Influence of the Cholinergic System on the Pathogenesis of Glioblastoma: Impact of the Neutrophil Granulocytes

Sep 30, 2026

Uploaded by Aurelia

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults, and cholinergic system components may contribute to tumor development. This study evaluates cholinergic system relevance in GBM cells and the microenvironment by analyzing bulk RNA-seq data with TIMER2.0, linking patient survival to muscarinic receptors (CHRM) and neutrophil infiltration. Survival decreases are associated with CHRMs, especially in low-grade glioma, while GBM shows higher neutrophil infiltration and reduced survival, notably with CHRM3.

LanguageEnglish

CategoryHealthcare

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Pages25

Reading Time1 h 3 min

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Abstract

Introduction

Article Influence of the Cholinergic System on the Pathogenesis of Glioblastoma: Impact of the Neutrophil Granulocytes Alejandra Infante Cruz 1,†, Paula María Saibene Vélez 1,2,†, Cynthia Arasanz 1,3, Micaela Rosato 1,2, Federico Remes Lenicov 4, Juan Iturrizaga 5, Martín Abelleyro 1, Marianela Candolfi 6, Eleonora Regueira 7, Gladys Hermida 7, Mónica Vermeulen 1,8, Silvia Berner 9, Francisco José Barrantes 10, Silvia de la Vega 11, Carolina Jancic 1,8, Marcela Solange Villaverde 12 and Gabriela Verónica Salamone 1,8, * Academic Editor: Stergios Boussios Received: 17 September 2025 Revised: 18 December 2025 Accepted: 19 December 2025 Published: 27 December 2025 Copyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1 Instituto de Medicina Experimental (IMEX–CONICET)–Academia Nacional de Medicina, Buenos Aires C1425AUM, Argentina; [cjancic@gmail.com](cjancic@gmail.com) (C.J.) 2 Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1053ABH, Argentina 3 Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”(CEMIC), Instituto Universitario, Buenos Aires C1037ACA, Argentina 4 Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires–CONICET, Buenos Aires C1053ABH, Argentina 5 División Neurocirugía, Instituto de Investigaciones Médicas A Lanari, Universidad de Buenos Aires, Buenos Aires C1053ABH, Argentina 6 Instituto de Investigaciones Biomédicas (INBIOMED UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1053ABH, Argentina 7 Laboratorio de Biología de Anfibios-Histología Animal, Departamento de Biodiversidad y Biología Experimental, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1053ABH, Argentina 8 Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1053ABH, Argentina 9 Servicio de Neurocirugía de la Clínica y Maternidad Santa Isabel, Buenos Aires C1406DKG, Argentina 10 Molecular Neurobiology Division, BIOMED UCA-CONICET, Buenos Aires C1107AAZ, Argentina; [rtfjb1@gmail.com](rtfjb1@gmail.com) 11 Sección Anatomía Patológica del Hospital de Quemados “Arturo U. Illia” CABA, Buenos Aires C1424BSD, Argentina 12 Unidad de Transferencia Genética y Laboratorio de Metabolismo, Departamento de Biología, Facultad de Medicina, Instituto de Oncología Ángel H. Roffo, Área Investigación, Universidad de Buenos Aires, Buenos Aires C1053ABH, Argentina * Correspondence: [salamone.gabriela@gmail.com or gsalamone@fmed.uba.ar](salamone.gabriela@gmail.com or gsalamone@fmed.uba.ar); Tel.: +54-11-4805-5759 (ext. 255); Fax: +54-11-4803-9475 † These authors contributed equally to this work. Abstract Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Since numerous studies highlight the significance of cholinergic system components in tumor development, acetylcholine (ACh) and the differential activation of its receptors could playa crucial role in GBM progression. The aim of this study was to test this hypothesis by assessing the relevance of the cholinergic system in GBM cells and their microenvironment. We analyzed bulk RNA-seq expression data using the TIMER2.0 web server, focusing on the impact of patient survival in relation to muscarinic receptors (CHRM) and neutrophil infiltration in low-grade glioma (LGG) and GBM. Our analysis revealed a marked decrease in survival associated with all CHRMs, particularly in LGG. Moreover, GBM showed higher neutrophil infiltration and reduced survival, especially in relation to CHRM3 . These findings were validated in the U251 cell line and in human GBM tumor biopsies (GBM-b), which also displayed CHRM3 expression. Additionally, we show

FAQs

What role does the cholinergic system play in glioblastoma pathogenesis according to this study?

The study investigates how cholinergic system signaling relates to GBM progression through tumor cells and the tumor microenvironment, including effects on neutrophil physiology.

How were the relationships between CHRM expression, neutrophil infiltration, and survival assessed?

Bulk RNA-seq expression data were analyzed using the TIMER2.0 web server, focusing on patient survival in relation to muscarinic receptors (CHRM) and neutrophil infiltration in low-grade glioma and GBM.

What experimental evidence supports the involvement of CHRM3 and cholinergic stimulation?

Findings were validated using the U251 cell line and human GBM tumor biopsies, showing CHRM3 expression, and cholinergic stimulation increased VEGF, IL-8, and PD-L1, with VEGF induction blocked by the CHRM3 antagonist tiotropium.

Sep 30, 2026

Uploaded by Aurelia