapy. 10B(n,α)7Li capture reaction produces alpha particles whose short paths (5–9 µm) lead to selective killing of tumor cells. P-boronophenylalanine (BPA) is a chemical compound used in clinical trials for BNCT. Here, we used mass cytometry (Cytof) to investigate whether glioma stem-like cells (GSLCs) take up BPA or not. We used GSLCs, and cells differentiated from GSLCs (DCs) by fetal bovine serum. After exposure to BPA for 24 h at 25 ppm in 5% CO2 incubator, we immune-stained them with twenty stem cell markers, anti-Ki-67, anti-BPA and anti-CD98 (heterodimer that forms the large BPA transporter) antibodies and analyzed them with Cytof. The percentage of BPA+ or CD98+ cells with stem cell markers (Oct3/4, Nestin, SOX2, Musashi-1, PDGFRα, Notch2, Nanog, STAT3 and C-myc, among others) was 2–4 times larger among GSLCs than among DCs. Analyses of in vivo orthotopic tumor also indicated that 100% of SOX2+ or Nestin+ GSLCs were BPA+, whereas only 36.9% of glial fibrillary acidic protein (GFAP)+ DCs were BPA+. Therefore, GSLCs may take up BPA and could be targeted by BNCT. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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30 pages, 9548 KiB  
Article
Radiosensitization and a Less Aggressive Phenotype of Human Malignant Glioma Cells Expressing Isocitrate Dehydrogenase 1 (IDH1) Mutant Protein: Dissecting the Mechanisms
by Jacqueline Kessler, Tim Hohmann, Antje Güttler, Marina Petrenko, Christian Ostheimer, Urszula Hohmann, Matthias Bache, Faramarz Dehghani and Dirk Vordermark
Cancers 2019, 11(6), 889; https://doi.org/10.3390/cancers11060889 - 25 Jun 2019
Cited by 18 | Viewed by 4205
Abstract
The presence of an isocitrate dehydrogenase 1 (IDH1) mutation is associated with a less aggressive phenotype, increased sensitivity to radiation, and increased overall survival in patients with diffuse glioma. Based on in vitro experimentations in malignant glioma cell lines, the consequences on cellular [...] Read more.
The presence of an isocitrate dehydrogenase 1 (IDH1) mutation is associated with a less aggressive phenotype, increased sensitivity to radiation, and increased overall survival in patients with diffuse glioma. Based on in vitro experimentations in malignant glioma cell lines, the consequences on cellular processes of IDH1R132H expression were analyzed. The results revealed that IDH1R132H expression enhanced the radiation induced accumulation of residual γH2AX foci and decreased the amount of glutathione (GSH) independent of the oxygen status. In addition, expression of the mutant IDH1 caused a significant increase of cell stiffness and induced an altered organization of the cytoskeleton, which has been shown to reinforce cell stiffness. Furthermore, IDH1R132H expression decreased the expression of vimentin, an important component of the cytoskeleton and regulator of the cell stiffness. The results emphasize the important role of mutant IDH1 in treatment of patients with diffuse gliomas especially in response to radiation. Hence, detection of the genetic status of IDH1 before therapy massively expands the utility of immunohistochemistry to accurately distinguish patients with a less aggressive and radiosensitive IDH1-mutant diffuse glioma suitable for radiotherapy from those with a more aggressive IDH1-wildtype diffuse glioma who might benefit from an individually intensified therapy comprising radiotherapy and alternative medical treatments. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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16 pages, 2820 KiB  
Article
NMDA Receptor-Mediated Signaling Pathways Enhance Radiation Resistance, Survival and Migration in Glioblastoma Cells—A Potential Target for Adjuvant Radiotherapy
by Adriana Müller-Längle, Henrik Lutz, Stephanie Hehlgans, Franz Rödel, Kerstin Rau and Bodo Laube
Cancers 2019, 11(4), 503; https://doi.org/10.3390/cancers11040503 - 09 Apr 2019
Cited by 26 | Viewed by 4964
Abstract
Glioblastoma is one of the most aggressive malignant brain tumors, with a survival time less than 15 months and characterized by a high radioresistance and the property of infiltrating the brain. Recent data indicate that the malignancy of glioblastomas depends on glutamatergic signaling [...] Read more.
Glioblastoma is one of the most aggressive malignant brain tumors, with a survival time less than 15 months and characterized by a high radioresistance and the property of infiltrating the brain. Recent data indicate that the malignancy of glioblastomas depends on glutamatergic signaling via ionotropic glutamate receptors. In this study we revealed functional expression of Ca2+-permeable NMDARs in three glioblastoma cell lines. Therefore, we investigated the impact of this receptor on cell survival, migration and DNA double-strand break (DSB) repair in the presence of both, glutamate and NMDAR antagonists, and after clinically relevant doses of ionizing radiation. Our results indicate that treatment with NMDAR antagonists slowed the growth and migration of glutamate-releasing LN229 cells, suggesting that activation of NMDARs facilitate tumor expansion. Furthermore, we found that DSB-repair upon radiation was more effective in the presence of glutamate. In contrast, antagonizing the NMDAR or the Ca2+-dependent transcription factor CREB impaired DSB-repair similarly and resulted in a radiosensitizing effect in LN229 and U-87MG cells, indicating a common link between NMDAR signaling and CREB activity in glioblastoma. Since the FDA-approved NMDAR antagonists memantine and ifenprodil showed differential radiosensitizing effects, these compounds may constitute novel optimizations for therapeutic interventions in glioblastoma. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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14 pages, 3337 KiB  
Article
Proteomic Analysis Implicates Vimentin in Glioblastoma Cell Migration
by Michal O. Nowicki, Josie L. Hayes, E. Antonio Chiocca and Sean E. Lawler
Cancers 2019, 11(4), 466; https://doi.org/10.3390/cancers11040466 - 03 Apr 2019
Cited by 22 | Viewed by 4570
Abstract
We previously showed lithium chloride (LiCl) and other inhibitors of glycogen synthase kinase-3 (GSK-3) including 6-bromo-indirubin-3-oxime (BIO), can block glioblastoma (GBM) cell migration. To investigate the mechanisms involved we used two-dimensional difference in-gel electrophoresis (2D-DIGE) and mass spectrometry to identify proteins altered after [...] Read more.
We previously showed lithium chloride (LiCl) and other inhibitors of glycogen synthase kinase-3 (GSK-3) including 6-bromo-indirubin-3-oxime (BIO), can block glioblastoma (GBM) cell migration. To investigate the mechanisms involved we used two-dimensional difference in-gel electrophoresis (2D-DIGE) and mass spectrometry to identify proteins altered after treatment of U251 GBM cells with 20 mM LiCl. Downregulation of the intermediate filament protein vimentin was the most significant change identified. Analysis of patient tumor samples revealed that vimentin is expressed abundantly in GBM, and is prognostic especially in lower grade tumors. Additionally, siRNA-mediated vimentin knockdown impaired GBM migration. Western blotting showed that treatment with LiCl or small molecule GSK-3 inhibitors led to the rapid downregulation of detergent soluble vimentin levels across a panel of GBM-derived cells. Fluorescence reactivation after photobleaching (FRAP) microscopy studies showed a significant reduction in the ability of the vimentin cytoskeleton to recover from photo-bleaching in the presence of LiCl or BIO. Biochemical studies revealed that GSK-3 and vimentin directly interact, and analysis of vimentin revealed a GSK-3 consensus phosphorylation site. We conclude that anti-migratory compounds with the ability to inhibit GSK-3 have effects on vimentin cytoskeletal dynamics, which may play a role in their anti-invasive activity. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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26 pages, 7443 KiB  
Article
Dysregulation of Macropinocytosis Processes in Glioblastomas May Be Exploited to Increase Intracellular Anti-Cancer Drug Levels: The Example of Temozolomide
by Margaux Colin, Cédric Delporte, Rekin’s Janky, Anne-Sophie Lechon, Gwendoline Renard, Pierre Van Antwerpen, William A. Maltese and Véronique Mathieu
Cancers 2019, 11(3), 411; https://doi.org/10.3390/cancers11030411 - 22 Mar 2019
Cited by 22 | Viewed by 5570
Abstract
Macropinocytosis is a clathrin-independent endocytosis of extracellular fluid that may contribute to cancer aggressiveness through nutrient supply, recycling of plasma membrane and receptors, and exosome internalization. Macropinocytosis may be notably triggered by epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR), [...] Read more.
Macropinocytosis is a clathrin-independent endocytosis of extracellular fluid that may contribute to cancer aggressiveness through nutrient supply, recycling of plasma membrane and receptors, and exosome internalization. Macropinocytosis may be notably triggered by epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR), two well-known markers for glioblastoma aggressiveness. Therefore, we studied whether the expression of key actors of macropinocytosis is modified in human glioma datasets. Strong deregulation has been evidenced at the mRNA level according to the grade of the tumor, and 38 macropinocytosis-related gene signatures allowed discrimination of the glioblastoma (GBM) samples. Honokiol-induced vacuolization was then compared to vacquinol-1 and MOMIPP, two known macropinocytosis inducers. Despite high phase-contrast morphological similarities, honokiol-induced vacuoles appeared to originate from both endocytosis and ER. Also, acridine orange staining suggested differences in the macropinosomes’ fate: their fusion with lysosomes appeared very limited in 3-(5-methoxy -2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one (MOMIPP)-treated cells. Nevertheless, each of the compounds markedly increased temozolomide uptake by glioma cells, as evidenced by LC-MS. In conclusion, the observed deregulation of macropinocytosis in GBM makes them prone to respond to various compounds affecting their formation and/or intracellular fate. Considering that sustained macropinocytosis may also trigger cell death of both sensitive and resistant GBM cells, we propose to envisage macropinocytosis inducers in combination approaches to obtain dual benefits: increased drug uptake and additive/synergistic effects. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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27 pages, 11879 KiB  
Article
The Small Molecule Ephrin Receptor Inhibitor, GLPG1790, Reduces Renewal Capabilities of Cancer Stem Cells, Showing Anti-Tumour Efficacy on Preclinical Glioblastoma Models
by Giovanni Luca Gravina, Andrea Mancini, Alessandro Colapietro, Simona Delle Monache, Roberta Sferra, Flora Vitale, Loredana Cristiano, Stefano Martellucci, Francesco Marampon, Vincenzo Mattei, Filip Beirinckx, Philippe Pujuguet, Laurent Saniere, Giocondo Lorenzon, Ellen van der Aar and Claudio Festuccia
Cancers 2019, 11(3), 359; https://doi.org/10.3390/cancers11030359 - 13 Mar 2019
Cited by 39 | Viewed by 5550
Abstract
Therapies against glioblastoma (GBM) show a high percentage of failure associated with the survival of glioma stem cells (GSCs) that repopulate treated tumours. Forced differentiation of GSCs is a promising new approach in cancer treatment. Erythropoietin-producing hepatocellular (Eph) receptors drive tumourigenicity and stemness [...] Read more.
Therapies against glioblastoma (GBM) show a high percentage of failure associated with the survival of glioma stem cells (GSCs) that repopulate treated tumours. Forced differentiation of GSCs is a promising new approach in cancer treatment. Erythropoietin-producing hepatocellular (Eph) receptors drive tumourigenicity and stemness in GBM. We tested GLPG1790, a first small molecule with inhibition activity versus inhibitor of various Eph receptor kinases, in preclinical GBM models using in vitro and in vivo assays. GLPG1790 rapidly and persistently inhibited Ephrin-A1-mediated phosphorylation of Tyr588 and Ser897, completely blocking EphA2 receptor signalling. Similarly, this compound blocks the ephrin B2-mediated EphA3 and EphB4 tyrosine phosphorylation. This resulted in anti-glioma effects. GLPG1790 down-modulated the expression of mesenchymal markers CD44, Sox2, nestin, octamer-binding transcription factor 3/4 (Oct3/4), Nanog, CD90, and CD105, and up-regulated that of glial fibrillary acidic protein (GFAP) and pro-neural/neuronal markers, βIII tubulin, and neurofilaments. GLPG1790 reduced tumour growth in vivo. These effects were larger compared to radiation therapy (RT; U251 and T98G xenografts) and smaller than those of temozolomide (TMZ; U251 and U87MG cell models). By contrast, GLPG1790 showed effects that were higher than Radiotherapy (RT) and similar to Temozolomide (TMZ) in orthotopic U87MG and CSCs-5 models in terms of disease-free survival (DFS) and overall survival (OS). Further experiments were necessary to study possible interactions with radio- and chemotherapy. GLPG1790 demonstrated anti-tumor effects regulating both the differentiative status of Glioma Initiating Cells (GICs) and the quality of tumor microenvironment, translating into efficacy in aggressive GBM mouse models. Significant common molecular targets to radio and chemo therapy supported the combination use of GLPG1790 in ameliorative antiglioma therapy. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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17 pages, 3329 KiB  
Article
Novel Curcumin Inspired Bis-Chalcone Promotes Endoplasmic Reticulum Stress and Glioblastoma Neurosphere Cell Death
by Lorenzo Sansalone, Eduardo A. Veliz, Nadia G. Myrthil, Vasileios Stathias, Winston Walters, Ingrid I. Torrens, Stephan C. Schürer, Steven Vanni, Roger M. Leblanc and Regina M. Graham
Cancers 2019, 11(3), 357; https://doi.org/10.3390/cancers11030357 - 13 Mar 2019
Cited by 25 | Viewed by 5671
Abstract
Glioblastoma (GBM) has a dismal prognosis and successful elimination of GBM stem cells (GSCs) is a high-priority as these cells are responsible for tumor regrowth following therapy and ultimately patient relapse. Natural products and their derivatives continue to be a source for the [...] Read more.
Glioblastoma (GBM) has a dismal prognosis and successful elimination of GBM stem cells (GSCs) is a high-priority as these cells are responsible for tumor regrowth following therapy and ultimately patient relapse. Natural products and their derivatives continue to be a source for the development of effective anticancer drugs and have been shown to effectively target pathways necessary for cancer stem cell self-renewal and proliferation. We generated a series of curcumin inspired bis-chalcones and examined their effect in multiple patient-derived GSC lines. Of the 19 compounds synthesized, four analogs robustly induced GSC death in six separate GSC lines, with a half maximal inhibitory concentration (IC50) ranging from 2.7–5.8 μM and significantly reduced GSC neurosphere formation at sub-cytotoxic levels. Structural analysis indicated that the presence of a methoxy group at position 3 of the lateral phenylic appendages was important for activity. Pathway and drug connectivity analysis of gene expression changes in response to treatment with the most active bis-chalcone 4j (the 3,4,5 trimethoxy substituted analog) suggested that the mechanism of action was the induction of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) mediated cell death. This was confirmed by Western blot analysis in which 4j induced robust increases in CHOP, p-jun and caspase 12. The UPR is believed to play a significant role in GBM pathogenesis and resistance to therapy and as such represents a promising therapeutic target. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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22 pages, 8300 KiB  
Article
Arsenic Trioxide and (−)-Gossypol Synergistically Target Glioma Stem-Like Cells via Inhibition of Hedgehog and Notch Signaling
by Benedikt Linder, Andrej Wehle, Stephanie Hehlgans, Florian Bonn, Ivan Dikic, Franz Rödel, Volker Seifert and Donat Kögel
Cancers 2019, 11(3), 350; https://doi.org/10.3390/cancers11030350 - 12 Mar 2019
Cited by 29 | Viewed by 4472
Abstract
Glioblastoma is one of the deadliest malignancies and is virtually incurable. Accumulating evidence indicates that a small population of cells with a stem-like phenotype is the major culprit of tumor recurrence. Enhanced DNA repair capacity and expression of stemness marker genes are the [...] Read more.
Glioblastoma is one of the deadliest malignancies and is virtually incurable. Accumulating evidence indicates that a small population of cells with a stem-like phenotype is the major culprit of tumor recurrence. Enhanced DNA repair capacity and expression of stemness marker genes are the main characteristics of these cells. Elimination of this population might delay or prevent tumor recurrence following radiochemotherapy. The aim of this study was to analyze whether interference with the Hedgehog signaling (Hh) pathway or combined Hh/Notch blockade using small-molecule inhibitors can efficiently target these cancer stem cells and sensitize them to therapy. Using tumor sphere lines and primary patient-derived glioma cultures we demonstrate that the Hh pathway inhibitor GANT61 (GANT) and the arsenic trioxide (ATO)-mediated Hh/Notch inhibition are capable to synergistically induce cell death in combination with the natural anticancer agent (−)-Gossypol (Gos). Only ATO in combination with Gos also strongly decreased stemness marker expression and prevented sphere formation and recovery. These synergistic effects were associated with distinct proteomic changes indicating diminished DNA repair and markedly reduced stemness. Finally, using an organotypic brain slice transplantation model, we show that combined ATO/Gos treatment elicits strong growth inhibition or even complete elimination of tumors. Collectively, our data show for the first time that ATO and Gos, two drugs that can be used in the clinic, represent a promising targeted therapy approach for the synergistic elimination of glioma stem-like cells. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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29 pages, 8810 KiB  
Article
Synergistic Effects of Bortezomib-OV Therapy and Anti-Invasive Strategies in Glioblastoma: A Mathematical Model
by Yangjin Kim, Junho Lee, Donggu Lee and Hans G. Othmer
Cancers 2019, 11(2), 215; https://doi.org/10.3390/cancers11020215 - 13 Feb 2019
Cited by 11 | Viewed by 4294
Abstract
It is well-known that the tumor microenvironment (TME) plays an important role in the regulation of tumor growth and the efficacy of anti-tumor therapies. Recent studies have demonstrated the potential of combination therapies, using oncolytic viruses (OVs) in conjunction with proteosome inhibitors for [...] Read more.
It is well-known that the tumor microenvironment (TME) plays an important role in the regulation of tumor growth and the efficacy of anti-tumor therapies. Recent studies have demonstrated the potential of combination therapies, using oncolytic viruses (OVs) in conjunction with proteosome inhibitors for the treatment of glioblastoma, but the role of the TME in such therapies has not been studied. In this paper, we develop a mathematical model for combination therapies based on the proteosome inhibitor bortezomib and the oncolytic herpes simplex virus (oHSV), with the goal of understanding their roles in bortezomib-induced endoplasmic reticulum (ER) stress, and how the balance between apoptosis and necroptosis is affected by the treatment protocol. We show that the TME plays a significant role in anti-tumor efficacy in OV combination therapy, and illustrate the effect of different spatial patterns of OV injection. The results illustrate a possible phenotypic switch within tumor populations in a given microenvironment, and suggest new anti-invasion therapies. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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12 pages, 2215 KiB  
Article
CircSMARCA5 Regulates VEGFA mRNA Splicing and Angiogenesis in Glioblastoma Multiforme Through the Binding of SRSF1
by Davide Barbagallo, Angela Caponnetto, Duilia Brex, Federica Mirabella, Cristina Barbagallo, Giovanni Lauretta, Antonio Morrone, Francesco Certo, Giuseppe Broggi, Rosario Caltabiano, Giuseppe M. Barbagallo, Vittoria Spina-Purrello, Marco Ragusa, Cinzia Di Pietro, Thomas B. Hansen and Michele Purrello
Cancers 2019, 11(2), 194; https://doi.org/10.3390/cancers11020194 - 07 Feb 2019
Cited by 138 | Viewed by 5602
Abstract
Circular RNAs are a large group of RNAs whose cellular functions are still being investigated. We recently proposed that circSMARCA5 acts as sponge for the splicing factor Serine and Arginine Rich Splicing Factor 1 (SRSF1) in glioblastoma multiforme (GBM). After demonstrating by RNA [...] Read more.
Circular RNAs are a large group of RNAs whose cellular functions are still being investigated. We recently proposed that circSMARCA5 acts as sponge for the splicing factor Serine and Arginine Rich Splicing Factor 1 (SRSF1) in glioblastoma multiforme (GBM). After demonstrating by RNA immunoprecipitation a physical interaction between SRFS1 and circSMARCA5, we assayed by real-time PCR in a cohort of 31 GBM biopsies and 20 unaffected brain parenchyma controls (UC) the expression of total, pro-angiogenic (Iso8a) and anti-angiogenic (Iso8b) mRNA isoforms of Vascular Endothelial Growth Factor A (VEGFA), a known splicing target of SRSF1. The Iso8a to Iso8b ratio: (i) increased in GBM biopsies with respect to UC (p-value < 0.00001); (ii) negatively correlated with the expression of circSMARCA5 (r-value = −0.46, p-value = 0.006); (iii) decreased in U87-MG overexpressing circSMARCA5 with respect to negative control (p-value = 0.0055). Blood vascular microvessel density, estimated within the same biopsies, negatively correlated with the expression of circSMARCA5 (r-value = −0.59, p-value = 0.00001), while positively correlated with that of SRSF1 (r-value = 0.38, p-value = 0.00663) and the Iso8a to Iso8b ratio (r-value = 0.41, p-value = 0.0259). Kaplan-Meier survival analysis showed that GBM patients with low circSMARCA5 expression had lower overall and progression free survival rates than those with higher circSMARCA5 expression (p-values = 0.033, 0.012, respectively). Our data convincingly suggest that circSMARCA5 is an upstream regulator of pro- to anti-angiogenic VEGFA isoforms ratio within GBM cells and a highly promising GBM prognostic and prospective anti-angiogenic molecule. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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17 pages, 4768 KiB  
Article
Intratumoural Heterogeneity Underlies Distinct Therapy Responses and Treatment Resistance in Glioblastoma
by Seçkin Akgül, Ann-Marie Patch, Rochelle C.J. D’Souza, Pamela Mukhopadhyay, Katia Nones, Sarah Kempe, Stephen H. Kazakoff, Rosalind L. Jeffree, Brett W. Stringer, John V. Pearson, Nicola Waddell and Bryan W. Day
Cancers 2019, 11(2), 190; https://doi.org/10.3390/cancers11020190 - 06 Feb 2019
Cited by 36 | Viewed by 5413
Abstract
Glioblastomas are the most common and lethal neoplasms of the central nervous system. Neighbouring glioma cells maintain extreme degrees of genetic and phenotypic variation that form intratumoural heterogeneity. This genetic diversity allows the most adaptive tumour clones to develop treatment resistance, ultimately leading [...] Read more.
Glioblastomas are the most common and lethal neoplasms of the central nervous system. Neighbouring glioma cells maintain extreme degrees of genetic and phenotypic variation that form intratumoural heterogeneity. This genetic diversity allows the most adaptive tumour clones to develop treatment resistance, ultimately leading to disease recurrence. We aimed to model this phenomenon and test the effectiveness of several targeted therapeutic interventions to overcome therapy resistance. Heterogeneous tumour masses were first deconstructed into single tumour cells, which were expanded independently as single-cell clones. Single nucleotide polymorphism arrays, whole-genome and RNA sequencing, and CpG methylation analysis validated the unique molecular profile of each tumour clone, which displayed distinct pathologic features, including cell morphology, growth rate, and resistance to temozolomide and ionizing radiation. We also identified variable sensitivities to AURK, CDK, and EGFR inhibitors which were consistent with the heterogeneous molecular alterations that each clone harboured. These targeted therapies effectively eliminated the temozolomide- and/or irradiation-resistant clones and also parental polyclonal cells. Our findings indicate that polyclonal tumours create a dynamic environment that consists of diverse tumour elements and treatment responses. Designing targeted therapies based on a range of molecular profiles can be a more effective strategy to eradicate treatment resistance, recurrence, and metastasis. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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12 pages, 1509 KiB  
Article
Mining-Guided Machine Learning Analyses Revealed the Latest Trends in Neuro-Oncology
by Taijun Hana, Shota Tanaka, Takahide Nejo, Satoshi Takahashi, Yosuke Kitagawa, Tsukasa Koike, Masashi Nomura, Shunsaku Takayanagi and Nobuhito Saito
Cancers 2019, 11(2), 178; https://doi.org/10.3390/cancers11020178 - 03 Feb 2019
Cited by 8 | Viewed by 3812
Abstract
In conducting medical research, a system which can objectively predict the future trends of the given research field is awaited. This study aims to establish a novel and versatile algorithm that predicts the latest trends in neuro-oncology. Seventy-nine neuro-oncological research fields were selected [...] Read more.
In conducting medical research, a system which can objectively predict the future trends of the given research field is awaited. This study aims to establish a novel and versatile algorithm that predicts the latest trends in neuro-oncology. Seventy-nine neuro-oncological research fields were selected with computational sorting methods such as text-mining analyses. Thirty journals that represent the recent trends in neuro-oncology were also selected. As a novel concept, the annual impact (AI) of each year was calculated for each journal and field (number of articles published in the journal × impact factor of the journal). The AI index (AII) for the year was defined as the sum of the AIs of the 30 journals. The AII trends of the 79 fields from 2008 to 2017 were subjected to machine learning predicting analyses. The accuracy of the predictions was validated using actual past data. With this algorithm, the latest trends in neuro-oncology were predicted. As a result, the linear prediction model achieved relatively good accuracy. The predicted hottest fields in recent neuro-oncology included some interesting emerging fields such as microenvironment and anti-mitosis. This algorithm may be an effective and versatile tool for prediction of future trends in a particular medical field. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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17 pages, 3598 KiB  
Article
Targeting Glioblastoma Stem Cells with 2-Deoxy-D-Glucose (2-DG) Potentiates Radiation-Induced Unfolded Protein Response (UPR)
by Sumedh S. Shah, Gregor A. Rodriguez, Alexis Musick, Winston M. Walters, Nicolas de Cordoba, Eric Barbarite, Megan M. Marlow, Brian Marples, Jeffrey S. Prince, Ricardo J. Komotar, Steven Vanni and Regina M. Graham
Cancers 2019, 11(2), 159; https://doi.org/10.3390/cancers11020159 - 31 Jan 2019
Cited by 37 | Viewed by 5945
Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, and despite optimized treatment options, median survival remains dismal. Contemporary evidence suggests disease recurrence results from expansion of a robustly radioresistant subset of GBM progenitor cells, termed GBM stem cells [...] Read more.
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, and despite optimized treatment options, median survival remains dismal. Contemporary evidence suggests disease recurrence results from expansion of a robustly radioresistant subset of GBM progenitor cells, termed GBM stem cells (GSCs). In this study, we utilized transmission electron microscopy to uncover ultrastructural effects on patient-derived GSC lines exposed to supratherapeutic radiotherapy levels. Elevated autophagosome formation and increased endoplasmic reticulum (ER) internal diameter, a surrogate for ER stress and activation of unfolded protein response (UPR), was uncovered. These observations were confirmed via protein expression through Western blot. Upon interrogating genomic data from an open-access GBM patient database, overexpression of UPR-related chaperone protein genes was inversely correlated with patient survival. This indicated controlled UPR may play a role in promoting radioresistance. To determine if potentiating UPR further can induce apoptosis, we exposed GSCs to radiation with an ER stress-inducing drug, 2-deoxy-D-glucose (2-DG), and found dose-dependent decreases in viability and increased apoptotic marker expression. Taken together, our results indicate GSC radioresistance is, in part, achieved by overexpression and overactivation of ER stress-related pathways, and this effect can be overcome via potentiation of UPR, leading to loss of GSC viability. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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17 pages, 3257 KiB  
Article
PKA at a Cross-Road of Signaling Pathways Involved in the Regulation of Glioblastoma Migration and Invasion by the Neuropeptides VIP and PACAP
by Souheyla Bensalma, Soumaya Turpault, Annie-Claire Balandre, Madryssa De Boisvilliers, Afsaneh Gaillard, Corinne Chadéneau and Jean-Marc Muller
Cancers 2019, 11(1), 123; https://doi.org/10.3390/cancers11010123 - 21 Jan 2019
Cited by 13 | Viewed by 4640
Abstract
Glioblastoma (GBM) remains an incurable disease, mainly due to the high migration and invasion potency of GBM cells inside the brain. PI3K/Akt, Sonic Hedgehog (SHH), and PKA pathways play major regulatory roles in the progression of GBM. The vasoactive intestinal peptide (VIP) family [...] Read more.
Glioblastoma (GBM) remains an incurable disease, mainly due to the high migration and invasion potency of GBM cells inside the brain. PI3K/Akt, Sonic Hedgehog (SHH), and PKA pathways play major regulatory roles in the progression of GBM. The vasoactive intestinal peptide (VIP) family of neuropeptides and their receptors, referred in this article as the “VIP-receptor system”, has been reported to regulate proliferation, differentiation, and migration in a number of tumor cell types and more particularly in GBM cells. These neuropeptides are potent activators of the cAMP/PKA pathway. The present study aimed to investigate the cross-talks between the above cited signaling cascades. Regulation by VIP-related neuropeptides of GBM migration and invasion was evaluated ex vivo in rat brain slices explanted in culture. Effects of different combinations of VIP-related neuropeptides and of pharmacological and siRNA inhibitors of PKA, Akt, and of the SHH/GLI1 pathways were tested on GBM migration rat C6 and human U87 GBM cell lines using the wound-healing technique. Quantification of nuclear GLI1, phospho-Akt, and phospho-PTEN was assessed by western-immunoblotting. The VIP-receptor system agonists VIP and PACAP-38 significantly reduced C6 cells invasion in the rat brain parenchyma ex vivo, and C6 and U87 migration in vitro. A VIP-receptor system antagonist, VIP10-28 increased C6 cell invasion in the rat brain parenchyma ex vivo, and C6 and migration in vitro. These effects on cell migration were abolished by selective inhibitors of the PI3K/Akt and of the SHH pathways. Furthermore, VIP and PACAP-38 reduced the expression of nuclear GLI1 while VIP10-28 increased this expression. Selective inhibitors of Akt and PKA abolished VIP, PACAP-38, and VIP10-28 effects on nuclear GLI1 expression in C6 cells. PACAP-38 induced a time-dependent inhibition of phospho-Akt expression and an increased phosphorylation of PTEN in C6 cells. All together, these data indicate that triggering the VIP-receptor system reduces migration and invasion in GBM cells through a PKA-dependent blockade of the PI3K/Akt and of the SHH/GLI1 pathways. Therefore, the VIP-receptor system displays anti-oncogenic properties in GBM cells and PKA is a central core in this process. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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17 pages, 1680 KiB  
Article
Location-Dependent Patient Outcome and Recurrence Patterns in IDH1-Wildtype Glioblastoma
by Christine Jungk, Rolf Warta, Andreas Mock, Sara Friauf, Bettina Hug, David Capper, Amir Abdollahi, Jürgen Debus, Martin Bendszus, Andreas von Deimling, Andreas Unterberg and Christel Herold-Mende
Cancers 2019, 11(1), 122; https://doi.org/10.3390/cancers11010122 - 21 Jan 2019
Cited by 25 | Viewed by 4485
Abstract
Recent studies suggest that glioblastomas (GBMs) contacting the subventricular zone (SVZ) as the main adult neurogenic niche confer a dismal prognosis but disregard the unique molecular and prognostic phenotype associated with isocitrate dehydrogenase 1 (IDH1) mutations. We therefore examined location-dependent prognostic factors, growth, [...] Read more.
Recent studies suggest that glioblastomas (GBMs) contacting the subventricular zone (SVZ) as the main adult neurogenic niche confer a dismal prognosis but disregard the unique molecular and prognostic phenotype associated with isocitrate dehydrogenase 1 (IDH1) mutations. We therefore examined location-dependent prognostic factors, growth, and recurrence patterns in a consecutive cohort of 285 IDH1-wildtype GBMs. Based on pre-operative contrast-enhanced MRI, patients were allotted to four location-dependent groups with (SVZ+; groups I, II) and without (SVZ−; groups III, IV) SVZ involvement or with (cortex+; groups I, III) and without (cortex−; groups II, IV) cortical involvement and compared for demographic, treatment, imaging, and survival data at first diagnosis and recurrence. SVZ involvement was associated with lower Karnofsky performance score (p < 0.001), lower frequency of complete resections at first diagnosis (p < 0.0001), and lower non-surgical treatment intensity at recurrence (p < 0.001). Multivariate survival analysis employing a Cox proportional hazards model identified SVZ involvement as an independent prognosticator of inferior overall survival (p < 0.001) and survival after relapse (p = 0.041). In contrast, multifocal growth at first diagnosis (p = 0.031) and recurrence (p < 0.001), as well as distant recurrences (p < 0.0001), was more frequent in cortex+ GBMs. These findings offer the prospect for location-tailored prognostication and treatment based on factors assessable on pre-operative MRI. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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12 pages, 2355 KiB  
Article
The Oncogene Addiction Switch from NOTCH to PI3K Requires Simultaneous Targeting of NOTCH and PI3K Pathway Inhibition in Glioblastoma
by Norihiko Saito, Nozomi Hirai, Kazuya Aoki, Ryo Suzuki, Satoshi Fujita, Haruo Nakayama, Morito Hayashi, Keisuke Ito, Takatoshi Sakurai and Satoshi Iwabuchi
Cancers 2019, 11(1), 121; https://doi.org/10.3390/cancers11010121 - 20 Jan 2019
Cited by 15 | Viewed by 4598
Abstract
The NOTCH pathway regulates neural stem cells and glioma initiating cells (GICs). However, blocking NOTCH activity with γ-secretase inhibitors (GSIs) fails to alter the growth of GICs, as GSIs seem to be active in only a fraction of GICs lines with constitutive NOTCH [...] Read more.
The NOTCH pathway regulates neural stem cells and glioma initiating cells (GICs). However, blocking NOTCH activity with γ-secretase inhibitors (GSIs) fails to alter the growth of GICs, as GSIs seem to be active in only a fraction of GICs lines with constitutive NOTCH activity. Here we report loss of PTEN function as a critical event leading to resistance to NOTCH inhibition, which causes the transfer of oncogene addiction from the NOTCH pathway to the PI3K pathway. Drug cytotoxicity testing of eight GICs showed a differential growth response to GSI, and the GICs were thus stratified into two groups: sensitive and resistant. In the sensitive group, GICs with loss of PTEN function appeared less sensitive to GSI treatment. Here we show that NOTCH regulates PTEN expression and the activity of the PI3K pathway in GICs, as treatment with GSI attenuated the NOTCH pathway and increased PTEN expression. NOTCH regulates PTEN expression via Hes-1, as knockdown of Notch or Hes1 increased expression of PTEN. This novel observation suggests that both pathways must be simultaneously inhibited in order to improve therapeutic efficacy in human glioblastomas (GBMs). Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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17 pages, 3919 KiB  
Article
Macrovascular Networks on Contrast-Enhanced Magnetic Resonance Imaging Improves Survival Prediction in Newly Diagnosed Glioblastoma
by Josep Puig, Carles Biarnés, Pepus Daunis-i-Estadella, Gerard Blasco, Alfredo Gimeno, Marco Essig, Carme Balaña, Angel Alberich-Bayarri, Ana Jimenez-Pastor, Eduardo Camacho, Santiago Thio-Henestrosa, Jaume Capellades, Javier Sanchez-Gonzalez, Marian Navas-Martí, Blanca Domenech-Ximenos, Sonia Del Barco, Montserrat Puigdemont, Carlos Leiva-Salinas, Max Wintermark, Kambiz Nael, Rajan Jain and Salvador Pedrazaadd Show full author list remove Hide full author list
Cancers 2019, 11(1), 84; https://doi.org/10.3390/cancers11010084 - 14 Jan 2019
Cited by 4 | Viewed by 5737
Abstract
A higher degree of angiogenesis is associated with shortened survival in glioblastoma. Feasible morphometric parameters for analyzing vascular networks in brain tumors in clinical practice are lacking. We investigated whether the macrovascular network classified by the number of vessel-like structures (nVS) visible on [...] Read more.
A higher degree of angiogenesis is associated with shortened survival in glioblastoma. Feasible morphometric parameters for analyzing vascular networks in brain tumors in clinical practice are lacking. We investigated whether the macrovascular network classified by the number of vessel-like structures (nVS) visible on three-dimensional T1-weighted contrast–enhanced (3D-T1CE) magnetic resonance imaging (MRI) could improve survival prediction models for newly diagnosed glioblastoma based on clinical and other imaging features. Ninety-seven consecutive patients (62 men; mean age, 58 ± 15 years) with histologically proven glioblastoma underwent 1.5T-MRI, including anatomical, diffusion-weighted, dynamic susceptibility contrast perfusion, and 3D-T1CE sequences after 0.1 mmol/kg gadobutrol. We assessed nVS related to the tumor on 1-mm isovoxel 3D-T1CE images, and relative cerebral blood volume, relative cerebral flow volume (rCBF), delay mean time, and apparent diffusion coefficient in volumes of interest for contrast-enhancing lesion (CEL), non-CEL, and contralateral normal-appearing white matter. We also assessed Visually Accessible Rembrandt Images scoring system features. We used ROC curves to determine the cutoff for nVS and univariate and multivariate cox proportional hazards regression for overall survival. Prognostic factors were evaluated by Kaplan-Meier survival and ROC analyses. Lesions with nVS > 5 were classified as having highly developed macrovascular network; 58 (60.4%) tumors had highly developed macrovascular network. Patients with highly developed macrovascular network were older, had higher volumeCEL, increased rCBFCEL, and poor survival; nVS correlated negatively with survival (r = −0.286; p = 0.008). On multivariate analysis, standard treatment, age at diagnosis, and macrovascular network best predicted survival at 1 year (AUC 0.901, 83.3% sensitivity, 93.3% specificity, 96.2% PPV, 73.7% NPV). Contrast-enhanced MRI macrovascular network improves survival prediction in newly diagnosed glioblastoma. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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15 pages, 702 KiB  
Article
Prognostic Gene Discovery in Glioblastoma Patients using Deep Learning
by Kelvin K. Wong, Robert Rostomily and Stephen T. C. Wong
Cancers 2019, 11(1), 53; https://doi.org/10.3390/cancers11010053 - 08 Jan 2019
Cited by 37 | Viewed by 6064
Abstract
This study aims to discover genes with prognostic potential for glioblastoma (GBM) patients’ survival in a patient group that has gone through standard of care treatments including surgeries and chemotherapies, using tumor gene expression at initial diagnosis before treatment. The Cancer Genome Atlas [...] Read more.
This study aims to discover genes with prognostic potential for glioblastoma (GBM) patients’ survival in a patient group that has gone through standard of care treatments including surgeries and chemotherapies, using tumor gene expression at initial diagnosis before treatment. The Cancer Genome Atlas (TCGA) GBM gene expression data are used as inputs to build a deep multilayer perceptron network to predict patient survival risk using partial likelihood as loss function. Genes that are important to the model are identified by the input permutation method. Univariate and multivariate Cox survival models are used to assess the predictive value of deep learned features in addition to clinical, mutation, and methylation factors. The prediction performance of the deep learning method was compared to other machine learning methods including the ridge, adaptive Lasso, and elastic net Cox regression models. Twenty-seven deep-learned features are extracted through deep learning to predict overall survival. The top 10 ranked genes with the highest impact on these features are related to glioblastoma stem cells, stem cell niche environment, and treatment resistance mechanisms, including POSTN, TNR, BCAN, GAD1, TMSB15B, SCG3, PLA2G2A, NNMT, CHI3L1 and ELAVL4. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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12 pages, 1782 KiB  
Article
Epilepsy Associates with Decreased HIF-1α/STAT5b Signaling in Glioblastoma
by Sharon Berendsen, Wim G. M. Spliet, Marjolein Geurts, Wim Van Hecke, Tatjana Seute, Tom J. Snijders, Vincent Bours, Erica H. Bell, Arnab Chakravarti and Pierre A. Robe
Cancers 2019, 11(1), 41; https://doi.org/10.3390/cancers11010041 - 04 Jan 2019
Cited by 12 | Viewed by 3678
Abstract
Epilepsy at presentation is an independent favorable prognostic factor in glioblastoma (GBM). In this study, we analyze the oncologic signaling pathways that associate with epilepsy in human GBMs, and that can underlie this prognostic effect. Following ethical approval and patient consent, fresh frozen [...] Read more.
Epilepsy at presentation is an independent favorable prognostic factor in glioblastoma (GBM). In this study, we analyze the oncologic signaling pathways that associate with epilepsy in human GBMs, and that can underlie this prognostic effect. Following ethical approval and patient consent, fresh frozen GBM tissue was obtained from 76 patient surgeries. Hospital records were screened for the presence of seizures at presentation of the disease. mRNA and miRNA expression-based and gene set enrichment analyses were performed on these tissues, to uncover candidate oncologic pathways that associate with epilepsy. We performed qPCR experiments and immunohistochemistry on tissue microarrays containing 286 GBMs to further explore the association of these candidate pathways and of markers of mesenchymal transformation (NF-κB, CEBP-β, STAT3, STAT5b, VEGFA, SRF) with epilepsy. Gene sets involved in hypoxia/HIF-1α, STAT5, CEBP-β and epithelial-mesenchymal transformation signaling were significantly downregulated in epileptogenic GBMs. On confirmatory protein expression analyses, epileptogenic tumors were characterized by a significant downregulation of phospho-STAT5b, a target of HIF-1α. Epilepsy status did not associate with molecular subclassification or miRNA expression patterns of the tumors. Epileptogenic GBMs correlate with decreased hypoxia/ HIF-1α/STAT5b signaling compared to glioblastomas that do not present with epilepsy. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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15 pages, 3436 KiB  
Article
Mifepristone Overcomes Tumor Resistance to Temozolomide Associated with DNA Damage Repair and Apoptosis in an Orthotopic Model of Glioblastoma
by Monserrat Llaguno-Munive, Mario Romero-Piña, Janeth Serrano-Bello, Luis A. Medina, Norma Uribe-Uribe, Ana Maria Salazar, Mauricio Rodríguez-Dorantes and Patricia Garcia-Lopez
Cancers 2019, 11(1), 16; https://doi.org/10.3390/cancers11010016 - 22 Dec 2018
Cited by 14 | Viewed by 4850
Abstract
The standard treatment for glioblastoma multiforme (GBM) is surgery followed by chemo/radiotherapy. A major limitation on patient improvement is the high resistance of tumors to drug treatment, likely responsible for their subsequent recurrence and rapid progression. Therefore, alternatives to the standard therapy are [...] Read more.
The standard treatment for glioblastoma multiforme (GBM) is surgery followed by chemo/radiotherapy. A major limitation on patient improvement is the high resistance of tumors to drug treatment, likely responsible for their subsequent recurrence and rapid progression. Therefore, alternatives to the standard therapy are necessary. The aim of the present study was to evaluate whether mifepristone, an antihormonal agent, has a synergistic effect with temozolomide (used in standard therapy for gliomas). Whereas the mechanism of temozolomide involves damage to tumor DNA leading to apoptosis, tumor resistance is associated with DNA damage repair through the O6-methylguanine-DNA-methyltransferase (MGMT) enzyme. Temozolomide/mifepristone treatment, herein examined in Wistar rats after orthotopically implanting C6 glioma cells, markedly reduced proliferation. This was evidenced by a decreased level of the following parameters: a proliferation marker (Ki-67), a tumor growth marker (18F-fluorothymidine uptake, determined by PET/CT images), and the MGMT enzyme. Increased apoptosis was detected by the relative expression of related proteins, (e.g. Bcl-2 (B-cell lymphoma 2), Bax (bcl-2-like protein 4) and caspase-3). Thus, greater apoptosis of tumor cells caused by their diminished capacity to repair DNA probably contributed significantly to the enhanced activity of temozolomide. The results suggest that mifepristone could possibly act as a chemo-sensitizing agent for temozolomide during chemotherapy for GBM. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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28 pages, 11017 KiB  
Article
A New Patient-Derived Metastatic Glioblastoma Cell Line: Characterisation and Response to Sodium Selenite Anticancer Agent
by Sylvie Berthier, Louis Larrouquère, Pierre Champelovier, Edwige Col, Christine Lefebvre, Cécile Cottet-Rouselle, Josiane Arnaud, Catherine Garrel, François Laporte, Jean Boutonnat, Patrice Faure and Florence Hazane-Puch
Cancers 2019, 11(1), 12; https://doi.org/10.3390/cancers11010012 - 21 Dec 2018
Cited by 7 | Viewed by 3779
Abstract
Glioblastoma multiform (GBM) tumors are very heterogeneous, organized in a hierarchical pattern, including cancer stem cells (CSC), and are responsible for development, maintenance, and cancer relapse. Therefore, it is relevant to establish new GBM cell lines with CSC characteristics to develop new treatments. [...] Read more.
Glioblastoma multiform (GBM) tumors are very heterogeneous, organized in a hierarchical pattern, including cancer stem cells (CSC), and are responsible for development, maintenance, and cancer relapse. Therefore, it is relevant to establish new GBM cell lines with CSC characteristics to develop new treatments. A new human GBM cell line, named R2J, was established from the cerebro-spinal fluid (CSF) of a patient affected by GBM with leptomeningeal metastasis. R2J cells exhibits an abnormal karyotype and form self-renewable spheres in a serum-free medium. Original tumor, R2J, cultured in monolayer (2D) and in spheres showed a persistence expression of CD44, CD56 (except in monolayer), EGFR, Ki67, Nestin, and vimentin. The R2J cell line is tumorigenic and possesses CSC properties. We tested in vitro the anticancer effects of sodium selenite (SS) compared to temozolomide TMZ. SS was absorbed by R2J cells, was cytotoxic, induced an oxidative stress, and arrested cell growth in G2M before inducing both necrosis and apoptosis via caspase-3. SS also modified dimethyl-histone-3-lysine-9 (H3K9m2) levels and decreased histone deacetylase (HDAC) activity, suggesting anti-invasiveness potential. This study highlights the value of this new GBM cell line for preclinical modeling of clinically relevant, patient specific GBM and opens a therapeutic window to test SS to target resistant and recurrent GBM. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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15 pages, 2764 KiB  
Article
EphA3 Pay-Loaded Antibody Therapeutics for the Treatment of Glioblastoma
by Carolin Offenhäuser, Fares Al-Ejeh, Simon Puttick, Kathleen S. Ensbey, Zara C. Bruce, Paul R. Jamieson, Fiona M. Smith, Brett W. Stringer, Benjamin Carrington, Adrian V. Fuchs, Craig A. Bell, Rosalind Jeffree, Stephen Rose, Kristofer J. Thurecht, Andrew W. Boyd and Bryan W. Day
Cancers 2018, 10(12), 519; https://doi.org/10.3390/cancers10120519 - 17 Dec 2018
Cited by 25 | Viewed by 6074
Abstract
The EphA3 receptor has recently emerged as a functional tumour-specific therapeutic target in glioblastoma (GBM). EphA3 is significantly elevated in recurrent disease, is most highly expressed on glioma stem cells (GSCs), and has a functional role in maintaining self-renewal and tumourigenesis. An unlabelled [...] Read more.
The EphA3 receptor has recently emerged as a functional tumour-specific therapeutic target in glioblastoma (GBM). EphA3 is significantly elevated in recurrent disease, is most highly expressed on glioma stem cells (GSCs), and has a functional role in maintaining self-renewal and tumourigenesis. An unlabelled EphA3-targeting therapeutic antibody is currently under clinical assessment in recurrent GBM patients. In this study, we assessed the efficacy of EphA3 antibody drug conjugate (ADC) and radioimmunotherapy (RIT) approaches using orthotopic animal xenograft models. Brain uptake studies, using positron emission tomography/computed tomography (PET/CT) imaging, show EphA3 antibodies are effectively delivered across the blood-tumour barrier and accumulate at the tumour site with no observed normal brain reactivity. A robust anti-tumour response, with no toxicity, was observed using EphA3, ADC, and RIT approaches, leading to a significant increase in overall survival. Our current research provides evidence that GBM patients may benefit from pay-loaded EphA3 antibody therapies. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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16 pages, 3600 KiB  
Article
The Disruption of the β-Catenin/TCF-1/STAT3 Signaling Axis by 4-Acetylantroquinonol B Inhibits the Tumorigenesis and Cancer Stem-Cell-Like Properties of Glioblastoma Cells, In Vitro and In Vivo
by Heng-Wei Liu, Yu-Kai Su, Oluwaseun Adebayo Bamodu, Dueng-Yuan Hueng, Wei-Hwa Lee, Chun-Chih Huang, Li Deng, Michael Hsiao, Ming-Hsien Chien, Chi-Tai Yeh and Chien-Min Lin
Cancers 2018, 10(12), 491; https://doi.org/10.3390/cancers10120491 - 05 Dec 2018
Cited by 25 | Viewed by 5457
Abstract
Background: Glioblastoma (GBM), a malignant form of glioma, is characterized by resistance to therapy and poor prognosis. Accumulating evidence shows that the initiation, propagation, and recurrence of GBM is attributable to the presence of GBM stem cells (GBM-CSCs). Experimental approach: Herein, we investigated [...] Read more.
Background: Glioblastoma (GBM), a malignant form of glioma, is characterized by resistance to therapy and poor prognosis. Accumulating evidence shows that the initiation, propagation, and recurrence of GBM is attributable to the presence of GBM stem cells (GBM-CSCs). Experimental approach: Herein, we investigated the effect of 4-Acetylantroquinonol B (4-AAQB), a bioactive isolate of Antrodia cinnamomea, on GBM cell viability, oncogenic, and CSCs-like activities. Results: We observed that aberrant expression of catenin is characteristic of GBM, compared to other glioma types (p = 0.0001, log-rank test = 475.2), and correlates with poor prognosis of GBM patients. Lower grade glioma and glioblastoma patients (n = 1152) with low catenin expression had 25% and 21.5% better overall survival than those with high catenin expression at the 5 and 10-year time-points, respectively (p = 3.57e-11, log-rank test = 43.8). Immunohistochemistry demonstrated that compared with adjacent non-tumor brain tissue, primary and recurrent GBM exhibited enhanced catenin expression (~10-fold, p < 0.001). Western blot analysis showed that 4-AAQB significantly downregulated β-catenin and dysregulated the catenin/LEF1/Stat3 signaling axis in U87MG and DBTRG-05MG cells, dose-dependently. 4-AAQB–induced downregulation of catenin positively correlated with reduced Sox2 and Oct4 nuclear expression in the cells. Furthermore, 4-AAQB markedly reduced the viability of U87MG and DBTRG-05MG cells with 48 h IC50 of 9.2 M and 12.5 M, respectively, effectively inhibited the nuclear catenin, limited the migration and invasion of GBM cells, with concurrent downregulation of catenin, vimentin, and slug; similarly, colony and tumorsphere formation was significantly attenuated with reduced expression of c-Myc and KLF4 proteins. Conclusions: Summarily, we show for the first time that 4-AAQB suppresses the tumor-promoting catenin/LEF1/Stat3 signaling, and inhibited CSCs-induced oncogenic activities in GBM in vitro, with in vivo validation; thus projecting 4-AAQB as a potent therapeutic agent for anti-GBM target therapy. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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14 pages, 2863 KiB  
Article
Intronic miR-744 Inhibits Glioblastoma Migration by Functionally Antagonizing Its Host Gene MAP2K4
by Max Hübner, Christian Ludwig Hinske, David Effinger, Tingting Wu, Niklas Thon, Friedrich-Wilhelm Kreth and Simone Kreth
Cancers 2018, 10(11), 400; https://doi.org/10.3390/cancers10110400 - 25 Oct 2018
Cited by 20 | Viewed by 4443
Abstract
Background: The second intron of Mitogen-Activated Protein Kinase Kinase 4 (MAP2K4), an important hub in the pro-invasive MAPK pathway, harbors miR-744. There is accumulating evidence that intronic micro-RNAs (miRNAs) are capable of either supporting or restraining functional pathways of their host genes, thereby [...] Read more.
Background: The second intron of Mitogen-Activated Protein Kinase Kinase 4 (MAP2K4), an important hub in the pro-invasive MAPK pathway, harbors miR-744. There is accumulating evidence that intronic micro-RNAs (miRNAs) are capable of either supporting or restraining functional pathways of their host genes, thereby creating intricate regulative networks. We thus hypothesized that miR-744 regulates glioma migration by interacting with its host’s pathways. Methods: Patients’ tumor specimens were obtained stereotactically. MiR-744 was overexpressed in U87, T98G, and primary glioblastoma (GBM) cell lines. Cell mobility was studied using migration and Boyden chamber assays. Protein and mRNA expression was quantified by SDS-PAGE and qRT-PCR. Interactions of miR-744 and 3’UTRs were analyzed by luciferase reporter assays, and SMAD2/3, p38, and beta-Catenin activities by TOP/FOPflash reporter gene assays. Results: As compared to a normal brain, miR-744 levels were dramatically decreased in GBM samples and in primary GBM cell lines. Astrocytoma WHO grade II/III exhibited intermediate expression levels. Re-expression of miR-744 in U87, T98G, and primary GBM cell lines induced focal growth and impaired cell mobility. Luciferase activity of 3’UTR reporter constructs revealed the pro-invasive factors TGFB1 and DVL2 as direct targets of miR-744. Re-expression of miR-744 reduced levels of TGFB1, DVL2, and the host MAP2K4, and mitigated activity of TGFB1 and DVL2 downstream targets SMAD2/3 and beta-Catenin. TGFB1 knock-down repressed MAP2K4 expression. Conclusion: MiR-744 acts as an intrinsic brake on its host. It impedes MAP2K4 functional pathways through simultaneously targeting SMAD-, beta-Catenin, and MAPK signaling networks, thereby strongly mitigating pro-migratory effects of MAP2K4. MiR-744 is strongly repressed in glioma, and its re-expression might attenuate tumor invasiveness. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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17 pages, 2707 KiB  
Article
Reduction of Human Glioblastoma Spheroids Using Cold Atmospheric Plasma: The Combined Effect of Short- and Long-Lived Reactive Species
by Angela Privat-Maldonado, Yury Gorbanev, Sylvia Dewilde, Evelien Smits and Annemie Bogaerts
Cancers 2018, 10(11), 394; https://doi.org/10.3390/cancers10110394 - 23 Oct 2018
Cited by 67 | Viewed by 6391
Abstract
Cold atmospheric plasma (CAP) is a promising technology against multiple types of cancer. However, the current findings on the effect of CAP on two-dimensional glioblastoma cultures do not consider the role of the tumour microenvironment. The aim of this study was to determine [...] Read more.
Cold atmospheric plasma (CAP) is a promising technology against multiple types of cancer. However, the current findings on the effect of CAP on two-dimensional glioblastoma cultures do not consider the role of the tumour microenvironment. The aim of this study was to determine the ability of CAP to reduce and control glioblastoma spheroid tumours in vitro. Three-dimensional glioblastoma spheroid tumours (U87-Red, U251-Red) were consecutively treated directly and indirectly with a CAP using dry He, He + 5% H2O or He + 20% H2O. The cytotoxicity and spheroid shrinkage were monitored using live imaging. The reactive oxygen and nitrogen species produced in phosphate buffered saline (PBS) were measured by electron paramagnetic resonance (EPR) and colourimetry. Cell migration was also assessed. Our results demonstrate that consecutive CAP treatments (He + 20% H2O) substantially shrank U87-Red spheroids and to a lesser degree, U251-Red spheroids. The cytotoxic effect was due to the short- and long-lived species delivered by CAP: they inhibited spheroid growth, reduced cell migration and decreased proliferation in CAP-treated spheroids. Direct treatments were more effective than indirect treatments, suggesting the importance of CAP-generated, short-lived species for the growth inhibition and cell cytotoxicity of solid glioblastoma tumours. We concluded that CAP treatment can effectively reduce glioblastoma tumour size and restrict cell migration, thus demonstrating the potential of CAP therapies for glioblastoma. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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15 pages, 2364 KiB  
Article
Targeting MicroRNA-143 Leads to Inhibition of Glioblastoma Tumor Progression
by Eunice L. Lozada-Delgado, Nilmary Grafals-Ruiz, Miguel A. Miranda-Román, Yasmarie Santana-Rivera, Fatma Valiyeva, Mónica Rivera-Díaz, María J. Marcos-Martínez and Pablo E. Vivas-Mejía
Cancers 2018, 10(10), 382; https://doi.org/10.3390/cancers10100382 - 12 Oct 2018
Cited by 23 | Viewed by 4637
Abstract
Glioblastoma (GBM) is the most common and aggressive of all brain tumors, with a median survival of only 14 months after initial diagnosis. Novel therapeutic approaches are an unmet need for GBM treatment. MicroRNAs (miRNAs) are a class of small non-coding RNAs that [...] Read more.
Glioblastoma (GBM) is the most common and aggressive of all brain tumors, with a median survival of only 14 months after initial diagnosis. Novel therapeutic approaches are an unmet need for GBM treatment. MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression at the post-transcriptional level. Several dysregulated miRNAs have been identified in all cancer types including GBM. In this study, we aimed to uncover the role of miR-143 in GBM cell lines, patient samples, and mouse models. Quantitative real-time RT-PCR of RNA extracted from formalin-fixed paraffin-embedded (FFPE) samples showed that the relative expression of miR-143 was higher in GBM patients compared to control individuals. Transient transfection of GBM cells with a miR-143 oligonucleotide inhibitor (miR-143-inh) resulted in reduced cell proliferation, increased apoptosis, and cell cycle arrest. SLC30A8, a glucose metabolism-related protein, was identified as a direct target of miR-143 in GBM cells. Moreover, multiple injections of GBM tumor-bearing mice with a miR-143-inh-liposomal formulation significantly reduced tumor growth compared to control mice. The reduced in vitro cell growth and in vivo tumor growth following miRNA-143 inhibition suggests that miR-143 is a potential therapeutic target for GBM therapy. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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Review

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12 pages, 978 KiB  
Review
The Role of Platelets in Cancer Pathophysiology: Focus on Malignant Glioma
by Sascha Marx, Yong Xiao, Marcel Baschin, Maximilian Splittstöhser, Robert Altmann, Eileen Moritz, Gabriele Jedlitschky, Sandra Bien-Möller, Henry W.S. Schroeder and Bernhard H. Rauch
Cancers 2019, 11(4), 569; https://doi.org/10.3390/cancers11040569 - 22 Apr 2019
Cited by 22 | Viewed by 4697
Abstract
The link between thrombocytosis and malignancy has been well known for many years and its associations with worse outcomes have been reported mainly for solid tumors. Besides measuring platelet count, it has become popular to assess platelet function in the context of malignant [...] Read more.
The link between thrombocytosis and malignancy has been well known for many years and its associations with worse outcomes have been reported mainly for solid tumors. Besides measuring platelet count, it has become popular to assess platelet function in the context of malignant diseases during the last decade. Malignant gliomas differ tremendously from malignancies outside the central nervous system because they virtually never form distant metastases. This review summarizes the current understanding of the platelet–immune cell communication and its potential role in glioma resistance and progression. Particularly, we focus on platelet-derived proinflammatory modulators, such as sphingosine-1-phosphate (S1P). The multifaceted interaction with immune cells puts the platelet into an interesting perspective regarding the recent advances in immunotherapeutic approaches in malignant glioma. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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23 pages, 2967 KiB  
Review
The Role of SVZ Stem Cells in Glioblastoma
by Christine Altmann, Stefanie Keller and Mirko H. H. Schmidt
Cancers 2019, 11(4), 448; https://doi.org/10.3390/cancers11040448 - 29 Mar 2019
Cited by 51 | Viewed by 7593
Abstract
As most common primary brain cancer, glioblastoma is also the most aggressive and malignant form of cancer in the adult central nervous system. Glioblastomas are genetic and transcriptional heterogeneous tumors, which in spite of intensive research are poorly understood. Over the years conventional [...] Read more.
As most common primary brain cancer, glioblastoma is also the most aggressive and malignant form of cancer in the adult central nervous system. Glioblastomas are genetic and transcriptional heterogeneous tumors, which in spite of intensive research are poorly understood. Over the years conventional therapies failed to affect a cure, resulting in low survival rates of affected patients. To improve the clinical outcome, an important approach is to identify the cells of origin. One potential source for these are neural stem cells (NSCs) located in the subventricular zone, which is one of two niches in the adult nervous system where NSCs with the capacity of self-renewal and proliferation reside. These cells normally give rise to neuronal as well as glial progenitor cells. This review summarizes current findings about links between NSCs and cancer stem cells in glioblastoma and discusses current therapeutic approaches, which arise as a result of identifying the cell of origin in glioblastoma. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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18 pages, 446 KiB  
Review
Lentiviral Vectors as Tools for the Study and Treatment of Glioblastoma
by Claudia Del Vecchio, Arianna Calistri, Cristina Parolin and Carla Mucignat-Caretta
Cancers 2019, 11(3), 417; https://doi.org/10.3390/cancers11030417 - 24 Mar 2019
Cited by 13 | Viewed by 4520
Abstract
Glioblastoma (GBM) has the worst prognosis among brain tumors, hence basic biology, preclinical, and clinical studies are necessary to design effective strategies to defeat this disease. Gene transfer vectors derived from the most-studied lentivirus—the Human Immunodeficiency Virus type 1—have wide application in dissecting [...] Read more.
Glioblastoma (GBM) has the worst prognosis among brain tumors, hence basic biology, preclinical, and clinical studies are necessary to design effective strategies to defeat this disease. Gene transfer vectors derived from the most-studied lentivirus—the Human Immunodeficiency Virus type 1—have wide application in dissecting GBM specific features to identify potential therapeutic targets. Last-generation lentiviruses (LV), highly improved in safety profile and gene transfer capacity, are also largely employed as delivery systems of therapeutic molecules to be employed in gene therapy (GT) approaches. LV were initially used in GT protocols aimed at the expression of suicide factors to induce GBM cell death. Subsequently, LV were adopted to either express small noncoding RNAs to affect different aspects of GBM biology or to overcome the resistance to both chemo- and radiotherapy that easily develop in this tumor after initial therapy. Newer frontiers include adoption of LV for engineering T cells to express chimeric antigen receptors recognizing specific GBM antigens, or for transducing specific cell types that, due to their biological properties, can function as carriers of therapeutic molecules to the cancer mass. Finally, LV allow the setting up of improved animal models crucial for the validation of GBM specific therapies. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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10 pages, 570 KiB  
Review
Allergic Signs in Glioma Pathology: Current Knowledge and Future Perspectives
by Massimo Costanza and Gaetano Finocchiaro
Cancers 2019, 11(3), 404; https://doi.org/10.3390/cancers11030404 - 22 Mar 2019
Cited by 7 | Viewed by 4054
Abstract
Historically restrained to immune defense against parasite infections, allergic inflammation has been recently rediscovered to protect from a wide array of environmental triggers, such as xenobiotics and carcinogens, which can induce DNA damage and ultimately lead to cancer development. Moreover, cells and mediators [...] Read more.
Historically restrained to immune defense against parasite infections, allergic inflammation has been recently rediscovered to protect from a wide array of environmental triggers, such as xenobiotics and carcinogens, which can induce DNA damage and ultimately lead to cancer development. Moreover, cells and mediators typical of allergic responses can importantly modulate the tissue inflammatory milieu, which represents a crucial gatekeeper towards the acquisition of malignancy by cancer cells through immune escape. Numerous studies have described an inverse association between allergies and glioma development. Mast cells, key players of allergic reactions, have been recently found at increased numbers in glioblastoma multiforme (GBM), the most common and lethal primary brain tumor, and they have been implicated in GBM pathogenesis. In this review, we summarize epidemiological studies and discuss the main evidence highlighting a potential interplay between allergic responses, and glioma formation and progression. Last, we draw future lines of research for better clarification whether and through which mechanisms allergic inflammation might impact on gliomagenesis. The comprehension of the immune mechanisms favoring or counteracting tumor growth might open the path to novel immunotherapy approaches. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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16 pages, 298 KiB  
Review
Glioblastoma in Elderly Patients: Current Management and Future Perspectives
by Giuseppe Minniti, Giuseppe Lombardi and Sergio Paolini
Cancers 2019, 11(3), 336; https://doi.org/10.3390/cancers11030336 - 08 Mar 2019
Cited by 57 | Viewed by 4331
Abstract
The incidence of glioblastoma (GBM) in the elderly population is slowly increasing in Western countries. Current management includes surgery, radiation therapy (RT) and chemotherapy; however, survival is significantly worse than that observed in younger patients and the optimal treatment in terms of efficacy [...] Read more.
The incidence of glioblastoma (GBM) in the elderly population is slowly increasing in Western countries. Current management includes surgery, radiation therapy (RT) and chemotherapy; however, survival is significantly worse than that observed in younger patients and the optimal treatment in terms of efficacy and safety remains a matter of debate. Surgical resection is often employed as initial treatment for elderly patients with GBM, although the survival benefit is modest. Better survival has been reported in elderly patients treated with RT compared with those receiving supportive care alone, with similar survival outcome for patients undergoing standard RT (60 Gy over 6 weeks) and hypofractionated RT (25–40 Gy in 5–15 daily fractions). Temozolomide, an alkylating agent, may represent an effective and safe therapy in patients with promoter methylation of O6-methylguanine-DNA-methyltransferase (MGMT) gene which is predictor of responsiveness to alkylating agents. An abbreviated course of RT, 40 Gy in 15 daily fractions in combination with adjuvant and concomitant temozolomide has emerged as an effective treatment for patients aged 65 years old or over with GBM. Results of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG CE6) and European Organization for Research and Treatment of Cancer (EORTC 26062/22061) randomized study of short-course RT with or without concurrent and adjuvant temozolomide have demonstrated a significant improvement in progression-free survival and overall survival for patients receiving RT and temozolomide over RT alone, without impairing either quality of life or functional status. Although combined chemoradiation has become the recommended treatment in fit elderly patients with GBM, several questions remain unanswered, including the survival impact of chemoradiation in patients with impaired neurological status, advanced age (>75–80 years old), or for those with severe comorbidities. In addition, the efficacy and safety of alternative therapeutic approaches according to the methylation status of the O6-methylguanine-DNA methyl-transferase (MGMT) gene promoter need to be explored in future trials. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
21 pages, 1159 KiB  
Review
EMT Regulation by Autophagy: A New Perspective in Glioblastoma Biology
by Barbara Colella, Fiorella Faienza and Sabrina Di Bartolomeo
Cancers 2019, 11(3), 312; https://doi.org/10.3390/cancers11030312 - 06 Mar 2019
Cited by 87 | Viewed by 7639
Abstract
Epithelial-to-mesenchymal transition (EMT) and its reverse process MET naturally occur during development and in tissue repair in vertebrates. EMT is also recognized as the crucial event by which cancer cells acquire an invasive phenotype through the activation of specific transcription factors and signalling [...] Read more.
Epithelial-to-mesenchymal transition (EMT) and its reverse process MET naturally occur during development and in tissue repair in vertebrates. EMT is also recognized as the crucial event by which cancer cells acquire an invasive phenotype through the activation of specific transcription factors and signalling pathways. Even though glial cells have a mesenchymal phenotype, an EMT-like process tends to exacerbate it during gliomagenesis and progression to more aggressive stages of the disease. Autophagy is an evolutionary conserved degradative process that cells use in order to maintain a proper homeostasis, and defects in autophagy have been associated to several pathologies including cancer. Besides modulating cell resistance or sensitivity to therapy, autophagy also affects the migration and invasion capabilities of tumor cells. Despite this evidence, few papers are present in literature about the involvement of autophagy in EMT-like processes in glioblastoma (GBM) so far. This review summarizes the current understanding of the interplay between autophagy and EMT in cancer, with special regard to GBM model. As the invasive behaviour is a hallmark of GBM aggressiveness, defining a new link between autophagy and EMT can open a novel scenario for targeting these processes in future therapeutical approaches. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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25 pages, 2024 KiB  
Review
Role of Notch Signaling Pathway in Glioblastoma Pathogenesis
by Riccardo Bazzoni and Angela Bentivegna
Cancers 2019, 11(3), 292; https://doi.org/10.3390/cancers11030292 - 01 Mar 2019
Cited by 95 | Viewed by 9859
Abstract
Notch signaling is an evolutionarily conserved pathway that regulates important biological processes, such as cell proliferation, apoptosis, migration, self-renewal, and differentiation. In mammals, Notch signaling is composed of four receptors (Notch1–4) and five ligands (Dll1-3–4, Jagged1–2) that mainly contribute to the development and [...] Read more.
Notch signaling is an evolutionarily conserved pathway that regulates important biological processes, such as cell proliferation, apoptosis, migration, self-renewal, and differentiation. In mammals, Notch signaling is composed of four receptors (Notch1–4) and five ligands (Dll1-3–4, Jagged1–2) that mainly contribute to the development and maintenance of the central nervous system (CNS). Neural stem cells (NSCs) are the starting point for neurogenesis and other neurological functions, representing an essential aspect for the homeostasis of the CNS. Therefore, genetic and functional alterations to NSCs can lead to the development of brain tumors, including glioblastoma. Glioblastoma remains an incurable disease, and the reason for the failure of current therapies and tumor relapse is the presence of a small subpopulation of tumor cells known as glioma stem cells (GSCs), characterized by their stem cell-like properties and aggressive phenotype. Growing evidence reveals that Notch signaling is highly active in GSCs, where it suppresses differentiation and maintains stem-like properties, contributing to Glioblastoma tumorigenesis and conventional-treatment resistance. In this review, we try to give a comprehensive view of the contribution of Notch signaling to Glioblastoma and its possible implication as a target for new therapeutic approaches. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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17 pages, 1032 KiB  
Review
Targeting the Post-Irradiation Tumor Microenvironment in Glioblastoma via Inhibition of CXCL12
by Frank A. Giordano, Barbara Link, Martin Glas, Ulrich Herrlinger, Frederik Wenz, Viktor Umansky, J. Martin Brown and Carsten Herskind
Cancers 2019, 11(3), 272; https://doi.org/10.3390/cancers11030272 - 26 Feb 2019
Cited by 15 | Viewed by 5156
Abstract
Radiotherapy is a mainstay in glioblastoma therapy as it not only directly targets tumor cells but also depletes the tumor microvasculature. The resulting intra-tumoral hypoxia initiates a chain of events that ultimately leads to re-vascularization, immunosuppression and, ultimately, tumor-regrowth. The key component of [...] Read more.
Radiotherapy is a mainstay in glioblastoma therapy as it not only directly targets tumor cells but also depletes the tumor microvasculature. The resulting intra-tumoral hypoxia initiates a chain of events that ultimately leads to re-vascularization, immunosuppression and, ultimately, tumor-regrowth. The key component of this cascade is overexpression of the CXC-motive chemokine ligand 12 (CXCL12), formerly known as stromal-cell derived factor 1 (SDF-1). We here review the role of CXCL12 in recruitment of pro-vasculogenic and immunosuppressive cells and give an overview on future and current drugs that target this axis. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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25 pages, 1482 KiB  
Review
Protein Phosphatases—A Touchy Enemy in the Battle Against Glioblastomas: A Review
by Arata Tomiyama, Tatsuya Kobayashi, Kentaro Mori and Koichi Ichimura
Cancers 2019, 11(2), 241; https://doi.org/10.3390/cancers11020241 - 19 Feb 2019
Cited by 14 | Viewed by 4420
Abstract
Glioblastoma (GBM) is the most common malignant tumor arising from brain parenchyma. Although many efforts have been made to develop therapies for GBM, the prognosis still remains poor, mainly because of the difficulty in total resection of the tumor mass from brain tissue [...] Read more.
Glioblastoma (GBM) is the most common malignant tumor arising from brain parenchyma. Although many efforts have been made to develop therapies for GBM, the prognosis still remains poor, mainly because of the difficulty in total resection of the tumor mass from brain tissue and the resistance of the residual tumor against standard chemoradiotherapy. Therefore, novel adjuvant therapies are urgently needed. Recent genome-wide analyses of GBM cases have clarified molecular signaling mechanisms underlying GBM biology. However, results of clinical trials targeting phosphorylation-mediated signaling have been unsatisfactory to date. Protein phosphatases are enzymes that antagonize phosphorylation signaling by dephosphorylating phosphorylated signaling molecules. Recently, the critical roles of phosphatases in the regulation of oncogenic signaling in malignant tumor cells have been reported, and tumorigenic roles of deregulated phosphatases have been demonstrated in GBM. However, a detailed mechanism underlying phosphatase-mediated signaling transduction in the regulation of GBM has not been elucidated, and such information is necessary to apply phosphatases as a therapeutic target for GBM. This review highlights and summarizes the phosphatases that have crucial roles in the regulation of oncogenic signaling in GBM cells. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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15 pages, 1899 KiB  
Review
Nitric Oxide Antagonism to Anti-Glioblastoma Photodynamic Therapy: Mitigation by Inhibitors of Nitric Oxide Generation
by Jonathan M. Fahey and Albert W. Girotti
Cancers 2019, 11(2), 231; https://doi.org/10.3390/cancers11020231 - 15 Feb 2019
Cited by 22 | Viewed by 3846
Abstract
Many studies have shown that low flux nitric oxide (NO) produced by inducible NO synthase (iNOS/NOS2) in various tumors, including glioblastomas, can promote angiogenesis, cell proliferation, and migration/invasion. Minimally invasive, site-specific photodynamic therapy (PDT) is a highly promising anti-glioblastoma modality. Recent research in [...] Read more.
Many studies have shown that low flux nitric oxide (NO) produced by inducible NO synthase (iNOS/NOS2) in various tumors, including glioblastomas, can promote angiogenesis, cell proliferation, and migration/invasion. Minimally invasive, site-specific photodynamic therapy (PDT) is a highly promising anti-glioblastoma modality. Recent research in the authors’ laboratory has revealed that iNOS-derived NO in glioblastoma cells elicits resistance to 5-aminolevulinic acid (ALA)-based PDT, and moreover endows PDT-surviving cells with greater proliferation and migration/invasion aggressiveness. In this contribution, we discuss iNOS/NO antagonism to glioblastoma PDT and how this can be overcome by judicious use of pharmacologic inhibitors of iNOS activity or transcription. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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16 pages, 2614 KiB  
Review
Virus-Based Immunotherapy of Glioblastoma
by Miika Martikainen and Magnus Essand
Cancers 2019, 11(2), 186; https://doi.org/10.3390/cancers11020186 - 05 Feb 2019
Cited by 95 | Viewed by 8361
Abstract
Glioblastoma (GBM) is the most common type of primary brain tumor in adults. Despite recent advances in cancer therapy, including the breakthrough of immunotherapy, the prognosis of GBM patients remains dismal. One of the new promising ways to therapeutically tackle the immunosuppressive GBM [...] Read more.
Glioblastoma (GBM) is the most common type of primary brain tumor in adults. Despite recent advances in cancer therapy, including the breakthrough of immunotherapy, the prognosis of GBM patients remains dismal. One of the new promising ways to therapeutically tackle the immunosuppressive GBM microenvironment is the use of engineered viruses that kill tumor cells via direct oncolysis and via stimulation of antitumor immune responses. In this review, we focus on recently published results of phase I/II clinical trials with different oncolytic viruses and the new interesting findings in preclinical models. From syngeneic preclinical GBM models, it seems evident that oncolytic virus-mediated destruction of GBM tissue coupled with strong adjuvant effect, provided by the robust stimulation of innate antiviral immune responses and adaptive anti-tumor T cell responses, can be harnessed as potent immunotherapy against GBM. Although clinical testing of oncolytic viruses against GBM is at an early stage, the promising results from these trials give hope for the effective treatment of GBM in the near future. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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12 pages, 236 KiB  
Review
Treatment of Glioblastoma (GBM) with the Addition of Tumor-Treating Fields (TTF): A Review
by Denise Fabian, Maria del Pilar Guillermo Prieto Eibl, Iyad Alnahhas, Nikhil Sebastian, Pierre Giglio, Vinay Puduvalli, Javier Gonzalez and Joshua D. Palmer
Cancers 2019, 11(2), 174; https://doi.org/10.3390/cancers11020174 - 02 Feb 2019
Cited by 142 | Viewed by 14442
Abstract
Glioblastoma (GBM) is the most common primary brain tumor. Despite aggressive treatment, GBM almost always recurs. The current standard-of-care for treatment of newly diagnosed GBM has remained relatively unchanged since 2005: maximal safe resection followed by concomitant chemoradiation (CRT) with temozolomide (TMZ), and [...] Read more.
Glioblastoma (GBM) is the most common primary brain tumor. Despite aggressive treatment, GBM almost always recurs. The current standard-of-care for treatment of newly diagnosed GBM has remained relatively unchanged since 2005: maximal safe resection followed by concomitant chemoradiation (CRT) with temozolomide (TMZ), and subsequent adjuvant TMZ. In 2011, the first-generation tumor treating fields (TTF) device, known at the time as the NovoTTF-100A System (renamed Optune), was approved by the Food and Drug Administration (FDA) for treatment of recurrent GBM. The TTF device was subsequently approved as an adjuvant therapy for newly-diagnosed GBM in 2015. The following is a review of the TTF device, including evidence supporting its use and limitations. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
13 pages, 964 KiB  
Review
Combined Amino Acid Positron Emission Tomography and Advanced Magnetic Resonance Imaging in Glioma Patients
by Philipp Lohmann, Jan-Michael Werner, N. Jon Shah, Gereon R. Fink, Karl-Josef Langen and Norbert Galldiks
Cancers 2019, 11(2), 153; https://doi.org/10.3390/cancers11020153 - 29 Jan 2019
Cited by 44 | Viewed by 4556
Abstract
Imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) provide valuable information about brain tumor patients. Particularly amino acid PET, advanced MRI techniques, and combinations thereof are of great interest for the non-invasive assessment of biological characteristics in patients [...] Read more.
Imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) provide valuable information about brain tumor patients. Particularly amino acid PET, advanced MRI techniques, and combinations thereof are of great interest for the non-invasive assessment of biological characteristics in patients with primary or secondary brain cancer. A methodological innovation that potentially advances research in patients with brain tumors is the increasing availability of hybrid PET/MRI systems, which enables the simultaneous acquisition of both imaging modalities. Furthermore, the advent of ultra-high field MRI scanners operating at magnetic field strengths of 7 T or more will allow further development of metabolic MR imaging at higher resolution. This review focuses on the combination of amino acid PET with MR spectroscopic imaging, perfusion- and diffusion-weighted imaging, as well as chemical exchange saturation transfer in patients with high-grade gliomas, especially glioblastomas. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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15 pages, 1077 KiB  
Review
Cholesterol Metabolism: A Potential Therapeutic Target in Glioblastoma
by Fahim Ahmad, Qian Sun, Deven Patel and Jayne M. Stommel
Cancers 2019, 11(2), 146; https://doi.org/10.3390/cancers11020146 - 26 Jan 2019
Cited by 55 | Viewed by 7971
Abstract
Glioblastoma is a highly lethal adult brain tumor with no effective treatments. In this review, we discuss the potential to target cholesterol metabolism as a new strategy for treating glioblastomas. Twenty percent of cholesterol in the body is in the brain, yet the [...] Read more.
Glioblastoma is a highly lethal adult brain tumor with no effective treatments. In this review, we discuss the potential to target cholesterol metabolism as a new strategy for treating glioblastomas. Twenty percent of cholesterol in the body is in the brain, yet the brain is unique among organs in that it has no access to dietary cholesterol and must synthesize it de novo. This suggests that therapies targeting cholesterol synthesis in brain tumors might render their effects without compromising cell viability in other organs. We will describe cholesterol synthesis and homeostatic feedback pathways in normal brain and brain tumors, as well as various strategies for targeting these pathways for therapeutic intervention. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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17 pages, 3426 KiB  
Review
Glioblastoma: Microenvironment and Niche Concept
by Davide Schiffer, Laura Annovazzi, Cristina Casalone, Cristiano Corona and Marta Mellai
Cancers 2019, 11(1), 5; https://doi.org/10.3390/cancers11010005 - 20 Dec 2018
Cited by 132 | Viewed by 7591
Abstract
The niche concept was originally developed to describe the location of normal neural stem cells (NSCs) in the subependymal layer of the sub-ventricular zone. In this paper, its significance has been extended to the location of tumor stem cells in glioblastoma (GB) to [...] Read more.
The niche concept was originally developed to describe the location of normal neural stem cells (NSCs) in the subependymal layer of the sub-ventricular zone. In this paper, its significance has been extended to the location of tumor stem cells in glioblastoma (GB) to discuss the relationship between GB stem cells (GSCs) and endothelial cells (ECs). Their interaction is basically conceived as responsible for tumor growth, invasion and recurrence. Niches are described as the points of utmost expression of the tumor microenvironment (TME), therefore including everything in the tumor except for tumor cells: NSCs, reactive astrocytes, ECs, glioma-associated microglia/macrophages (GAMs), myeloid cells, pericytes, fibroblasts, etc. and all intrinsic and extrinsic signaling pathways. Perivascular (PVNs), perinecrotic (PNNs) and invasive niches were described from the pathological point of view, highlighting the basic significance of the EC/tumor stem cell couple. PNN development was reinterpreted based on the concept that hyperproliferative areas of GB are composed of GSCs/progenitors. TME was depicted in its function as the main regulator of everything that happens in the tumor. A particular emphasis was given to GAMs, pericytes and reactive astrocytes as important elements affecting proliferation, growth, invasion and resistance to therapies of tumor cells. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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24 pages, 1554 KiB  
Review
Recent Advances in Oncolytic Virotherapy and Immunotherapy for Glioblastoma: A Glimmer of Hope in the Search for an Effective Therapy?
by Aleksei A. Stepanenko and Vladimir P. Chekhonin
Cancers 2018, 10(12), 492; https://doi.org/10.3390/cancers10120492 - 05 Dec 2018
Cited by 46 | Viewed by 5992
Abstract
To date, no targeted drugs, antibodies or combinations of chemotherapeutics have been demonstrated to be more efficient than temozolomide, or to increase efficacy of standard therapy (surgery, radiotherapy, temozolomide, steroid dexamethasone). According to recent phase III trials, standard therapy may ensure a median [...] Read more.
To date, no targeted drugs, antibodies or combinations of chemotherapeutics have been demonstrated to be more efficient than temozolomide, or to increase efficacy of standard therapy (surgery, radiotherapy, temozolomide, steroid dexamethasone). According to recent phase III trials, standard therapy may ensure a median overall survival of up to 18–20 months for adult patients with newly diagnosed glioblastoma. These data explain a failure of positive non-controlled phase II trials to predict positive phase III trials and should result in revision of the landmark Stupp trial as a historical control for median overall survival in non-controlled trials. A high rate of failures in clinical trials and a lack of effective chemotherapy on the horizon fostered the development of conceptually distinct therapeutic approaches: dendritic cell/peptide immunotherapy, chimeric antigen receptor (CAR) T-cell therapy and oncolytic virotherapy. Recent early phase trials with the recombinant adenovirus DNX-2401 (Ad5-delta24-RGD), polio-rhinovirus chimera (PVSRIPO), parvovirus H-1 (ParvOryx), Toca 511 retroviral vector with 5-fluorocytosine, heat shock protein-peptide complex-96 (HSPPC-96) and dendritic cell vaccines, including DCVax-L vaccine, demonstrated that subsets of patients with glioblastoma/glioma may benefit from oncolytic virotherapy/immunotherapy (>3 years of survival after treatment). However, large controlled trials are required to prove efficacy of next-generation immunotherapeutics and oncolytic vectors. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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3 pages, 170 KiB  
Perspective
The ‘Ins and Outs’ of Early Preclinical Models for Brain Tumor Research: Are They Valuable and Have We Been Doing It Wrong?
by Ola Rominiyi, Yahia Al-Tamimi and Spencer J. Collis
Cancers 2019, 11(3), 426; https://doi.org/10.3390/cancers11030426 - 25 Mar 2019
Cited by 9 | Viewed by 2975
Abstract
In this perspective, we congratulate the international efforts to highlight critical challenges in brain tumor research through a recent Consensus Statement. We also illustrate the importance of developing more accurate and clinically relevant early translational in vitro brain tumor models—a perspective given limited [...] Read more.
In this perspective, we congratulate the international efforts to highlight critical challenges in brain tumor research through a recent Consensus Statement. We also illustrate the importance of developing more accurate and clinically relevant early translational in vitro brain tumor models—a perspective given limited emphasis in the Consensus Statement, despite in vitro models being widely used to prioritize candidate therapeutic strategies prior to in vivo studies and subsequent clinical trials. We argue that successful translation of effective novel treatments into the clinic will require investment into the development of more predictive early pre-clinical models. It is in the interest of researchers, clinicians, and ultimately, patients that the most promising therapeutic candidates are identified and translated toward use in the clinic. Highlighting the value of early pre-clinical brain tumor models and debating how such models can be improved is of the utmost importance to the neuro-oncology research community and cancer research more broadly. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
11 pages, 605 KiB  
Perspective
Finding the Right Way to Target EGFR in Glioblastomas; Lessons from Lung Adenocarcinomas
by Ya Gao, Wies R. Vallentgoed and Pim J. French
Cancers 2018, 10(12), 489; https://doi.org/10.3390/cancers10120489 - 04 Dec 2018
Cited by 16 | Viewed by 3678
Abstract
The EGFR gene is one of the most frequently mutated and/or amplified gene both in lung adenocarcinomas (LUAD) and in glioblastomas (GBMs). Although both tumor types depend on the mutation for growth, clinical benefit of EGFR tyrosine kinase inhibitors (TKIs) has only been [...] Read more.
The EGFR gene is one of the most frequently mutated and/or amplified gene both in lung adenocarcinomas (LUAD) and in glioblastomas (GBMs). Although both tumor types depend on the mutation for growth, clinical benefit of EGFR tyrosine kinase inhibitors (TKIs) has only been observed in LUAD patients and, thus-far, not in GBM patients. Also in LUAD patients however, responses are restricted to specific EGFR mutations only and these ‘TKI-sensitive’ mutations hardly occur in GBMs. This argues for mutation-specific (as opposed to tumor-type specific) responses to EGFR-TKIs. We here discuss potential reasons for the differences in mutation spectrum and highlight recent evidence for specific functions of different EGFR mutations. These mutation-specific effects likely underlie the differential treatment response between LUAD and GBMs and provide new insights into how to target EGFR in GBM patients. Full article
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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