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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (26 June 2021) | Viewed by 47851

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Special Issue Editor

Dr. Gaetano Finocchiaro

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Guest Editor

Foundation IRCCS Neurological Institute "C. Besta", Milan, Italy
Interests: glioblastoma; glioma; dendritic cell immunotherapy; neurofibromatosis type 1

Special Issue Information

Dear Colleagues,

Glioblastoma (GBM: the “M” keeps a signature of the old definition, “multiforme”) remains the most aggressive of gliomas and all primary brain tumors. Primary GBMs are those that present themselves as such since disease onset, without a previous history of lower-grade gliomas. In this series of papers hosted by “Cancers” we would like not only to point out what the state of the art is at present but also to add novel data and intriguing findings deriving from the considerable research flow on GBM that is growing in recent years.

The first area relates to GBM diagnosis. As Dr. Vogelstein pointed out in his introduction to the 2017 AACR meeting, to improve our success in treating tumors, and GBM makes no exception to this, we need to diagnose them earlier, when they are much smaller. Analysis of cell-free GBM DNA in the cerebrospinal fluid and, possibly, in peripheral blood could give hints on the aggressiveness of the tumor, which is molecularly and consequently clinically heterogeneous, and help to accelerate therapeutic strategies for the most aggressive forms. Epigenetic profiling can then help to refine diagnosis and provide novel hints on its evolution as well as therapeutic perspectives.

The other area of research is related to the characterization of the immunological texture of GBM. The recent, negative results of phase III immunotherapy studies with checkpoint inhibitors and vaccines based on specific mutations like EGFRvIII, are telling us that without an in-depth understanding of immunosuppressive strategies of GBM it will be difficult to design a second wave of immunotherapy therapeutic “attacks” with increased chances of success.

Dr. Gaetano Finocchiaro
Guest Editor

Manuscript Submission Information

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

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

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Glioblastoma
GBM diagnosis
immunotherapy
checkpoint inhibitors
vaccines

Published Papers (12 papers)

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Editorial

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4 pages, 321 KiB

Open AccessEditorial

Glioblastomas

by Gaetano Finocchiaro and Giulia Berzero

Cancers 2022, 14(1), 104; https://doi.org/10.3390/cancers14010104 - 27 Dec 2021

Viewed by 2666

Abstract

Years ago, glioblastoma lost its second name, multiforme, which possibly was an unfortunate decision given the extraordinary heterogeneity of this overly aggressive primary brain tumor, as effectively exemplified by this Latin adjective [...] Full article

(This article belongs to the Special Issue Glioblastomas)

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Research

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22 pages, 53837 KiB

Open AccessArticle

SLUG and Truncated TAL1 Reduce Glioblastoma Stem Cell Growth Downstream of Notch1 and Define Distinct Vascular Subpopulations in Glioblastoma Multiforme

by Sophie Guelfi, Béatrice Orsetti, Virginie Deleuze, Valérie Rigau, Luc Bauchet, Hugues Duffau, Bernard Rothhut and Jean-Philippe Hugnot

Cancers 2021, 13(21), 5393; https://doi.org/10.3390/cancers13215393 - 27 Oct 2021

Cited by 9 | Viewed by 2560

Abstract

Glioblastomas (GBM) are high-grade brain tumors, containing cells with distinct phenotypes and tumorigenic potentials, notably aggressive and treatment-resistant multipotent glioblastoma stem cells (GSC). The molecular mechanisms controlling GSC plasticity and growth have only partly been elucidated. Contact with endothelial cells and the Notch1 pathway control GSC proliferation and fate. We used three GSC cultures and glioma resections to examine the expression, regulation, and role of two transcription factors, SLUG (SNAI2) and TAL1 (SCL), involved in epithelial to mesenchymal transition (EMT), hematopoiesis, vascular identity, and treatment resistance in various cancers. In vitro, SLUG and a truncated isoform of TAL1 (TAL1-PP22) were strongly upregulated upon Notch1 activation in GSC, together with LMO2, a known cofactor of TAL1, which formed a complex with truncated TAL1. SLUG was also upregulated by TGF-β1 treatment and by co-culture with endothelial cells. In patient samples, the full-length isoform TAL1-PP42 was expressed in all glioma grades. In contrast, SLUG and truncated TAL1 were preferentially overexpressed in GBMs. SLUG and TAL1 are expressed in the tumor microenvironment by perivascular and endothelial cells, respectively, and to a minor extent, by a fraction of epidermal growth factor receptor (EGFR) -amplified GBM cells. Mechanistically, both SLUG and truncated TAL1 reduced GSC growth after their respective overexpression. Collectively, this study provides new evidence for the role of SLUG and TAL1 in regulating GSC plasticity and growth. Full article

(This article belongs to the Special Issue Glioblastomas)

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Graphical abstract

21 pages, 7009 KiB

Open AccessArticle

Intrinsic Interferon Signaling Regulates the Cell Death and Mesenchymal Phenotype of Glioblastoma Stem Cells

by Sabbir Khan, Rajasekaran Mahalingam, Shayak Sen, Emmanuel Martinez-Ledesma, Arshad Khan, Kaitlin Gandy, Frederick F. Lang, Erik P. Sulman, Kristin D. Alfaro-Munoz, Nazanin K. Majd, Veerakumar Balasubramaniyan and John F. de Groot

Cancers 2021, 13(21), 5284; https://doi.org/10.3390/cancers13215284 - 21 Oct 2021

Cited by 15 | Viewed by 3042

Abstract

Interferon (IFN) signaling contributes to stemness, cell proliferation, cell death, and cytokine signaling in cancer and immune cells; however, the role of IFN signaling in glioblastoma (GBM) and GBM stem-like cells (GSCs) is unclear. Here, we investigated the role of cancer-cell-intrinsic IFN signaling in tumorigenesis in GBM. We report here that GSCs and GBM tumors exhibited differential cell-intrinsic type I and type II IFN signaling, and high IFN/STAT1 signaling was associated with mesenchymal phenotype and poor survival outcomes. In addition, chronic inhibition of IFN/STAT1 signaling decreased cell proliferation and mesenchymal signatures in GSCs with intrinsically high IFN/STAT1 signaling. IFN-β exposure induced apoptosis in GSCs with intrinsically high IFN/STAT1 signaling, and this effect was abolished by the pharmacological inhibitor ruxolitinib and STAT1 knockdown. We provide evidence for targeting IFN signaling in a specific sub-group of GBM patients. IFN-β may be a promising candidate for adjuvant GBM therapy. Full article

(This article belongs to the Special Issue Glioblastomas)

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20 pages, 6218 KiB

Open AccessArticle

Novel Insights into the Antagonistic Effects of Losartan against Angiotensin II/AGTR1 Signaling in Glioblastoma Cells

by Salvatore Panza, Rocco Malivindi, Amanda Caruso, Umberto Russo, Francesca Giordano, Balázs Győrffy, Luca Gelsomino, Francesca De Amicis, Ines Barone, Francesca Luisa Conforti, Cinzia Giordano, Daniela Bonofiglio, Stefania Catalano and Sebastiano Andò

Cancers 2021, 13(18), 4555; https://doi.org/10.3390/cancers13184555 - 10 Sep 2021

Cited by 6 | Viewed by 2558

Abstract

New avenues for glioblastoma therapy are required due to the limited mortality benefit of the current treatments. The renin-angiotensin system (RAS) exhibits local actions and works as a paracrine system in different tissues and tumors, including glioma. The glioblastoma cell lines U-87 MG and T98G overexpresses Angiotensin II (Ang II)/Angiotensin II type I receptor (AGTR1) signaling, which enhances in vitro and in vivo local estrogen production through a direct up-regulation of the aromatase gene promoters p I.f and p I.4. In addition, Ang II/AGTR1 signaling transactivates estrogen receptor-α in a ligand-independent manner through mitogen-activated protein kinase (MAPK) activation. The higher aromatase mRNA expression in patients with glioblastoma was associated with the worst survival prognostic, according to The Cancer Genome Atlas (TCGA). An intrinsic immunosuppressive glioblastoma tumor milieu has been previously documented. We demonstrate how Ang II treatment in glioblastoma cells increases programmed death-ligand 1 (PD-L1) expression reversed by combined exposure to Losartan (LOS) in vitro and in vivo. Our findings highlight how LOS, in addition, antagonizes the previously documented neoangiogenetic, profibrotic, and immunosuppressive effects of Ang II and drastically inhibits its stimulatory effects on local estrogen production, sustaining glioblastoma cell growth. Thus, Losartan may represent an adjuvant pharmacological tool to be repurposed prospectively for glioblastoma treatment. Full article

(This article belongs to the Special Issue Glioblastomas)

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10 pages, 1611 KiB

Open AccessArticle

How about Levetiracetam in Glioblastoma? An Institutional Experience and Meta-Analysis

by Ramazan Jabbarli, Yahya Ahmadipour, Laurèl Rauschenbach, Alejandro N. Santos, Marvin Darkwah Oppong, Daniela Pierscianek, Carlos M. Quesada, Sied Kebir, Philipp Dammann, Nika Guberina, Björn Scheffler, Klaus Kaier, Martin Stuschke, Ulrich Sure and Karsten H. Wrede

Cancers 2021, 13(15), 3770; https://doi.org/10.3390/cancers13153770 - 27 Jul 2021

Cited by 11 | Viewed by 2141

Abstract

Despite multimodal treatment, the prognosis of patients with glioblastoma (GBM) remains poor. Previous studies showed conflicting results on the effect of antiepileptic drugs (AED) on GBM survival. We investigated the associations of different AED with overall survival (OS) and progression-free survival (PFS) in a large institutional GBM cohort (n = 872) treated January 2006 and December 2018. In addition, we performed a meta-analysis of previously published studies, including this study, to summarize the evidence on the value of AED for GBM prognosis. Of all perioperatively administered AED, only the use of levetiracetam (LEV) was associated with longer OS (median: 12.8 vs. 8.77 months, p < 0.0001) and PFS (7 vs. 4.5 months, p = 0.001). In the multivariable analysis, LEV was independently associated with longer OS (aHR = 0.74, p = 0.017) and PFS (aHR = 0.68, p = 0.008). In the meta-analysis with 5614 patients from the present and seven previously published studies, outcome benefit for OS (HR = 0.83, p = 0.02) and PFS (HR = 0.77, p = 0.02) in GBM individuals with LEV was confirmed. Perioperative treatment with LEV might improve the prognosis of GBM patients. We recommend a prospective randomized controlled trial addressing the efficacy of LEV in GBM treatment. Full article

(This article belongs to the Special Issue Glioblastomas)

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20 pages, 6406 KiB

Open AccessArticle

A Set of Cell Lines Derived from a Genetic Murine Glioblastoma Model Recapitulates Molecular and Morphological Characteristics of Human Tumors

by Barbara Costa, Michael N. C. Fletcher, Pavle Boskovic, Ekaterina L. Ivanova, Tanja Eisemann, Sabrina Lohr, Lukas Bunse, Martin Löwer, Stefanie Burchard, Andrey Korshunov, Nadia Coltella, Melania Cusimano, Luigi Naldini, Hai-Kun Liu, Michael Platten, Bernhard Radlwimmer, Peter Angel and Heike Peterziel

Cancers 2021, 13(2), 230; https://doi.org/10.3390/cancers13020230 - 10 Jan 2021

Cited by 10 | Viewed by 5134

Abstract

Glioblastomas (GBM) are the most aggressive tumors affecting the central nervous system in adults, causing death within, on average, 15 months after diagnosis. Immunocompetent in-vivo models that closely mirror human GBM are urgently needed for deciphering glioma biology and for the development of effective treatment options. The murine GBM cell lines currently available for engraftment in immunocompetent mice are not only exiguous but also inadequate in representing prominent characteristics of human GBM such as infiltrative behavior, necrotic areas, and pronounced tumor heterogeneity. Therefore, we generated a set of glioblastoma cell lines by repeated in vivo passaging of cells isolated from a neural stem cell-specific Pten/p53 double-knockout genetic mouse brain tumor model. Transcriptome and genome analyses of the cell lines revealed molecular heterogeneity comparable to that observed in human glioblastoma. Upon orthotopic transplantation into syngeneic hosts, they formed high-grade gliomas that faithfully recapitulated the histopathological features, invasiveness and immune cell infiltration characteristic of human glioblastoma. These features make our cell lines unique and useful tools to study multiple aspects of glioblastoma pathomechanism and to test novel treatments in an intact immune microenvironment. Full article

(This article belongs to the Special Issue Glioblastomas)

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13 pages, 1579 KiB

Open AccessArticle

The Suitability of Glioblastoma Cell Lines as Models for Primary Glioblastoma Cell Metabolism

by Anya L. Arthurs, Damien J. Keating, Brett W. Stringer and Simon J. Conn

Cancers 2020, 12(12), 3722; https://doi.org/10.3390/cancers12123722 - 11 Dec 2020

Cited by 9 | Viewed by 2534

Abstract

In contrast to most non-malignant tissue, cells comprising the brain tumour glioblastoma (GBM) preferentially utilise glycolysis for metabolism via “the Warburg effect”. Research into therapeutics targeting the disease’s highly glycolytic state offer a promising avenue to improve patient survival. These studies often employ GBM cell lines for in vitro studies which translate poorly to the in vivo patient context. The metabolic traits of five of the most used GBM cell lines were assessed and compared to primary GBM and matched, healthy brain tissue. In patient-derived GBM cell lines, the basal mitochondrial rate (p = 0.043) and ATP-linked respiration (p < 0.001) were lower than primary adjacent normal cells from the same patient, while reserve capacity (p = 0.037) and Krebs cycle capacity (p = 0.002) were higher. Three cell lines, U251MG, U373MG and D54, replicate the mitochondrial metabolism of primary GBM cells. Surprisingly, glycolytic capacity is not different between healthy and GBM tissue. The T98G cell line recapitulated glycolysis-related metabolic parameters of the primary GBM cells and is recommended for research relating to glycolysis. These findings can guide preclinical research into the development of novel therapeutics targeting metabolic pathways in GBM. Full article

(This article belongs to the Special Issue Glioblastomas)

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Review

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25 pages, 3655 KiB

Open AccessReview

Tumor-Associated Microglia and Macrophages in the Glioblastoma Microenvironment and Their Implications for Therapy

by Rikke Sick Andersen, Atul Anand, Dylan Scott Lykke Harwood and Bjarne Winther Kristensen

Cancers 2021, 13(17), 4255; https://doi.org/10.3390/cancers13174255 - 24 Aug 2021

Cited by 54 | Viewed by 5794

Abstract

Glioblastoma is the most frequent and malignant primary brain tumor. Standard of care includes surgery followed by radiation and temozolomide chemotherapy. Despite treatment, patients have a poor prognosis with a median survival of less than 15 months. The poor prognosis is associated with an increased abundance of tumor-associated microglia and macrophages (TAMs), which are known to play a role in creating a pro-tumorigenic environment and aiding tumor progression. Most treatment strategies are directed against glioblastoma cells; however, accumulating evidence suggests targeting of TAMs as a promising therapeutic strategy. While TAMs are typically dichotomously classified as M1 and M2 phenotypes, recent studies utilizing single cell technologies have identified expression pattern differences, which is beginning to give a deeper understanding of the heterogeneous subpopulations of TAMs in glioblastomas. In this review, we evaluate the role of TAMs in the glioblastoma microenvironment and discuss how their interactions with cancer cells have an extensive impact on glioblastoma progression and treatment resistance. Finally, we summarize the effects and challenges of therapeutic strategies, which specifically aim to target TAMs. Full article

(This article belongs to the Special Issue Glioblastomas)

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23 pages, 11957 KiB

Open AccessReview

Targeting CDK9 for the Treatment of Glioblastoma

by Alice Ranjan, Ying Pang, Madison Butler, Mythili Merchant, Olga Kim, Guangyang Yu, Yu-Ting Su, Mark R. Gilbert, David Levens and Jing Wu

Cancers 2021, 13(12), 3039; https://doi.org/10.3390/cancers13123039 - 18 Jun 2021

Cited by 14 | Viewed by 6657

Abstract

Glioblastoma is the most common and aggressive primary malignant brain tumor, and more than two-thirds of patients with glioblastoma die within two years of diagnosis. The challenges of treating this disease mainly include genetic and microenvironmental features that often render the tumor resistant to treatments. Despite extensive research efforts, only a small number of drugs tested in clinical trials have become therapies for patients. Targeting cyclin-dependent kinase 9 (CDK9) is an emerging therapeutic approach that has the potential to overcome the challenges in glioblastoma management. Here, we discuss how CDK9 inhibition can impact transcription, metabolism, DNA damage repair, epigenetics, and the immune response to facilitate an anti-tumor response. Moreover, we discuss small-molecule inhibitors of CDK9 in clinical trials and future perspectives on the use of CDK9 inhibitors in treating patients with glioblastoma. Full article

(This article belongs to the Special Issue Glioblastomas)

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19 pages, 1912 KiB

Open AccessReview

Permeabilizing Cell Membranes with Electric Fields

by Alondra A. Aguilar, Michelle C. Ho, Edwin Chang, Kristen W. Carlson, Arutselvan Natarajan, Tal Marciano, Ze’ev Bomzon and Chirag B. Patel

Cancers 2021, 13(9), 2283; https://doi.org/10.3390/cancers13092283 - 10 May 2021

Cited by 35 | Viewed by 4937

Abstract

The biological impact of exogenous, alternating electric fields (AEFs) and direct-current electric fields has a long history of study, ranging from effects on embryonic development to influences on wound healing. In this article, we focus on the application of electric fields for the treatment of cancers. In particular, we outline the clinical impact of tumor treating fields (TTFields), a form of AEFs, on the treatment of cancers such as glioblastoma and mesothelioma. We provide an overview of the standard mechanism of action of TTFields, namely, the capability for AEFs (e.g., TTFields) to disrupt the formation and segregation of the mitotic spindle in actively dividing cells. Though this standard mechanism explains a large part of TTFields’ action, it is by no means complete. The standard theory does not account for exogenously applied AEFs’ influence directly upon DNA nor upon their capacity to alter the functionality and permeability of cancer cell membranes. This review summarizes the current literature to provide a more comprehensive understanding of AEFs’ actions on cell membranes. It gives an overview of three mechanistic models that may explain the more recent observations into AEFs’ effects: the voltage-gated ion channel, bioelectrorheological, and electroporation models. Inconsistencies were noted in both effective frequency range and field strength between TTFields versus all three proposed models. We addressed these discrepancies through theoretical investigations into the inhomogeneities of electric fields on cellular membranes as a function of disease state, external microenvironment, and tissue or cellular organization. Lastly, future experimental strategies to validate these findings are outlined. Clinical benefits are inevitably forthcoming. Full article

(This article belongs to the Special Issue Glioblastomas)

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21 pages, 795 KiB

Open AccessReview

Adenosinergic Pathway: A Hope in the Immunotherapy of Glioblastoma

by Ketao Jin, Chunsen Mao, Lin Chen, Lude Wang, Yuyao Liu and Jianlie Yuan

Cancers 2021, 13(2), 229; https://doi.org/10.3390/cancers13020229 - 10 Jan 2021

Cited by 14 | Viewed by 3770

Abstract

Brain tumors comprise different types of malignancies, most of which are originated from glial cells. Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor with a poor response to conventional therapies and dismal survival rates (15 months) despite multimodal therapies. The development of immunotherapeutic strategies seems to be necessary to enhance the overall survival of GBM patients. So far, the immunotherapies applied in GBM had promising results in the primary phases of clinical trials but failed to continue their beneficial effects in later phases. GBM-microenvironment (GME) is a heterogenic and rigorously immunosuppressive milieu wrapping by an impenetrable blood-brain barrier. Hence, in-depth knowledge about the dominant immunosuppressive mechanisms in the GME could foster GBM immunotherapy. Recently, the adenosinergic pathway (AP) is found to be a major player in the suppression of antitumor immune responses in the GME. Tumor cells evolve to metabolize pro-inflammatory ATP to anti-inflammatory adenosine. Adenosine can suppress immune responses through the signaling of adenosine receptors on immune cells. The preclinical results targeting AP in GBM showed promising results in reinvigorating antitumor responses, overriding chemoresistance, and increasing survival. We reviewed the current GBM immunotherapies and elaborated on the role of AP in the immunopathogenesis, treatment, and even prognosis of GBM. We suggest that future clinical studies should consider this pathway in their combination therapies along with other immunotherapeutic approaches. Full article

(This article belongs to the Special Issue Glioblastomas)

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Other

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18 pages, 2208 KiB

Open AccessSystematic Review

Palliative Care Service Utilization and Advance Care Planning for Adult Glioblastoma Patients: A Systematic Review

by Adela Wu, Gabriela Ruiz Colón, Rebecca Aslakson, Erqi Pollom and Chirag B. Patel

Cancers 2021, 13(12), 2867; https://doi.org/10.3390/cancers13122867 - 8 Jun 2021

Cited by 18 | Viewed by 3980

Abstract

Glioblastoma (GBM) has a median overall survival of 16–21 months. As patients with GBM suffer concurrently from terminal cancer and a disease with progressive neurocognitive decline, advance care planning (ACP) and palliative care (PC) are critical. We conducted a systematic review exploring published literature on the prevalence of ACP, end-of-life (EOL) services utilization (including PC services), and experiences among adults with GBM. We searched from database inception until 20 December 2020. Preferred reporting items for systematic reviews guidelines were followed. Included studies were assessed for quality using the Newcastle-Ottawa Scale. The 16 articles were all nonrandomized studies conducted in six countries with all but two published in 2014 or later. ACP documentation varied from 4–55%, PC referral was pursued in 39–40% of cases, and hospice referrals were made for 66–76% of patients. Hospitalizations frequently occurred at the EOL with 20–56% of patients spending over 25% of their overall survival time hospitalized. Many GBM patients do not pursue ACP or have access to PC. There is a dearth of focused and high-quality studies on ACP, PC, and hospice use among adults with GBM. Prospective studies that address these and additional aspects related to EOL care, such as healthcare costs and inpatient supportive care needs, are needed. Full article

(This article belongs to the Special Issue Glioblastomas)

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