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Molecular and Cellular Research on the Glioma and Tumor Microenvironment
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Molecular and Cellular Research on the Glioma and Tumor Microenvironment

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 August 2025 | Viewed by 1242

Special Issue Editor

Dr. Maria Beatrice Morelli

E-Mail Website
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
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

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 (2 papers)

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21 pages, 4035 KiB  
Article
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
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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 [...] Read more.
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 KiB  
Perspective
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
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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. [...] Read more.
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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