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Molecular and Cellular Mechanisms of Human Astrocytomas Progression: Knowledge Increasing to Reach Therapeutic Horizons

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A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 38430

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Dr. Sergio Comincini

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Dipartimento di Biologia e Biotecnologie, Università di Pavia, Pavia, Italy
Interests: astrocytic tumors; programmed cell death; autophagy; gene-interfering; exosome
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

As you well know, human astrocytic tumors are primary central nervous system tumors that either arise from astrocytes or from precursor cells. A growing number of epidemiological and incidence studies in different countries underlined that, in addition to increasing economical costs for health systems, these cancers are still representing one of the main hurdles in developing a successful therapeutic goal for patients. On the other hand, new -omic technologies are offering customized instruments and more and more advantageous results toward personalized medicine approaches, underlining the concept that each tumor mass underwent a peculiar transformation process under the control of specific genes’ and proteins’ functional signatures. The main aim of this Special Issue is to collect novel contributions in the wide field of human tumor astrocytic basic and translational research to suggest further potential therapeutic targets that might interfere, possibly at the earliest stage of tranformation, with tumor progression, and to increase the molecular-based arsenal to counteract the prognostic poverty of high grade astrocytic tumors.

Dr. Sergio Comincini
Guest Editor

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Keywords

astrocytic tumor
glioblastoma multiforme
glioma
gene-therapy
gene-interfering
programmed cell death

Published Papers (10 papers)

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Editorial

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5 pages, 197 KiB

Open AccessEditorial

Molecular and Cellular Mechanisms of Human Astrocytoma Progression: Advances in Knowledge to Reach Therapeutic Horizons

by Sergio Comincini

Cells 2020, 9(10), 2216; https://doi.org/10.3390/cells9102216 - 30 Sep 2020

Viewed by 1693

Abstract

Human astrocytic tumors are primary central nervous system (CNS) tumors that arise either from astrocytes or from precursor cells. A growing number of epidemiological and incidence studies in different countries underlined that, in addition to increasing economic costs for health systems, these cancers are still representing one of the main hurdles in developing a successful therapeutic goal for patients. On the other hand, new-omics technologies are offering customized instruments and more and more advantageous results toward personalized medicine approaches, underlining the concept that each tumor mass undergoes a peculiar transformation process under the control of specific genes’ and proteins’ functional signatures. The main aim of this Special Issue was to collect novel contributions in the wide field of human tumor astrocytic basic and translational research, to suggest further potential therapeutic targets/strategies that might interfere, possibly at the earliest stage of transformation, with the tumor progression, and to increase the molecular-based arsenal to counteract the prognostic poverty of high-grade astrocytic tumors. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Human Astrocytomas Progression: Knowledge Increasing to Reach Therapeutic Horizons)

Research

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19 pages, 11528 KiB

Open AccessArticle

Chondroitin Sulphate Proteoglycan 4 (NG2/CSPG4) Localization in Low- and High-Grade Gliomas

by Marta Mellai, Laura Annovazzi, Ilaria Bisogno, Cristiano Corona, Paola Crociara, Barbara Iulini, Paola Cassoni, Cristina Casalone, Renzo Boldorini and Davide Schiffer

Cells 2020, 9(6), 1538; https://doi.org/10.3390/cells9061538 - 24 Jun 2020

Cited by 5 | Viewed by 3173

Abstract

Background: Neuron glial antigen 2 or chondroitin sulphate proteoglycan 4 (NG2/CSPG4) is expressed by immature precursors/progenitor cells and is possibly involved in malignant cell transformation. The aim of this study was to investigate its role on the progression and survival of sixty-one adult gliomas and nine glioblastoma (GB)-derived cell lines. Methods: NG2/CSPG4 protein expression was assessed by immunohistochemistry and immunofluorescence. Genetic and epigenetic alterations were detected by molecular genetic techniques. Results: NG2/CSPG4 was frequently expressed in IDH-mutant/1p19q-codel oligodendrogliomas (59.1%) and IDH-wild type GBs (40%) and rarely expressed in IDH-mutant or IDH-wild type astrocytomas (14.3%). Besides tumor cells, NG2/CSPG4 immunoreactivity was found in the cytoplasm and/or cell membranes of reactive astrocytes and vascular pericytes/endothelial cells. In GB-derived neurospheres, it was variably detected according to the number of passages of the in vitro culture. In GB-derived adherent cells, a diffuse positivity was found in most cells. NG2/CSPG4 expression was significantly associated with EGFR gene amplification (p = 0.0005) and poor prognosis (p = 0.016) in astrocytic tumors. Conclusion: The immunoreactivity of NG2/CSPG4 provides information on the timing of the neoplastic transformation and could have prognostic and therapeutic relevance as a promising tumor-associated antigen for antibody-based immunotherapy in patients with malignant gliomas. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Human Astrocytomas Progression: Knowledge Increasing to Reach Therapeutic Horizons)

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16 pages, 2847 KiB

Open AccessArticle

Large-Scale Drug Screening in Patient-Derived IDH^mut Glioma Stem Cells Identifies Several Efficient Drugs among FDA-Approved Antineoplastic Agents

by Philip Dao Trong, Gerhard Jungwirth, Tao Yu, Stefan Pusch, Andreas Unterberg, Christel Herold-Mende and Rolf Warta

Cells 2020, 9(6), 1389; https://doi.org/10.3390/cells9061389 - 3 Jun 2020

Cited by 18 | Viewed by 3077

Abstract

The discovery of the isocitrate dehydrogenase (IDH) mutation in glioma led to a paradigm shift on how we see glioma biology. Difficulties in cultivating IDH mutant glioma stem cells (IDH^mut GSCs) resulted in a paucity of preclinical models in IDH^mut glioma, limiting the discovery of new effective chemotherapeutic agents. To fill this gap, we used six recently developed patient-derived IDH^mut GSC lines and performed a large-scale drug screening with 147 Food and Drug Administration (FDA)-approved anticancer drugs. GSCs were subjected to the test compounds for 72 h in concentrations ranging from 0.0001 to 1 µM. Cell viability was assessed by CellTiterGlo and the induction of apoptosis by flow cytometry with Annexin V/propidium iodide staining. The initial screen was performed with two IDH^mut GSC lines and identified seven drugs (bortezomib, carfilzomib, daunorubicin, doxorubicin, epirubicin, omacetaxine, plicamycin) with a substantial antiproliferative activity, as reflected by half maximal inhibitory concentrations (IC₅₀) below 1 µM and maximum inhibitory effects (E_max) below 25%. These findings were validated in an additional four IDH^mut GSC lines. The candidate drugs, of which plicamycin and omacetaxine are known to cross the blood brain barrier, were used for subsequent cell death analyses. A significant induction of apoptosis was observed at IC₅₀ values of the respective drugs. In summary, we were able to identify seven FDA-approved drugs that should be further taken into clinical investigations for the treatment of IDH^mut gliomas. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Human Astrocytomas Progression: Knowledge Increasing to Reach Therapeutic Horizons)

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25 pages, 2807 KiB

Open AccessArticle

Hypoxia and EGF Stimulation Regulate VEGF Expression in Human Glioblastoma Multiforme (GBM) Cells by Differential Regulation of the PI3K/Rho-GTPase and MAPK Pathways

by Samer Nicolas, Sandra Abdellatef, Maria Al Haddad, Isabelle Fakhoury and Mirvat El-Sibai

Cells 2019, 8(11), 1397; https://doi.org/10.3390/cells8111397 - 6 Nov 2019

Cited by 50 | Viewed by 5463

Abstract

Glioblastoma multiforme (GBM) is one of the most common and deadly cancers of the central nervous system (CNS). It is characterized by the presence of hypoxic regions, especially in the core, leading to an increase in vascularity. This increased vascularization is driven by the expression of the major angiogenic inducer VEGF and the indirect angiogenic inducer Epidermal growth factor (EGF), which stimulates VEGF expression. In this study, we examine the regulation of VEGF by both hypoxia and the EGF signaling pathway. We also examine the involvement of pathways downstream from EGF signaling, including the mitogen-activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway and the Phosphatidylinositol-3-kinase/RhoA/C (PI3K/RhoA/C) pathway in this regulation. Our results show that VEGF expression and secretion levels increase following either hypoxia or EGF stimulation, with the two stimuli signaling in parallel. We also observed an increase in ERK and protein kinase B (Akt) phosphorylation, in response to EGF stimulation, with kinetics that correlated with the kinetics of the effect on VEGF. Using pharmacological inhibitors against ERK and PI3K and small interfering RNAs (siRNAs) against RhoA and RhoC, we found that both the ERK and the PI3K/RhoA/C pathways have to cooperate in order to lead to an increase in VEGF expression, downstream from EGF. In response to hypoxia, however, only ERK was involved in the regulation of VEGF. Hypoxia also led to a surprising decrease in the activation of PI3K and RhoA/C. Finally, the decrease in the activation of these Rho-GTPases was found to be mediated through a hypoxia-driven overexpression of the Rho-GTPase GTPase activating protein (GAP), StarD13. Therefore, while under normoxic conditions, EGF stimulates the activation of both the PI3K and the MAPK pathways and the induction of VEGF, in glioblastoma cells, hypoxic conditions lead to the suppression of the PI3K/RhoA/C pathway and an exclusive switch to the MAPK pathway. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Human Astrocytomas Progression: Knowledge Increasing to Reach Therapeutic Horizons)

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15 pages, 2862 KiB

Open AccessArticle

Adenosine Depletion as A New Strategy to Decrease Glioblastoma Stem-Like Cells Aggressiveness

by Ignacio Niechi, Atenea Uribe-Ojeda, José Ignacio Erices, Ángelo Torres, Daniel Uribe, José Dellis Rocha, Pamela Silva, Hans G. Richter, Rody San Martín and Claudia Quezada

Cells 2019, 8(11), 1353; https://doi.org/10.3390/cells8111353 - 30 Oct 2019

Cited by 16 | Viewed by 3370

Abstract

Glioblastoma is the brain tumor with the worst prognosis. This is mainly due to a cell subpopulation with an extremely aggressive potential, called glioblastoma stem-like cells (GSCs). These cells produce high levels of extracellular adenosine, which are increased even more under hypoxic conditions. Under hypoxia, adenosine signaling is related to HIF-2α expression, enhancing cell aggressiveness. Adenosine can be degraded using recombinant adenosine deaminase (ADA) to revert its pathological effects. The aim of this study was to degrade adenosine using ADA in order to decrease malignancy of GSCs. Adenosine depletion was performed using recombinant ADA. Migration and invasion were measured by transwell and matrigel-coated transwell assay, respectively. HIF-2α-dependent cell migration/invasion decreased in GSCs treated with ADA under hypoxia. MRPs-mediated chemoresistance and colony formation decreased in treatment with ADA. In conclusion, adenosine depletion using adenosine deaminase decreases GSCs aggressiveness. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Human Astrocytomas Progression: Knowledge Increasing to Reach Therapeutic Horizons)

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15 pages, 5080 KiB

Open AccessArticle

Promising Prognosis Marker Candidates on the Status of Epithelial–Mesenchymal Transition and Glioma Stem Cells in Glioblastoma

by Yasuo Takashima, Atsushi Kawaguchi and Ryuya Yamanaka

Cells 2019, 8(11), 1312; https://doi.org/10.3390/cells8111312 - 24 Oct 2019

Cited by 23 | Viewed by 4686

Abstract

Multivariable analyses of global expression profiling are valid indicators of the prognosis of various diseases including brain cancers. To identify the candidates for markers of prognosis of glioblastoma, we performed multivariable analyses on the status of epithelial (EPI)–mesenchymal (MES) transition (EMT), glioma (GLI) stem cells (GSCs), molecular target therapy (MTT), and potential glioma biomarkers (PGBs) using the expression data and clinical information from patients. Random forest survival and Cox proportional hazards regression analyses indicated significant variable values for DSG3, CLDN1, CDH11, FN1, HDAC3/7, PTEN, L1CAM, OLIG2, TIMP4, IGFBP2, and GFAP. The analyses also comprised prognosis prediction formulae that could distinguish between the survival curves of the glioblastoma patients. In addition to the genes mentioned above, HDAC1, FLT1, EGFR, MGMT, PGF, STAT3, SIRT1, and GADD45A constituted complex genetic interaction networks. The calculated status scores obtained by principal component analysis indicated that GLI genes covered the status of EPI, GSC, and MTT-related genes. Moreover, survival tree analyses indicated that MES^high, MES^highGLI^low, GSC^highGLI^low, MES^highMTT^low, and PGB^high showed poor prognoses and MES^middle, GSC^low, and PGB^low showed good prognoses, suggesting that enhanced EMT and GSC are associated with poor survival and that lower expression of EPI markers and the pre-stages of EMT are relatively less malignant in glioblastoma. These results demonstrate that the assessment of EMT and GSC enables the prediction of the prognosis of glioblastoma that would help develop novel therapeutics and de novo marker candidates for the prognoses of glioblastoma. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Human Astrocytomas Progression: Knowledge Increasing to Reach Therapeutic Horizons)

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22 pages, 7582 KiB

Open AccessArticle

Acetylcholine Receptor Activation as a Modulator of Glioblastoma Invasion

by Emily G. Thompson and Harald Sontheimer

Cells 2019, 8(10), 1203; https://doi.org/10.3390/cells8101203 - 5 Oct 2019

Cited by 32 | Viewed by 3741

Abstract

Grade IV astrocytomas, or glioblastomas (GBMs), are the most common malignant primary brain tumor in adults. The median GBM patient survival of 12–15 months has remained stagnant, in spite of treatment strategies, making GBMs a tremendous challenge clinically. This is at least in part due to the complex interaction of GBM cells with the brain microenvironment and their tendency to aggressively infiltrate normal brain tissue. GBMs frequently invade supratentorial brain regions that are richly innervated by neurotransmitter projections, most notably acetylcholine (ACh). Here, we asked whether ACh signaling influences the biology of GBMs. We examined the expression and function of known ACh receptors (AChRs) in large GBM datasets, as well as, human GBM cell lines and patient-derived xenograft lines. Using RNA-Seq data from the “The Cancer Genome Atlas” (TCGA), we confirmed the expression of AChRs and demonstrated the functionality of these receptors in GBM cells with time-lapse calcium imaging. AChR activation did not alter cell proliferation or migration, however, it significantly increased cell invasion through complex extracellular matrices. This was due to the enhanced activity of matrix metalloproteinase-9 (MMP-9) from GBM cells, which we found to be dependent on an intracellular calcium-dependent mechanism. Consistent with these findings, AChRs were significantly upregulated in regions of GBM infiltration in situ (Ivy Glioblastoma Atlas Project) and elevated expression of muscarinic AChR M₃ correlated with reduced patient survival (TCGA). Data from the Repository for Molecular Brain Neoplasia Data (REMBRANDT) dataset also showed the co-expression of choline transporters, choline acetyltransferase, and vesicular acetylcholine transporters, suggesting that GBMs express all the proteins required for ACh synthesis and release. These findings identify ACh as a modulator of GBM behavior and posit that GBMs may utilize ACh as an autocrine signaling molecule. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Human Astrocytomas Progression: Knowledge Increasing to Reach Therapeutic Horizons)

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Review

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14 pages, 1161 KiB

Open AccessReview

Exploring Novel Molecular Targets for the Treatment of High-Grade Astrocytomas Using Peptide Therapeutics: An Overview

by Giulia Guidotti, Liliana Brambilla and Daniela Rossi

Cells 2020, 9(2), 490; https://doi.org/10.3390/cells9020490 - 20 Feb 2020

Cited by 8 | Viewed by 3702

Abstract

Diffuse astrocytomas are the most aggressive and lethal glial tumors of the central nervous system (CNS). Their high cellular heterogeneity and the presence of specific barriers, i.e., blood–brain barrier (BBB) and tumor barrier, make these cancers poorly responsive to all kinds of currently available therapies. Standard therapeutic approaches developed to prevent astrocytoma progression, such as chemotherapy and radiotherapy, do not improve the average survival of patients. However, the recent identification of key genetic alterations and molecular signatures specific for astrocytomas has allowed the advent of novel targeted therapies, potentially more efficient and characterized by fewer side effects. Among others, peptides have emerged as promising therapeutic agents, due to their numerous advantages when compared to standard chemotherapeutics. They can be employed as (i) pharmacologically active agents, which promote the reduction of tumor growth; or (ii) carriers, either to facilitate the translocation of drugs through brain, tumor, and cellular barriers, or to target tumor-specific receptors. Since several pathways are normally altered in malignant gliomas, better outcomes may result from combining multi-target strategies rather than targeting a single effector. In the last years, several preclinical studies with different types of peptides moved in this direction, providing promising results in murine models of disease and opening new perspectives for peptide applications in the treatment of high-grade brain tumors. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Human Astrocytomas Progression: Knowledge Increasing to Reach Therapeutic Horizons)

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23 pages, 1060 KiB

Open AccessReview

Emerging Role of Cellular Prion Protein in the Maintenance and Expansion of Glioma Stem Cells

by Stefano Thellung, Alessandro Corsaro, Alessia G. Bosio, Martina Zambito, Federica Barbieri, Michele Mazzanti and Tullio Florio

Cells 2019, 8(11), 1458; https://doi.org/10.3390/cells8111458 - 18 Nov 2019

Cited by 12 | Viewed by 3972

Abstract

Cellular prion protein (PrP^C) is a membrane-anchored glycoprotein representing the physiological counterpart of PrP scrapie (PrP^Sc), which plays a pathogenetic role in prion diseases. Relatively little information is however available about physiological role of PrP^C. Although PrP^C ablation in mice does not induce lethal phenotypes, impairment of neuronal and bone marrow plasticity was reported in embryos and adult animals. In neurons, PrP^C stimulates neurite growth, prevents oxidative stress-dependent cell death, and favors antiapoptotic signaling. However, PrP^C activity is not restricted to post-mitotic neurons, but promotes cell proliferation and migration during embryogenesis and tissue regeneration in adult. PrP^C acts as scaffold to stabilize the binding between different membrane receptors, growth factors, and basement proteins, contributing to tumorigenesis. Indeed, ablation of PrP^C expression reduces cancer cell proliferation and migration and restores cell sensitivity to chemotherapy. Conversely, PrP^C overexpression in cancer stem cells (CSCs) from different tumors, including gliomas—the most malignant brain tumors—is predictive for poor prognosis, and correlates with relapses. The mechanisms of the PrP^C role in tumorigenesis and its molecular partners in this activity are the topic of the present review, with a particular focus on PrP^C contribution to glioma CSCs multipotency, invasiveness, and tumorigenicity. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Human Astrocytomas Progression: Knowledge Increasing to Reach Therapeutic Horizons)

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11 pages, 1057 KiB

Open AccessReview

Sonodynamic Therapy for Gliomas. Perspectives and Prospects of Selective Sonosensitization of Glioma Cells

by Krzysztof Bilmin, Tamara Kujawska and Paweł Grieb

Cells 2019, 8(11), 1428; https://doi.org/10.3390/cells8111428 - 13 Nov 2019

Cited by 51 | Viewed by 4958

Abstract

Malignant glial tumors (gliomas) are the second (after cerebral stroke) cause of death from diseases of the central nervous system. The current routine therapy, involving a combination of tumor resection, radio-, and chemo-therapy, only modestly improves survival. Sonodynamic therapy (SDT) has been broadly defined as a synergistic effect of sonication applied in combination with substances referred to as “sonosensitizers”. The current review focuses on the possibility of the use of tumor-seeking sonosensitizers, in particular 5-aminolevulinic acid, to control recurring gliomas. In this application, SDT employs a principle similar to that of the more widely-known photodynamic therapy of superficially located cancers, the difference being the use of ultrasound instead of light to deliver the energy necessary to eliminate the sensitized malignant cells. The ability of ultrasound to penetrate brain tissues makes it possible to reach deeply localized intracranial tumors such as gliomas. The major potential advantage of this variant of SDT is its relative non-invasiveness and possibility of repeated application. Until now, there have been no clinical data regarding the efficacy and safety of such treatment for malignant gliomas, but the preclinical data are encouraging. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Human Astrocytomas Progression: Knowledge Increasing to Reach Therapeutic Horizons)

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