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M2 Receptor Activation Counteracts the Glioblastoma Cancer Stem Cell Response to Hypoxia Condition
Open AccessArticle

Hypoxia, Inflammation and Necrosis as Determinants of Glioblastoma Cancer Stem Cells Progression

Department of Experimental Medicine, Sapienza University, 00161 Rome, Italy
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy
Institute of Translational Pharmacology, National Research Council, 00133 Rome, Italy
Department of Neuroscience, Istituto Superiore di Sanità, 00161 Rome, Italy
IRCCS San Raffaele Pisana, 00163 Rome, Italy
MEBIC Consortium, San Raffaele Open University, 00166 Rome, Italy
Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
Institute of Neurosurgery, Catholic University School of Medicine, 00168 Rome, Italy
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(8), 2660;
Received: 18 February 2020 / Revised: 8 April 2020 / Accepted: 9 April 2020 / Published: 11 April 2020
(This article belongs to the Special Issue Molecular Biology of Brain Tumors)
Tumor hypoxic microenvironment causes hypoxia inducible factor 1 alpha (HIF-1α) activation and necrosis with alarmins release. Importantly, HIF-1α also controls the expression of alarmin receptors in tumor cells that can bind to and be activated by alarmins. Human tumor tissues possess 1–2% of cancer stem cells (CSCs) residing in hypoxic niches and responsible for the metastatic potential of tumors. Our hypothesis is that hypoxic CSCs express alarmin receptors that can bind alarmins released during necrosis, an event favoring CSCs migration. To investigate this aspect, glioblastoma stem-like cell (GSC) lines were kept under hypoxia to determine the expression of hypoxic markers as well as receptor for advanced glycation end products (RAGE). The presence of necrotic extracts increased migration, invasion and cellular adhesion. Importantly, HIF-1α inhibition by digoxin or acriflavine prevented the response of GSCs to hypoxia alone or plus necrotic extracts. In vivo, GSCs injected in one brain hemisphere of NOD/SCID mice were induced to migrate to the other one in which a necrotic extract was previously injected. In conclusion, our results show that hypoxia is important not only for GSCs maintenance but also for guiding their response to external necrosis. Inhibition of hypoxic pathway may therefore represent a target for preventing brain invasion by glioblastoma stem cells (GSCs). View Full-Text
Keywords: hypoxia; glioblastoma; cancer stem cells; molecular rehabilitation; alarmins hypoxia; glioblastoma; cancer stem cells; molecular rehabilitation; alarmins
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Papale, M.; Buccarelli, M.; Mollinari, C.; Russo, M.A.; Pallini, R.; Ricci-Vitiani, L.; Tafani, M. Hypoxia, Inflammation and Necrosis as Determinants of Glioblastoma Cancer Stem Cells Progression. Int. J. Mol. Sci. 2020, 21, 2660.

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