Clémentine Fulbert1, Christophe Gaude2, Eric Sulpice3, Stéphan Chabardès2,4,5, David Ratel6. 1. Univ. Grenoble Alpes, CEA, LETI, Clinatec, 38000, Grenoble, France. clementine.fulbert@cea.fr. 2. Univ. Grenoble Alpes, CEA, LETI, Clinatec, 38000, Grenoble, France. 3. Univ. Grenoble Alpes, CEA, INSERM, IRIG-BGE U1038, 38000, Grenoble, France. 4. Neurosurgery Department, CHU Grenoble Alpes, 38000, Grenoble, France. 5. Grenoble Institut des Neurosciences, Univ. Grenoble Alpes, Inserm U1216, 38000, Grenoble, France. 6. Univ. Grenoble Alpes, CEA, LETI, Clinatec, 38000, Grenoble, France. david.ratel@cea.fr.
Abstract
PURPOSE: Glioblastoma is the most aggressive malignant brain tumor. Despite multimodal treatments, median survival is only 15 months for glioblastoma patients, with tumor recurring in the resection margins after surgical removal. Hypothermia is emerging as an interesting and safe treatment for several conditions. In the context of glioblastoma, we propose that moderate hypothermia could inhibit both cell proliferation and migration, and thus help prevent secondary tumor growth. METHODS: In vitro experiments on A172, U251, U87 and T98G human glioblastoma cell lines explored the effects of severe (23 °C), moderate (28 °C), and mild (33 °C) hypothermia. We further investigated the effects of moderate hypothermia on cell proliferation, migration, morphology, and cell cycle distribution. RESULTS: Similar results were obtained with all four cell lines, indicating a consistent and broad effect of moderate hypothermia. Hypothermia inhibited both cell proliferation and non-oriented migration in a dose-dependent manner, with a significant reduction at 33 °C and almost total arrest at 28 °C. Cell proliferation arrest was long-lasting and oriented cell migration was also reduced at 28 °C. Moreover, moderate hypothermia significantly altered cell cycle distribution, with cells accumulating in the G2/M phase, leading to cell cycle arrest. Lastly, hypothermia at 28 °C also affected cell morphology by deteriorating cell membranes and altering cell shape. CONCLUSIONS: The presented results demonstrate that moderate hypothermia could be a promising adjuvant therapy for glioblastoma treatment as it strongly inhibits both cell proliferation and migration. If in vivo preclinical results corroborate our findings, therapeutic hypothermia applied at the resection margins could probably delay tumor recurrence, combined with current treatments.
PURPOSE:Glioblastoma is the most aggressive malignant brain tumor. Despite multimodal treatments, median survival is only 15 months for glioblastomapatients, with tumor recurring in the resection margins after surgical removal. Hypothermia is emerging as an interesting and safe treatment for several conditions. In the context of glioblastoma, we propose that moderate hypothermia could inhibit both cell proliferation and migration, and thus help prevent secondary tumor growth. METHODS: In vitro experiments on A172, U251, U87 and T98G humanglioblastoma cell lines explored the effects of severe (23 °C), moderate (28 °C), and mild (33 °C) hypothermia. We further investigated the effects of moderate hypothermia on cell proliferation, migration, morphology, and cell cycle distribution. RESULTS: Similar results were obtained with all four cell lines, indicating a consistent and broad effect of moderate hypothermia. Hypothermia inhibited both cell proliferation and non-oriented migration in a dose-dependent manner, with a significant reduction at 33 °C and almost total arrest at 28 °C. Cell proliferation arrest was long-lasting and oriented cell migration was also reduced at 28 °C. Moreover, moderate hypothermia significantly altered cell cycle distribution, with cells accumulating in the G2/M phase, leading to cell cycle arrest. Lastly, hypothermia at 28 °C also affected cell morphology by deteriorating cell membranes and altering cell shape. CONCLUSIONS: The presented results demonstrate that moderate hypothermia could be a promising adjuvant therapy for glioblastoma treatment as it strongly inhibits both cell proliferation and migration. If in vivo preclinical results corroborate our findings, therapeutic hypothermia applied at the resection margins could probably delay tumor recurrence, combined with current treatments.
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