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Molecular and Cellular Research on the Glioma and Tumor Microenvironment

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A Special Issue of International Journal of Molecular Sciences (ISSN 1422-0067) belonging to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 April 2026) | Viewed by 10900

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Dr. Maria Beatrice Morelli

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Guest Editor

School of Pharmacy, University of Camerino, 62032 Camerino, Italy
Interests: glioblastoma; TRP channel; mucolipins; autophagy; overall survival; transient receptor potential channels; tumor progression; chemotherapy resistance; cancer biology; cancer stem cell; circulating tumor cell; liquid biopsy; biomarkers; ion channel; natural compound; cannabinoids
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Dear Colleagues,

Gliomas are the most prevalent primary brain cancer among adults, accounting for 75% of all cases. Known as a grade IV glioma, GBM is the most aggressive form of this disease. As a standard treatment, tumors are surgically resected, followed by postoperative radiation therapy, followed by concurrent and adjuvant Temozolomide treatment. As a result of the development of resistance to TMZ in GBM, and the high-level heterogeneity between and within tumors, the prognosis remains poor. In this scenario, the tumour microenvironment (TME) plays a central role. It is believed that glioblastoma cells subvert the microglia and macrophages for tumor growth to form the bulk of a tumor microenvironment dominated by inflammatory infiltrates. There are also different cell populations within the TME, including fibroblasts, precursor cells, endothelial cells, signaling molecules, and extracellular matrix components. As a consequence, developing models and techniques that allow the monitoring of the TME during growth or treatment is essential for an improved understanding of tumors and for more precise diagnosis and treatment.

This Special Issue of the International Journal of Molecular Sciences welcomes both original research articles and review papers that deal with the molecular mechanisms underlying the role of microenvironment signaling in gliomas.

Dr. Maria Beatrice Morelli
Guest Editor

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Keywords

tumour microenvironment
immune cells
cell siganling
tumor niche
tumor heterogeneity
TMZ resistance
new therapeutic strategies
endothelial cells
fibroblasts
extracellular matrix

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Published Papers (5 papers)

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25 pages, 8999 KB

Open AccessArticle

Synergistic In Vitro Effects of Minor Phytocannabinoids and Melatonin Combinations Against Human Glioblastoma Cells

by Maria Beatrice Morelli, Giorgio Cameli, Martina Giangrossi, Laura Zeppa, Margherita Luongo, Consuelo Amantini and Massimo Nabissi

Int. J. Mol. Sci. 2026, 27(15), 6774; https://doi.org/10.3390/ijms27156774 - 29 Jul 2026

Viewed by 1011

Abstract

The prognosis of glioblastoma (GBM) patients remains dismal due to chemoresistance. Repurposing of natural and endogenous compounds, such as the pineal hormone melatonin (MLT) and minor phytocannabinoids like cannabinol (CBN) or cannabigerol (CBG), represents a promising strategy. This study investigates the cytotoxic potential of combining these phytocannabinoids with MLT, evaluating their efficacy both alone and synergistically with temozolomide (TMZ) to overcome drug resistance. To achieve this, cytotoxicity, synergy (Bliss model), and selectivity were evaluated in U87, T98, and U251 GBM lines and normal astrocytes. Mechanisms of damage were characterized via Western blot (γH2AX and PARP-1), flow cytometry using fluorescent dyes/probes (DCFDA, JC-1, MitoBright, BODIPY, PI, and Annexin-V), or the protein marker COX IV and confocal analysis. The results demonstrated that CBN-MLT and CBG-MLT regimens exerted synergistic cytotoxicity while sparing healthy astrocytes. Notably, combining these regimens (U87: MLT 0.3 mg/mL + CBN 25 µM; MLT 0.2 mg/mL + CBG 15 µM. T98: MLT 0.7 mg/mL + CBN 25 µM; MLT 0.6 mg/mL + CBG 30 µM. U251: MLT 0.4 mg/mL + CBN 20 µM; MLT 0.5 mg/mL + CBG 35 µM) with TMZ significantly enhanced chemotherapeutic efficacy, overcoming baseline effects of TMZ in these cell lines. The combinations induced necrotic cell death characterized by severe double-strand DNA damage. This was driven by an early accumulation of intracellular ROS, which triggered mitochondrial depolarization, loss of organelle mass, and lipid peroxidation. CBN combinations consistently triggered more robust biochemical alterations than CBG-based treatments. Taken together, this study provides a strong preclinical basis for utilizing minor cannabinoids combined with MLT in GBM management. Crucially, this co-treatment emerges as a promising approach to potentiate TMZ efficacy, offering a novel and potentially effective therapeutic strategy to counter GBM resilience. Full article

(This article belongs to the Special Issue Molecular and Cellular Research on the Glioma and Tumor Microenvironment)

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31 pages, 32849 KB

Open AccessArticle

Loss of Neuropeptide Y Signaling Accompanies the Neural-to-Mesenchymal Transcriptional Transition in Glioblastoma: A Multi-Scale Transcriptomic Analysis

by Fareeha Arshad, Nouran Abualsaud, Arshiya Akbar, Mohammed Imran Khan, Bushra Rasheed, Adnan Hussain, Fahad Ali Alghamdi, Faisal Abdulhameed Farrash, Edwin N. Aroke, Khalid Walid Freij, Itika Arora and Ahmed Yaqinuddin

Int. J. Mol. Sci. 2026, 27(13), 6068; https://doi.org/10.3390/ijms27136068 - 6 Jul 2026

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Abstract

Neuropeptide Y [NPY; encoded by the NPY gene] is a widely expressed 36-amino-acid neuropeptide that regulates neuronal function, vascular regulation, and immune regulation; its role in glioblastoma [GBM] remains incompletely characterized. We performed an integrative in silico multi-scale transcriptomic analysis combining bulk RNA-sequencing of IDH-wildtype GBM [n = 169] and lower-grade glioma [n = 510] surgical resections from TCGA, normal cortical tissue from GTEx [n = 207], and four independent GEO validation cohorts of surgical GBM and non-tumor brain specimens [GSE4290, GSE50161, GSE131928 scRNA-seq of ~20,426 cells from 28 patients, and GSE194329 10X Visium spatial transcriptomics from five patients], along with survival modeling, pathway enrichment, single-cell RNA sequencing, spatial transcriptomics, and cell–cell communication analysis. NPY and its principal receptor, NPY1R, were significantly downregulated in GBM, while genes associated with hypoxia, angiogenesis, invasion, and immune suppression were upregulated. Single-cell analysis showed that NPY-axis transcript expression was elevated in neural progenitor-like populations. In contrast, hypoxia and metabolic programs were concentrated in mesenchymal tumors and stromal compartments, indicating distinct cellular contexts. Spatial analysis revealed a weak and heterogeneous relationship between NPY and hypoxia signatures, with substantial inter-patient variability and no significant global spatial cross-correlation. These findings indicate that loss of NPY signaling is a consistent feature of GBM and is associated with hypoxia-driven tumor states, while the spatial relationship between NPY and hypoxia appears weak, heterogeneous, and patient-specific. Full article

(This article belongs to the Special Issue Molecular and Cellular Research on the Glioma and Tumor Microenvironment)

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20 pages, 3372 KB

Open AccessArticle

SDK1 as an Independent Prognostic Biomarker in Primary Glioma: A Multi-Cohort Validation Study with Functional Characterization

by Jun Hyun Lee

Int. J. Mol. Sci. 2026, 27(10), 4199; https://doi.org/10.3390/ijms27104199 - 8 May 2026

Viewed by 718

Abstract

Glioma prognosis is shaped by molecular markers such as IDH mutation, WHO grade, and MGMT methylation, yet heterogeneity persists within defined subgroups. Sidekick Cell Adhesion Molecule 1 (SDK1), an immunoglobulin superfamily member mediating homophilic adhesion, has been documented in glioma tissue but lacks systematic prognostic evaluation. I assessed SDK1’s prognostic value using the Chinese Glioma Genome Atlas (CGGA, N = 503) and The Cancer Genome Atlas (TCGA, N = 572) through multivariate Cox regression, subgroup analyses, differential gene expression, pathway enrichment, ssGSEA-based immune profiling, and molecular subtype association. High SDK1 expression was independently associated with poor overall survival in both cohorts (CGGA: adjusted HR = 1.48, 95% CI 1.16–1.89, p = 0.002; TCGA: HR = 1.76, 95% CI 1.19–2.61, p = 0.005; pooled HR = 1.55, I² = 0%). Effect estimates varied across subgroups, with significant associations in WHO grade IV and IDH-wildtype strata but not in grade II or older patients. Cross-validated differentially expressed genes were enriched in extracellular matrix organization and focal adhesion pathways. Notably, SDK1 expression showed weak but statistically significant correlations with COL1A1-associated mesenchymal program scores (CGGA: R = 0.12, p = 0.008; TCGA: R = 0.15, p < 0.001) and oncostream-related gene signatures (CGGA: R = 0.16, p < 0.001; TCGA: R = 0.086, p = 0.039), suggesting a modest association with mesenchymal invasion programs. SDK1-high tumors showed elevated M2 macrophage and Treg signatures with upregulated immune checkpoints, though cohort-dependent differences were observed. Multivariate Cox analysis demonstrated that the prognostic significance of SDK1 is independent of tumor mutational burden (TMB), with no significant correlation or interaction observed between them (p > 0.05). SDK1 is a candidate prognostic biomarker in glioma co-occurring with ECM remodeling and immunosuppressive features, warranting experimental validation for clinical translation. Full article

(This article belongs to the Special Issue Molecular and Cellular Research on the Glioma and Tumor Microenvironment)

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21 pages, 4035 KB

Open AccessArticle

Exploring the Role of Peripheral Macrophages in Glioma Progression: The Metabolic Significance of Cyclooxygenase-2 (COX-2)

by Jens Pietzsch, Magali Toussaint, Cornelius Kurt Donat, Alina Doctor, Sebastian Meister, Johanna Wodtke, Markus Laube, Frank Hofheinz, Jan Rix, Winnie Deuther-Conrad and Cathleen Haase-Kohn

Int. J. Mol. Sci. 2025, 26(13), 6198; https://doi.org/10.3390/ijms26136198 - 27 Jun 2025

Cited by 6 | Viewed by 1953

Abstract

Glioblastoma (GBM) is the most aggressive form of malignant gliomas, with the eicosanoid-synthesizing enzyme cyclooxygenase-2 (COX-2) playing a pivotal role in its progression via the COX-2/prostaglandin E2/4 axis. COX-2 upregulations in tumor cells induces a pro-inflammatory tumor microenvironment (TME), affecting the behavior of invading bone marrow-derived macrophages (Mϕ) and brain-resident microglia (MG) through unclear autocrine and paracrine mechanisms. Using CRISPR/Cas9 technology, we generated COX-2 knockout U87 glioblastoma cells. In spheroids and in vivo xenografts, this resulted in a significant inhibition of tumorigenic properties, while not observed in standard adherent monolayer culture. Here, the knockout induced a G1 cell cycle arrest in adherent cells, accompanied by increased ROS, mitochondrial activity, and cytochrome c-mediated apoptosis. In spheroids and xenograft models, COX-2 knockout led to notable growth delays and increased cell death, characterized by features of both apoptosis and autophagy. Interestingly, these effects were partially reversed in subcutaneous xenografts after co-culture with Mϕ, while co-culture with MG enhanced the growth-suppressive effects. In an orthotopic model, COX-2 knockout tumors displayed reduced proliferation (fewer Ki-67 positive cells), increased numbers of GFAP-positive astrocytes, and signs of membrane blebbing. These findings highlight the potential of COX-2 knockout and suppression as a therapeutic strategy in GBM, particularly when combined with suppression of infiltrating macrophages and stabilization of resident microglia populations to enhance anti-tumor effects. Full article

(This article belongs to the Special Issue Molecular and Cellular Research on the Glioma and Tumor Microenvironment)

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29 pages, 1083 KB

Open AccessPerspective

A New Adjuvant Treatment for Glioblastoma Using Aprepitant, Vortioxetine, Roflumilast and Olanzapine: The AVRO Regimen

by Richard E. Kast, Bruno Marques Vieira and Erasmo Barros da Silva, Jr.

Int. J. Mol. Sci. 2025, 26(13), 6158; https://doi.org/10.3390/ijms26136158 - 26 Jun 2025

Cited by 5 | Viewed by 4840

Abstract

AVRO is an adjunctive four-drug regimen designed to increase the effectiveness of current standard treatment of glioblastoma (GB). AVRO is a repurposed drug regimen consisting of the antinausea drug aprepitant, the antidepressant vortioxetine, the emphysema treatment drug roflumilast, and the antipsychotic drug olanzapine. All four are EMA/FDA approved for nononcology indications, all four have strong research evidence showing inhibition of GB growth, and all four carry a low side effect risk. The goal of adding AVRO is to further retard GB growth, improving survival. Aprepitant is an antinausea drug that blocks NK-1 signaling, with a database of 59 studies showing growth inhibition in 22 different cancers, 12 of which were specific to GB. Fully 30 studies demonstrated that the SSRI class of antidepressants inhibited GB growth; accordingly, we chose one such agent, vortioxetine, to add to AVRO. Elevation of intracellular cAMP slowed GB growth in 21 independent studies. Accordingly, we added the emphysema treatment drug roflumilast, which inhibits cAMP degradation. Among the 27 currently marketed D2-blocking antipsychotic drugs, 24 have preclinical evidence of GB growth inhibition in a combined 84 independent study database. One of these 24 drugs is olanzapine, added to AVRO. Given the short median survival of GB as of mid-2025, the clinician and researcher community will benefit from wider awareness of the anti-GB effects of these four nononcology drugs. Full article

(This article belongs to the Special Issue Molecular and Cellular Research on the Glioma and Tumor Microenvironment)

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