{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T04:20:58Z","timestamp":1783830058851,"version":"3.55.0"},"reference-count":98,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,27]],"date-time":"2025-12-27T00:00:00Z","timestamp":1766793600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondos para la Investigaci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","award":["PICT2019\/03811"],"award-info":[{"award-number":["PICT2019\/03811"]}]},{"DOI":"10.13039\/100008056","name":"Fundaci\u00f3n Florencio Fiorini","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008056","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 play a 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 that GBM cells exposed to cholinergic stimulation exhibited increased vascular endothelial growth factor (VEGF), IL-8 production, and PD-L1 expression, while the VEGF increase was blocked by tiotropium (Tio), a CHRM3 antagonist. Similarly, polymorphonuclear cells from GBM patients (PMN-p) displayed increased PD-L1 expression and IL-8 production upon cholinergic stimulation. Finally, as we previously reported on the relevance of thymic stromal lymphopoietin (TSLP) in GBM pathophysiology, here, we found that TSLP upregulated CHRM3 expression. Our findings highlight the importance of the cholinergic system in the tumor microenvironment, where it may act directly on tumor cells or influence neutrophil physiology, thereby modulating tumor progression.<\/jats:p>","DOI":"10.3390\/ijms27010321","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T05:28:19Z","timestamp":1766986099000},"page":"321","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Influence of the Cholinergic System on the Pathogenesis of Glioblastoma: Impact of the Neutrophil Granulocytes"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5865-0346","authenticated-orcid":false,"given":"Alejandra","family":"Infante Cruz","sequence":"first","affiliation":[{"name":"Instituto de Medicina Experimental (IMEX\u2013CONICET)\u2013Academia Nacional de Medicina, Buenos Aires C1425AUM, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3580-9901","authenticated-orcid":false,"given":"Paula Mar\u00eda","family":"Saibene V\u00e9lez","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Experimental (IMEX\u2013CONICET)\u2013Academia Nacional de Medicina, Buenos Aires C1425AUM, Argentina"},{"name":"Departamento de Qu\u00edmica Biol\u00f3gica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1053ABH, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Arasanz","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Experimental (IMEX\u2013CONICET)\u2013Academia Nacional de Medicina, Buenos Aires C1425AUM, Argentina"},{"name":"Centro de Educaci\u00f3n M\u00e9dica e Investigaciones Cl\u00ednicas \u201cNorberto Quirno\u201d (CEMIC), Instituto Universitario, Buenos Aires C1037ACA, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4176-3976","authenticated-orcid":false,"given":"Micaela","family":"Rosato","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Experimental (IMEX\u2013CONICET)\u2013Academia Nacional de Medicina, Buenos Aires C1425AUM, Argentina"},{"name":"Departamento de Qu\u00edmica Biol\u00f3gica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1053ABH, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4108-6341","authenticated-orcid":false,"given":"Federico","family":"Remes Lenicov","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biom\u00e9dicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires\u2013CONICET, Buenos Aires C1053ABH, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3244-8512","authenticated-orcid":false,"given":"Juan","family":"Iturrizaga","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n Neurocirug\u00eda, Instituto de Investigaciones M\u00e9dicas A Lanari, Universidad de Buenos Aires, Buenos Aires C1053ABH, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9961-9414","authenticated-orcid":false,"given":"Mart\u00edn","family":"Abelleyro","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Experimental (IMEX\u2013CONICET)\u2013Academia Nacional de Medicina, Buenos Aires C1425AUM, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0843-6568","authenticated-orcid":false,"given":"Marianela","family":"Candolfi","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biom\u00e9dicas 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Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4984-6555","authenticated-orcid":false,"given":"M\u00f3nica","family":"Vermeulen","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Experimental (IMEX\u2013CONICET)\u2013Academia Nacional de Medicina, Buenos Aires C1425AUM, Argentina"},{"name":"Departamento de Microbiolog\u00eda, Parasitolog\u00eda e Inmunolog\u00eda, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1053ABH, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1801-469X","authenticated-orcid":false,"given":"Silvia","family":"Berner","sequence":"additional","affiliation":[{"name":"Servicio de Neurocirug\u00eda de la Cl\u00ednica y Maternidad Santa Isabel, Buenos Aires C1406DKG, 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Roffo, \u00c1rea Investigaci\u00f3n, Universidad de Buenos Aires, Buenos Aires C1053ABH, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0438-1942","authenticated-orcid":false,"given":"Gabriela Ver\u00f3nica","family":"Salamone","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Experimental (IMEX\u2013CONICET)\u2013Academia Nacional de Medicina, Buenos Aires C1425AUM, Argentina"},{"name":"Departamento de Microbiolog\u00eda, Parasitolog\u00eda e Inmunolog\u00eda, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1053ABH, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Silantyev, A.S., Falzone, L., Libra, M., Gurina, O.I., Kardashova, K.S., Nikolouzakis, T.K., Nosyrev, A.E., Sutton, C.W., Mitsias, P.D., and Tsatsakis, A. (2019). 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