Submit to Cancers Review for Cancers Propose a Special Issue

Journal Browser

► Journal Browser

Brain Tumor Microenvironment

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 18725

Share This Special Issue

Special Issue Editors

Prof. Annunziato Mangiola

E-Mail Website
Guest Editor

Department of Neurosciences, Imaging and Clinical Sciences, “G. D’Annunzio” University, Chieti, Italy
Interests: neurosurgery; neuro-oncology; brain tumor microenvironment; intraoperative imaging; functional neuro-oncology

Dr. Gianluca Trevisi

E-Mail Website
Guest Editor

Special Issue Information

Aim: In this Special Issue authors will focus on molecular, histopathological and imaging features of primary and metastatic brain tumor microenvironment. This Special Issue will include pre-clinical and clinical studies focusing on biological characterization, physio-pathological insights, clinico-pathological applications including advanced imaging techniques and the identification of new potential therapeutic targets and agents. Included studies may be based on preclinical models as well as clinical series. Original research manuscript are favored. High quality systematic reviews and meta-analysis will be also considered for publication.

Scope: Identification, through pre-clinical and clinical models, of molecular features and mechanisms, possible targets, therapeutic agents, and innovative imaging strategies in primary and metastatic brain tumors.

Dear Colleagues,

The unique brain microenvironment, with peculiar cell types and immune environment, anatomical structures including blood-brain-barrier, and metabolic constraints represent the landscape where primary and metastatic brain tumors origin and grow, influencing their biological behavior.

Indeed, gliomas, the most common malignant primary brain tumors, are still a major challenge for neurosurgeons and neuro-oncologists due to their high recurrence rate and overall poor survival.

Cellular interactions among cancer cells and resident and recruited, tumor-associated, immune cells, stromal cells, glial cells, extracellular matrix, affect tumor growth and resistance to therapies. Recently, extracellular vesicles/exosomes have been shown to take part to the cross-talk between tumor cells and adjacent brain, with a possible role as brain tumors biomarker.

Similar mechanisms favor the seeding and development of metastatic brain tumors, with the brain microenvironment, drastically different from microenvironments of extracranial lesions, imposing a distinct and profound selective pressure on tumor cells that, in turn, shapes the metastatic process and therapeutic responses.

We are pleased to invite you (…)

Submit your research focusing on molecular, histopathological and imaging features of primary and metastatic brain tumor microenvironment. This Special Issue will include pre-clinical and clinical studies focusing on biological characterization, physio-pathological insights, clinico-pathological applications including advanced imaging techniques and the identification of new potential therapeutic targets and agents. Included studies may be based on preclinical models as well as clinical series. Original research manuscript are favored. High quality systematic reviews and meta-analysis will be also considered for publication.

This Special Issue aims to

Underpin genomic, transcriptomic, proteomic, and metabolomic characteristics of brain tumor microenvironment which influence tumor growth, behavior, and resistance to therapy. This will help to develop or validate pre-clinical and clinical models aimed to detect therapeutic targets and agents for primary and metastatic brain tumors. Also studies on extracellular vesicles/exosomes and their role in the cross-talk between tumor cells and adjacent brain are welcome.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:

genomic, transcriptomic, proteomic, and metabolomic studies on brain tumor microenvironment
preclinical models aimed to detect possible biomarkers, therapeutic targets and/or therapeutic agents
clinical series on possible biomarkers, therapeutic targets and/or therapeutic agents
advanced imaging techniques, including nuclear medicine studies and intraoperative imaging to characterize brain tumor microenvironment
surgical series using innovative tools or strategies to target brain tumor microenvironment

We look forward to receiving your contributions.

Prof. Annunziato Mangiola
Dr. Gianluca Trevisi
Guest Editors

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

CNS immunity
brain metastasis
brain tumor
glioma
microenvironment
microglia
niche
immunotherapy
peripheral brain zone
tumor microenvironment

Published Papers (11 papers)

Download All Papers

Research

Jump to: Review, Other

16 pages, 18753 KiB

Open AccessArticle

Classification of Brainstem Gliomas Based on Tumor Microenvironment Status

by Xiong Xiao, Xiaoou Li, Yi Wang, Changcun Pan, Peng Zhang, Guocan Gu, Tian Li, Zhuang Jiang, Yang Zhang and Liwei Zhang

Cancers 2023, 15(17), 4224; https://doi.org/10.3390/cancers15174224 - 23 Aug 2023

Cited by 1 | Viewed by 1088

Abstract

The inter-tumor heterogeneity of the tumor microenvironment (TME) and how it correlates with clinical profiles and biological characteristics in brainstem gliomas (BSGs) remain unknown, dampening the development of novel therapeutics against BSGs. The TME status was determined with a list of pan-cancer conserved gene expression signatures using a single-sample gene set enrichment analysis (ssGSEA) and was subsequently clustered via consensus clustering. BSGs exhibited a high inter-tumor TME heterogeneity and were classified into four clusters: “immune-enriched, fibrotic”, “immune-enriched, non-fibrotic”, “fibrotic”, and “depleted”. The “fibrotic” cluster had a higher proportion of diffuse intrinsic pontine gliomas (p = 0.041), and “PA-like” tumors were more likely to be “immune-enriched, fibrotic” (p = 0.044). The four TME clusters exhibited distinct overall survival (p < 0.001) and independently impacted BSG outcomes. A four-gene panel as well as a radiomics approach were constructed to identify the TME clusters and achieved high accuracy for determining the classification. Together, BSGs exhibited high inter-tumor heterogeneity in the TME and were classified into four clusters with distinct clinical outcomes and tumor biological properties. The TME classification was accurately identified using a four-gene panel that can potentially be examined with the immunohistochemical method and a non-invasive radiomics method, facilitating its clinical application. Full article

(This article belongs to the Special Issue Brain Tumor Microenvironment)

► Show Figures

Figure 1

18 pages, 14346 KiB

Open AccessArticle

Characterization and Optimization of the Tumor Microenvironment in Patient-Derived Organotypic Slices and Organoid Models of Glioblastoma

by Vera Nickl, Juliana Eck, Nicolas Goedert, Julian Hübner, Thomas Nerreter, Carsten Hagemann, Ralf-Ingo Ernestus, Tim Schulz, Robert Carl Nickl, Almuth Friederike Keßler, Mario Löhr, Andreas Rosenwald, Maria Breun and Camelia Maria Monoranu

Cancers 2023, 15(10), 2698; https://doi.org/10.3390/cancers15102698 - 10 May 2023

Viewed by 1393

Abstract

While glioblastoma (GBM) is still challenging to treat, novel immunotherapeutic approaches have shown promising effects in preclinical settings. However, their clinical breakthrough is hampered by complex interactions of GBM with the tumor microenvironment (TME). Here, we present an analysis of TME composition in a patient-derived organoid model (PDO) as well as in organotypic slice cultures (OSC). To obtain a more realistic model for immunotherapeutic testing, we introduce an enhanced PDO model. We manufactured PDOs and OSCs from fresh tissue of GBM patients and analyzed the TME. Enhanced PDOs (ePDOs) were obtained via co-culture with PBMCs (peripheral blood mononuclear cells) and compared to normal PDOs (nPDOs) and PT (primary tissue). At first, we showed that TME was not sustained in PDOs after a short time of culture. In contrast, TME was largely maintained in OSCs. Unfortunately, OSCs can only be cultured for up to 9 days. Thus, we enhanced the TME in PDOs by co-culturing PDOs and PBMCs from healthy donors. These cellular TME patterns could be preserved until day 21. The ePDO approach could mirror the interaction of GBM, TME and immunotherapeutic agents and may consequently represent a realistic model for individual immunotherapeutic drug testing in the future. Full article

(This article belongs to the Special Issue Brain Tumor Microenvironment)

► Show Figures

Figure 1

20 pages, 3532 KiB

Open AccessArticle

Extracellular Vesicles Potentiate Medulloblastoma Metastasis in an EMMPRIN and MMP-2 Dependent Manner

by Hannah K. Jackson, Christine Mitoko, Franziska Linke, Donald Macarthur, Ian D. Kerr and Beth Coyle

Cancers 2023, 15(9), 2601; https://doi.org/10.3390/cancers15092601 - 04 May 2023

Cited by 1 | Viewed by 1737

Abstract

Extracellular vesicles (EVs) have emerged as pivotal mediators of communication in the tumour microenvironment. More specifically, nanosized extracellular vesicles termed exosomes have been shown to contribute to the establishment of a premetastatic niche. Here, we sought to determine what role exosomes play in medulloblastoma (MB) progression and elucidate the underlying mechanisms. Metastatic MB cells (D458 and CHLA-01R) were found to secrete markedly more exosomes compared to their nonmetastatic, primary counterparts (D425 and CHLA-01). In addition, metastatic cell-derived exosomes significantly enhanced the migration and invasiveness of primary MB cells in transwell migration assays. Protease microarray analysis identified that matrix metalloproteinase-2 (MMP-2) was enriched in metastatic cells, and zymography and flow cytometry assays of metastatic exosomes demonstrated higher levels of functionally active MMP-2 on their external surface. Stable genetic knockdown of MMP-2 or extracellular matrix metalloproteinase inducer (EMMPRIN) in metastatic MB cells resulted in the loss of this promigratory effect. Analysis of serial patient cerebrospinal fluid (CSF) samples showed an increase in MMP-2 activity in three out of four patients as the tumour progressed. This study demonstrates the importance of EMMPRIN and MMP-2-associated exosomes in creating a favourable environment to drive medulloblastoma metastasis via extracellular matrix signalling. Full article

(This article belongs to the Special Issue Brain Tumor Microenvironment)

► Show Figures

Graphical abstract

15 pages, 904 KiB

Open AccessArticle

Combining CNN Features with Voting Classifiers for Optimizing Performance of Brain Tumor Classification

by Nazik Alturki, Muhammad Umer, Abid Ishaq, Nihal Abuzinadah, Khaled Alnowaiser, Abdullah Mohamed, Oumaima Saidani and Imran Ashraf

Cancers 2023, 15(6), 1767; https://doi.org/10.3390/cancers15061767 - 14 Mar 2023

Cited by 8 | Viewed by 1820

Abstract

Brain tumors and other nervous system cancers are among the top ten leading fatal diseases. The effective treatment of brain tumors depends on their early detection. This research work makes use of 13 features with a voting classifier that combines logistic regression with stochastic gradient descent using features extracted by deep convolutional layers for the efficient classification of tumorous victims from the normal. From the first and second-order brain tumor features, deep convolutional features are extracted for model training. Using deep convolutional features helps to increase the precision of tumor and non-tumor patient classification. The proposed voting classifier along with convoluted features produces results that show the highest accuracy of 99.9%. Compared to cutting-edge methods, the proposed approach has demonstrated improved accuracy. Full article

(This article belongs to the Special Issue Brain Tumor Microenvironment)

► Show Figures

Figure 1

11 pages, 1460 KiB

Open AccessArticle

Magnetic Resonance Spectroscopy Metabolites as Biomarkers of Disease Status in Pediatric Diffuse Intrinsic Pontine Gliomas (DIPG) Treated with Glioma-Associated Antigen Peptide Vaccines

by Ashok Panigrahy, Regina I. Jakacki, Ian F. Pollack, Rafael Ceschin, Hideho Okada, Marvin D. Nelson, Gary Kohanbash, Girish Dhall and Stefan Bluml

Cancers 2022, 14(23), 5995; https://doi.org/10.3390/cancers14235995 - 05 Dec 2022

Cited by 2 | Viewed by 1684

Abstract

Purpose: Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive tumors with no currently available curative therapy. This study evaluated whether measurements of in vivo cell metabolites using magnetic resonance spectroscopy (MRS) may serve as biomarkers of response to therapy, including progression. Methods: Single-voxel MR spectra were serially acquired in two cohorts of patients with DIPG treated with radiation therapy (RT) with or without concurrent chemotherapy and prior to progression: 14 participants were enrolled in a clinical trial of adjuvant glioma-associated antigen peptide vaccines and 32 patients were enrolled who did not receive adjuvant vaccine therapy. Spearman correlations measured overall survival associations with absolute metabolite concentrations of myo-inositol (mI), creatine (Cr), and n-acetyl-aspartate (NAA) and their ratios relative to choline (Cho) during three specified time periods following completion of RT. Linear mixed-effects regression models evaluated the longitudinal associations between metabolite ratios and time from death (terminal decline). Results: Overall survival was not associated with metabolite ratios obtained shortly after RT (1.9–3.8 months post-diagnosis) in either cohort. In the vaccine cohort, an elevated mI/Cho ratio after 2–3 doses (3.9–5.2 months post-diagnosis) was associated with longer survival (rho = 0.92, 95% CI 0.67–0.98). Scans performed up to 6 months before death showed a terminal decline in the mI/Cho ratio, with an average of 0.37 ratio/month in vaccine patients (95% CI 0.11–0.63) and 0.26 (0.04–0.48) in the non-vaccine cohort. Conclusion: Higher mI/Cho ratios following RT, consistent with less proliferate tumors and decreased cell turnover, were associated with longer survival, suggesting that this ratio can serve as a biomarker of prognosis following RT. This finding was seen in both cohorts, although the association with OS was detected earlier in the vaccine cohort. Increased mI/Cho (possibly reflecting immune-effector cell influx into the tumor as a mechanism of tumor response) requires further study. Full article

(This article belongs to the Special Issue Brain Tumor Microenvironment)

► Show Figures

Figure 1

17 pages, 6071 KiB

Open AccessArticle

Glucose and Inositol Transporters, SLC5A1 and SLC5A3, in Glioblastoma Cell Migration

by Philippa K. Brosch, Tessa Korsa, Danush Taban, Patrick Eiring, Philipp Kreisz, Sascha Hildebrand, Julia Neubauer, Heiko Zimmermann, Markus Sauer, Ryo Shirakashi, Cholpon S. Djuzenova, Dmitri Sisario and Vladimir L. Sukhorukov

Cancers 2022, 14(23), 5794; https://doi.org/10.3390/cancers14235794 - 24 Nov 2022

Cited by 4 | Viewed by 2162 | Correction

Abstract

(1) Background: The recurrence of glioblastoma multiforme (GBM) is mainly due to invasion of the surrounding brain tissue, where organic solutes, including glucose and inositol, are abundant. Invasive cell migration has been linked to the aberrant expression of transmembrane solute-linked carriers (SLC). Here, we explore the role of glucose (SLC5A1) and inositol transporters (SLC5A3) in GBM cell migration. (2) Methods: Using immunofluorescence microscopy, we visualized the subcellular localization of SLC5A1 and SLC5A3 in two highly motile human GBM cell lines. We also employed wound-healing assays to examine the effect of SLC inhibition on GBM cell migration and examined the chemotactic potential of inositol. (3) Results: While GBM cell migration was significantly increased by extracellular inositol and glucose, it was strongly impaired by SLC transporter inhibition. In the GBM cell monolayers, both SLCs were exclusively detected in the migrating cells at the monolayer edge. In single GBM cells, both transporters were primarily localized at the leading edge of the lamellipodium. Interestingly, in GBM cells migrating via blebbing, SLC5A1 and SLC5A3 were predominantly detected in nascent and mature blebs, respectively. (4) Conclusion: We provide several lines of evidence for the involvement of SLC5A1 and SLC5A3 in GBM cell migration, thereby complementing the migration-associated transportome. Our findings suggest that SLC inhibition is a promising approach to GBM treatment. Full article

(This article belongs to the Special Issue Brain Tumor Microenvironment)

► Show Figures

Figure 1

Review

Jump to: Research, Other

18 pages, 1560 KiB

Open AccessEditor’s ChoiceReview

Therapeutic Targeting of Glioblastoma and the Interactions with Its Microenvironment

by Vassilis Genoud, Ben Kinnersley, Nicholas F. Brown, Diego Ottaviani and Paul Mulholland

Cancers 2023, 15(24), 5790; https://doi.org/10.3390/cancers15245790 - 10 Dec 2023

Cited by 1 | Viewed by 1284

Abstract

Glioblastoma (GBM) is the most common primary malignant brain tumour, and it confers a dismal prognosis despite intensive multimodal treatments. Whilst historically, research has focussed on the evolution of GBM tumour cells themselves, there is growing recognition of the importance of studying the tumour microenvironment (TME). Improved characterisation of the interaction between GBM cells and the TME has led to a better understanding of therapeutic resistance and the identification of potential targets to block these escape mechanisms. This review describes the network of cells within the TME and proposes treatment strategies for simultaneously targeting GBM cells, the surrounding immune cells, and the crosstalk between them. Full article

(This article belongs to the Special Issue Brain Tumor Microenvironment)

► Show Figures

Figure 1

22 pages, 2538 KiB

Open AccessReview

Current Knowledge about the Peritumoral Microenvironment in Glioblastoma

by Gianluca Trevisi and Annunziato Mangiola

Cancers 2023, 15(22), 5460; https://doi.org/10.3390/cancers15225460 - 17 Nov 2023

Cited by 2 | Viewed by 1505

Abstract

Glioblastoma is a deadly disease, with a mean overall survival of less than 2 years from diagnosis. Recurrence after gross total surgical resection and adjuvant chemo-radiotherapy almost invariably occurs within the so-called peritumoral brain zone (PBZ). The aim of this narrative review is to summarize the most relevant findings about the biological characteristics of the PBZ currently available in the medical literature. The PBZ presents several peculiar biological characteristics. The cellular landscape of this area is different from that of healthy brain tissue and is characterized by a mixture of cell types, including tumor cells (seen in about 30% of cases), angiogenesis-related endothelial cells, reactive astrocytes, glioma-associated microglia/macrophages (GAMs) with anti-inflammatory polarization, tumor-infiltrating lymphocytes (TILs) with an “exhausted” phenotype, and glioma-associated stromal cells (GASCs). From a genomic and transcriptomic point of view, compared with the tumor core and healthy brain tissue, the PBZ presents a “half-way” pattern with upregulation of genes related to angiogenesis, the extracellular matrix, and cellular senescence and with stemness features and downregulation in tumor suppressor genes. This review illustrates that the PBZ is a transition zone with a pre-malignant microenvironment that constitutes the base for GBM progression/recurrence. Understanding of the PBZ could be relevant to developing more effective treatments to prevent GBM development and recurrence. Full article

(This article belongs to the Special Issue Brain Tumor Microenvironment)

► Show Figures

Figure 1

22 pages, 3152 KiB

Open AccessReview

The Role of Hypoxia and Cancer Stem Cells in Development of Glioblastoma

by Tingyu Shi, Jun Zhu, Xiang Zhang and Xinggang Mao

Cancers 2023, 15(9), 2613; https://doi.org/10.3390/cancers15092613 - 04 May 2023

Cited by 7 | Viewed by 2389

Abstract

Glioblastoma multiform (GBM) is recognized as the most malignant brain tumor with a high level of hypoxia, containing a small population of glioblastoma stem like cells (GSCs). These GSCs have the capacity of self-renewal, proliferation, invasion and recapitulating the parent tumor, and are major causes of radio-and chemoresistance of GBM. Upregulated expression of hypoxia inducible factors (HIFs) in hypoxia fundamentally contributes to maintenance and progression of GSCs. Therefore, we thoroughly reviewed the currently acknowledged roles of hypoxia-associated GSCs in development of GBM. In detail, we recapitulated general features of GBM, especially GSC-related features, and delineated essential responses resulted from interactions between GSC and hypoxia, including hypoxia-induced signatures, genes and pathways, and hypoxia-regulated metabolic alterations. Five hypothesized GSC niches are discussed and integrated into one comprehensive concept: hypoxic peri-arteriolar niche of GSCs. Autophagy, another protective mechanism against chemotherapy, is also closely related to hypoxia and is a potential therapeutic target for GBM. In addition, potential causes of therapeutic resistance (chemo-, radio-, surgical-, immuno-), and chemotherapeutic agents which can improve the therapeutic effects of chemo-, radio-, or immunotherapy are introduced and discussed. At last, as a potential approach to reverse the hypoxic microenvironment in GBM, hyperbaric oxygen therapy (HBOT) might be an adjuvant therapy to chemo-and radiotherapy after surgery. In conclusion, we focus on demonstrating the important role of hypoxia on development of GBM, especially by affecting the function of GSCs. Important advantages have been made to understand the complicated responses induced by hypoxia in GBM. Further exploration of targeting hypoxia and GSCs can help to develop novel therapeutic strategies to improve the survival of GBM patients. Full article

(This article belongs to the Special Issue Brain Tumor Microenvironment)

► Show Figures

Figure 1

Other

Jump to: Research, Review

1 pages, 183 KiB

Open AccessCorrection

Correction: Brosch et al. Glucose and Inositol Transporters, SLC5A1 and SLC5A3, in Glioblastoma Cell Migration. Cancers 2022, 14, 5794

Cancers 2023, 15(21), 5139; https://doi.org/10.3390/cancers15215139 - 25 Oct 2023

Viewed by 541

Abstract

Philipp Kreisz was not included as an author in the original publication [...] Full article

(This article belongs to the Special Issue Brain Tumor Microenvironment)

20 pages, 933 KiB

Open AccessSystematic Review

The Extracellular Matrix in Glioblastomas: A Glance at Its Structural Modifications in Shaping the Tumoral Microenvironment—A Systematic Review

by Salvatore Marino, Grazia Menna, Rina Di Bonaventura, Lucia Lisi, Pierpaolo Mattogno, Federica Figà, Lal Bilgin, Quintino Giorgio D’Alessandris, Alessandro Olivi and Giuseppe Maria Della Pepa

Cancers 2023, 15(6), 1879; https://doi.org/10.3390/cancers15061879 - 21 Mar 2023

Cited by 5 | Viewed by 2097

Abstract

Background and aim: While many components of the ECM have been isolated and characterized, its modifications in the specific setting of GBMs have only been recently explored in the literature. The aim of this paper is to provide a systematic review on the topic and to assess the ECM’s role in shaping tumoral development. Methods: An online literature search was launched on PubMed/Medline and Scopus using the research string “((Extracellular matrix OR ECM OR matrix receptor OR matrix proteome) AND (glioblastoma OR GBM) AND (tumor invasion OR tumor infiltration))”, and a systematic review was conducted in accordance with the PRISMA-P guidelines. Results: The search of the literature yielded a total of 693 results. The duplicate records were then removed (n = 13), and the records were excluded via a title and abstract screening; 137 studies were found to be relevant to our research question and were assessed for eligibility. Upon a full-text review, 59 articles were finally included and were summarized as follows based on their focus: (1) proteoglycans; (2) fibrillary proteins, which were further subdivided into the three subcategories of collagen, fibronectin, and laminins; (3) glycoproteins; (4) degradative enzymes; (5) physical forces; (6) and glioma cell and microglia migratory and infiltrative patterns. Conclusions: Our systematic review demonstrates that the ECM should not be regarded anymore as a passive scaffold statically contributing to mechanical support in normal and pathological brain tissue but as an active player in tumor-related activity. Full article

(This article belongs to the Special Issue Brain Tumor Microenvironment)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Brain Tumor Microenvironment

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (11 papers)

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI