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Molecular Biology in Glioblastoma Multiforme Treatment

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

Deadline for manuscript submissions: closed (10 November 2021) | Viewed by 35218

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Special Issue Editor

Dr. Marco G. Paggi

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Guest Editor

IRCCS Regina Elena National Cancer Institute, Roma, Italy
Interests: glioblastoma; signal transduction; energy metabolism; small molecule inhibitors; drug repurposing; gender differences; clinical trials

Special Issue Information

Dear Colleagues,

Glioblastoma multiforme (GBM, glioblastoma) therapy remains an unmet medical need. Indeed, the best available therapy for newly diagnosed glioblastoma patients, i.e., surgical ablation followed by radiotherapy plus concomitant and adjuvant chemotherapy with temozolomide, is associated with a median survival of less than 15 months, with very few cases of long-term survivors. Such an adverse scenario creates an urgent need for novel therapeutic approaches.

Glioblastoma is characterized by aggressive, chemo-resistant, and relapse-prone behavior, all of which are mainly attributed to its remarkable intra-tumor molecular heterogeneity, which makes it difficult to eradicate, even by means of targeted therapies, which are typically able to eliminate only a percentage of cancer cells, thus increasing the chance of relapse and drug resistance. If we also consider that this last one is associated with unpredictable genetic drifts under therapeutic pressure, the whole picture appears to be quite challenging, especially for the choice of second-line treatment.

For these reasons, it is crucial to explore in-depth the bio-molecular features of this disease, turning our attention towards those common traits that could involve the majority of the glioblastoma cell population, such as energy metabolism requirements, signal transduction pathways, the stability of the mitotic apparatus, immunological features, and, finally, the neurotransmitter-mediated interplay between glioblastoma cells and neurons/astrocytes.

This Special Issue aims to present a collection of studies that expand our knowledge of the molecular features of glioblastoma, with the purpose of identifying and tackling its specific vulnerabilities and swiftly transitioning this information from the bench to the bedside.

Dr. Marco G. Paggi
Guest Editor

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Keywords

glioblastoma
signal transduction
energy metabolism
small molecule inhibitors
drug therapy
tumor immune microenvironment
neurotransmitters
clinical trials.

Published Papers (10 papers)

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Editorial

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4 pages, 210 KiB

Open AccessEditorial

Molecular Biology in Glioblastoma Multiforme Treatment

by Claudia Abbruzzese, Michele Persico, Silvia Matteoni and Marco G. Paggi

Cells 2022, 11(11), 1850; https://doi.org/10.3390/cells11111850 - 05 Jun 2022

Cited by 3 | Viewed by 2264

Abstract

Glioblastoma (GBM, grade IV astrocytoma), the most frequently occurring primary brain tumor, presents unique challenges to therapy due to its location, aggressive biological behavior, and diffuse infiltrative growth, thus contributing to having disproportionately high morbidity and mortality [...] Full article

(This article belongs to the Special Issue Molecular Biology in Glioblastoma Multiforme Treatment)

Research

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16 pages, 2819 KiB

Open AccessArticle

Proliferating CD8⁺ T Cell Infiltrates Are Associated with Improved Survival in Glioblastoma

by Ileana S. Mauldin, Jasmin Jo, Nolan A. Wages, Lalanthica V. Yogendran, Adela Mahmutovic, Samuel J. Young, Maria Beatriz Lopes, Craig L. Slingluff, Jr., Loren D. Erickson and Camilo E. Fadul

Cells 2021, 10(12), 3378; https://doi.org/10.3390/cells10123378 - 01 Dec 2021

Cited by 27 | Viewed by 3332

Abstract

Background: tumor-infiltrating lymphocytes are prognostic in many human cancers. However, the prognostic value of lymphocytes infiltrating glioblastoma (GBM), and roles in tumor control or progression are unclear. We hypothesized that B and T cell density, and markers of their activity, proliferation, differentiation, or function, would have favorable prognostic significance for patients with GBM. Methods: initial resection specimens from 77 patients with IDH1/2 wild type GBM who received standard-of-care treatment were evaluated with multiplex immunofluorescence histology (mIFH), for the distribution, density, differentiation, and proliferation of T cells and B cells, as well as for the presence of tertiary lymphoid structures (TLS), and IFNγ expression. Immune infiltrates were evaluated for associations with overall survival (OS) by univariate and multivariate Cox proportional hazards modeling. Results: in univariate analyses, improved OS was associated with high densities of proliferating (Ki67⁺) CD8⁺ cells (HR 0.36, p = 0.001) and CD20⁺ cells (HR 0.51, p = 0.008), as well as CD8⁺Tbet⁺ cells (HR 0.46, p = 0.004), and RORγt⁺ cells (HR 0.56, p = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, p = 0.036). In multivariable analyses, adjusting for clinical variables, including age, resection extent, Karnofsky Performance Status (KPS), and MGMT methylation status, improved OS was associated with high densities of proliferating (Ki67⁺) CD8⁺ cells (HR 0.15, p < 0.001), and higher ratios of CD8⁺ cells to CD4⁺ cells (HR 0.31, p = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, p = 0.005) and higher mean intensities of IFNγ (HR 2.13, p = 0.027). Conclusions: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. These findings suggest that survival may be enhanced by increasing proliferation of tumor-reactive CD8⁺ T cells and that approaches may be needed to promote CD8⁺ T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment. Full article

(This article belongs to the Special Issue Molecular Biology in Glioblastoma Multiforme Treatment)

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15 pages, 3496 KiB

Open AccessArticle

Kynurenine Monooxygenase Expression and Activity in Human Astrocytomas

by Gustavo Ignacio Vázquez Cervantes, Benjamín Pineda, Daniela Ramírez Ortega, Alelí Salazar, Dinora Fabiola González Esquivel, Daniel Rembao, Sergio Zavala Vega, Saúl Gómez-Manzo, Gonzalo Pérez de la Cruz and Verónica Pérez de la Cruz

Cells 2021, 10(8), 2028; https://doi.org/10.3390/cells10082028 - 08 Aug 2021

Cited by 8 | Viewed by 2785

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. The enzyme indoleamine-2,3-dioxygenase (IDO), which participates in the rate-limiting step of tryptophan catabolism through the kynurenine pathway (KP), is associated with poor prognosis in patients with GBM. The metabolites produced after tryptophan oxidation have immunomodulatory properties that can support the immunosuppressor environment. In this study, mRNA expression, protein expression, and activity of the enzyme kynurenine monooxygenase (KMO) were analyzed in GBM cell lines (A172, LN-18, U87, U373) and patient-derived astrocytoma samples. KMO mRNA expression was assessed by real-time RT-qPCR, KMO protein expression was evaluated by flow cytometry and immunofluorescence, and KMO activity was determined by quantifying 3-hydroxykynurenine by HPLC. Heterogenous patterns of both KMO expression and activity were observed among the GBM cell lines, with the A172 cell line showing the highest KMO expression and activity. Higher KMO mRNA expression was observed in glioma samples than in patients diagnosed with only a neurological disease; high KMO mRNA expression was also observed when using samples from patients with GBM in the TCGA program. The KMO protein expression was localized in GFAP⁺ cells in tumor tissue. These results suggest that KMO is a relevant target to be explored in glioma since it might play a role in supporting tumor metabolism and immune suppression. Full article

(This article belongs to the Special Issue Molecular Biology in Glioblastoma Multiforme Treatment)

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17 pages, 2358 KiB

Open AccessArticle

Involvement of the Catecholamine Pathway in Glioblastoma Development

by Zoltán Kraboth, Bela Kajtár, Bence Gálik, Attila Gyenesei, Attila Miseta and Bernadette Kalman

Cells 2021, 10(3), 549; https://doi.org/10.3390/cells10030549 - 04 Mar 2021

Cited by 5 | Viewed by 2204

Abstract

Glioblastoma (GBM) is the most aggressive tumor of the central nervous system (CNS). The standard of care improves the overall survival of patients only by a few months. Explorations of new therapeutic targets related to molecular properties of the tumor are under way. Even though neurotransmitters and their receptors normally function as mediators of interneuronal communication, growing data suggest that these molecules are also involved in modulating the development and growth of GBM by acting on neuronal and glioblastoma stem cells. In our previous DNA CpG methylation studies, gene ontology analyses revealed the involvement of the monoamine pathway in sequential GBM. In this follow-up study, we quantitated the expression levels of four selected catecholamine pathway markers (alpha 1D adrenergic receptor—ADRA1D; adrenergic beta receptor kinase 1 or G protein-coupled receptor kinase 2—ADRBK1/GRK2; dopamine receptor D2—DRD2; and synaptic vesicle monoamine transporter—SLC18A2) by immunohistochemistry, and compared the histological scores with the methylation levels within the promoters + genes of these markers in 21 pairs of sequential GBM and in controls. Subsequently, we also determined the promoter and gene methylation levels of the same markers in an independent database cohort of sequential GBM pairs. These analyses revealed partial inverse correlations between the catecholamine protein expression and promoter + gene methylation levels, when the tumor and control samples were compared. However, we found no differences in the promoter + gene methylation levels of these markers in either our own or in the database primary–recurrent GBM pairs, despite the higher protein expression of all markers in the primary samples. This observation suggests that regulation of catecholamine expression is only partially related to CpG methylation within the promoter + gene regions, and additional mechanisms may also influence the expression of these markers in progressive GBM. These analyses underscore the involvement of certain catecholamine pathway markers in GBM development and suggest that these molecules mediating or modulating tumor growth merit further exploration. Full article

(This article belongs to the Special Issue Molecular Biology in Glioblastoma Multiforme Treatment)

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16 pages, 2459 KiB

Open AccessArticle

Different Calculation Strategies Are Congruent in Determining Chemotherapy Resistance of Brain Tumors In Vitro

by Igor Fischer, Ann-Christin Nickel, Nan Qin, Kübra Taban, David Pauck, Hans-Jakob Steiger, Marcel Kamp, Sajjad Muhammad, Daniel Hänggi, Ellen Fritsche, Marc Remke and Ulf Dietrich Kahlert

Cells 2020, 9(12), 2689; https://doi.org/10.3390/cells9122689 - 15 Dec 2020

Cited by 4 | Viewed by 2197

Abstract

In cancer pharmacology, a drug candidate’s therapeutic potential is typically expressed as its ability to suppress cell growth. Different methods in assessing the cell phenotype and calculating the drug effect have been established. However, inconsistencies in drug response outcomes have been reported, and it is still unclear whether and to what extent the choice of data post-processing methods is responsible for that. Studies that systematically examine these questions are rare. Here, we compare three established calculation methods on a collection of nine in vitro models of glioblastoma, exposed to a library of 231 clinical drugs. The therapeutic potential of the drugs is determined on the growth curves, using growth inhibition 50% (GI

_{50}

) and point-of-departure (PoD) as the criteria. An effect is detected on 36% of the drugs when relying on GI

_{50}

and on 27% when using PoD. For the area under the curve (AUC), a threshold of 9.5 or 10 could be set to discriminate between the drugs with and without an effect. GI

_{50}

, PoD, and AUC are highly correlated. The ranking of substances by different criteria varies somewhat, but the group of the top 20 substances according to one criterion typically includes 17–19 top candidates according to another. In addition to generating preclinical values with high clinical potential, we present off-target appreciation of top substance predictions by interrogating the drug response data of non-cancer cells in our calculation technology. Full article

(This article belongs to the Special Issue Molecular Biology in Glioblastoma Multiforme Treatment)

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Review

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18 pages, 1038 KiB

Open AccessReview

Tackling the Behavior of Cancer Cells: Molecular Bases for Repurposing Antipsychotic Drugs in the Treatment of Glioblastoma

by Michele Persico, Claudia Abbruzzese, Silvia Matteoni, Paola Matarrese, Anna Maria Campana, Veronica Villani, Andrea Pace and Marco G. Paggi

Cells 2022, 11(2), 263; https://doi.org/10.3390/cells11020263 - 13 Jan 2022

Cited by 10 | Viewed by 2745

Abstract

Glioblastoma (GBM) is associated with a very dismal prognosis, and current therapeutic options still retain an overall unsatisfactorily efficacy in clinical practice. Therefore, novel therapeutic approaches and effective medications are highly needed. Since the development of new drugs is an extremely long, complex and expensive process, researchers and clinicians are increasingly considering drug repositioning/repurposing as a valid alternative to the standard research process. Drug repurposing is also under active investigation in GBM therapy, since a wide range of noncancer and cancer therapeutics have been proposed or investigated in clinical trials. Among these, a remarkable role is played by the antipsychotic drugs, thanks to some still partially unexplored, interesting features of these agents. Indeed, antipsychotic drugs have been described to interfere at variable incisiveness with most hallmarks of cancer. In this review, we analyze the effects of antipsychotics in oncology and how these drugs can interfere with the hallmarks of cancer in GBM. Overall, according to available evidence, mostly at the preclinical level, it is possible to speculate that repurposing of antipsychotics in GBM therapy might contribute to providing potentially effective and inexpensive therapies for patients with this disease. Full article

(This article belongs to the Special Issue Molecular Biology in Glioblastoma Multiforme Treatment)

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28 pages, 1330 KiB

Open AccessReview

Friend or Foe: Paradoxical Roles of Autophagy in Gliomagenesis

by Don Carlo Ramos Batara, Moon-Chang Choi, Hyeon-Uk Shin, Hyunggee Kim and Sung-Hak Kim

Cells 2021, 10(6), 1411; https://doi.org/10.3390/cells10061411 - 06 Jun 2021

Cited by 15 | Viewed by 4399

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor in adults, with a poor median survival of approximately 15 months after diagnosis. Despite several decades of intensive research on its cancer biology, treatment for GBM remains a challenge. Autophagy, a fundamental homeostatic mechanism, is responsible for degrading and recycling damaged or defective cellular components. It plays a paradoxical role in GBM by either promoting or suppressing tumor growth depending on the cellular context. A thorough understanding of autophagy’s pleiotropic roles is needed to develop potential therapeutic strategies for GBM. In this paper, we discussed molecular mechanisms and biphasic functions of autophagy in gliomagenesis. We also provided a summary of treatments for GBM, emphasizing the importance of autophagy as a promising molecular target for treating GBM. Full article

(This article belongs to the Special Issue Molecular Biology in Glioblastoma Multiforme Treatment)

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22 pages, 1710 KiB

Open AccessEditor’s ChoiceReview

Glutamatergic Mechanisms in Glioblastoma and Tumor-Associated Epilepsy

by Falko Lange, Julia Hörnschemeyer and Timo Kirschstein

Cells 2021, 10(5), 1226; https://doi.org/10.3390/cells10051226 - 17 May 2021

Cited by 39 | Viewed by 5383

Abstract

The progression of glioblastomas is associated with a variety of neurological impairments, such as tumor-related epileptic seizures. Seizures are not only a common comorbidity of glioblastoma but often an initial clinical symptom of this cancer entity. Both, glioblastoma and tumor-associated epilepsy are closely linked to one another through several pathophysiological mechanisms, with the neurotransmitter glutamate playing a key role. Glutamate interacts with its ionotropic and metabotropic receptors to promote both tumor progression and excitotoxicity. In this review, based on its physiological functions, our current understanding of glutamate receptors and glutamatergic signaling will be discussed in detail. Furthermore, preclinical models to study glutamatergic interactions between glioma cells and the tumor-surrounding microenvironment will be presented. Finally, current studies addressing glutamate receptors in glioma and tumor-related epilepsy will be highlighted and future approaches to interfere with the glutamatergic network are discussed. Full article

(This article belongs to the Special Issue Molecular Biology in Glioblastoma Multiforme Treatment)

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15 pages, 2604 KiB

Open AccessReview

The Mechanism of Asparagine Endopeptidase in the Progression of Malignant Tumors: A Review

by Wenrui Zhang and Yingying Lin

Cells 2021, 10(5), 1153; https://doi.org/10.3390/cells10051153 - 10 May 2021

Cited by 28 | Viewed by 4163

Abstract

Asparagine endopeptidase (AEP), also called legumain, is currently the only known cysteine protease that specifically cleaves peptide bonds in asparaginyl residue in the mammalian genome. Since 2003, AEP has been reported to be widely expressed in a variety of carcinomas and is considered a potential therapeutic target. In the following years, researchers intensively investigated the substrates of AEP and the mechanism of AEP in partial tumors. With the identification of substrate proteins such as P53, integrin αvβ3, MMP-2, and MMP-9, the biochemical mechanism of AEP in carcinomas is also more precise. This review will clarify the probable mechanisms of AEP in the progression of breast carcinoma, glioblastoma, gastric carcinoma, and epithelial ovarian carcinoma. This review will also discuss the feasibility of targeted therapy with AEP inhibitor (AEPI) in these carcinomas. Full article

(This article belongs to the Special Issue Molecular Biology in Glioblastoma Multiforme Treatment)

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16 pages, 949 KiB

Open AccessReview

Oncogenesis, Microenvironment Modulation and Clinical Potentiality of FAP in Glioblastoma: Lessons Learned from Other Solid Tumors

by Yixin Shi, Ziren Kong, Penghao Liu, Guozhu Hou, Jiaming Wu, Wenbin Ma, Xin Cheng and Yu Wang

Cells 2021, 10(5), 1142; https://doi.org/10.3390/cells10051142 - 10 May 2021

Cited by 13 | Viewed by 4206

Abstract

Currently, glioblastoma (GBM) is the most common malignant tumor of the central nervous system in adults. Fibroblast activation protein (FAP) is a member of the dipeptidyl peptidase family, which has catalytic activity and is engaged in protein recruitment and scaffolds. Recent studies have found that FAP expression in different types of cells within the GBM microenvironment is typically upregulated compared with that in lower grade glioma and is most pronounced in the mesenchymal subtype of GBM. As a marker of cancer-associated fibroblasts (CAFs) with tumorigenic activity, FAP has been proven to promote tumor growth and invasion via hydrolysis of molecules such as brevican in the extracellular matrix and targeting of downstream pathways and substrates, such as fibroblast growth factor 21 (FGF21). In addition, based on its ability to suppress antitumor immunity in GBM and induce temozolomide resistance, FAP may be a potential target for immunotherapy and reversing temozolomide resistance; however, current studies on therapies targeting FAP are still limited. In this review, we summarized recent progress in FAP expression profiling and the understanding of the biological function of FAP in GBM and raised the possibility of FAP as an imaging biomarker and therapeutic target. Full article

(This article belongs to the Special Issue Molecular Biology in Glioblastoma Multiforme Treatment)

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