Abstract
BACKGROUND
Glioblastoma is the most common and aggressive primary brain tumor in adults. In spite of intensive treatment, patients have a poor prognosis with a median survival of 14–16 months. After surgical resection followed by postoperative chemoradiation (combined temozolomide treatment and radiotherapy), tumor recurs in the resection margin for more than 90% of patients. This recurrence results from the activation of residual glioblastoma cells beyond the resection cavity by therapy-induced injuries. To handle this issue, we propose therapeutic hypothermia as an adjuvant treatment, in order to place the resection margin in a state of hibernation. In fact, hypothermia was introduced as a promising therapeutic approach in various medical applications like cardiac arrest and pharmaco-resistant epilepsy. Only a few in vitro studies explored the effects of hypothermia on cancer cells and showed promising results. The aim of our work is to investigate the effects of hypothermia on glioblastoma cell proliferation and migration, two key cellular processes involved in cancer progression.
MATERIAL AND METHODS
We performed in vitro experiments on glioblastoma cell lines with different p53 status and various growth rates. For exploring the therapeutic potential of both mild and moderate hypothermia, we studied their impact on cell viability, proliferation and migration. We also performed cell cycle analysis by quantitation of DNA content using flow cytometry.
RESULTS
Results were similar for all glioblastoma cell lines, and demonstrated that cells were extremely sensitive to hypothermia. We showed that both mild and moderate hypothermia induced significant changes on glioblastoma cell lines behavior with a strong inhibition of cell proliferation and migration. Moderate hypothermia also affected glioblastoma cell viability and modified their distribution into the cell cycle phases.
CONCLUSION
Our results were comparable in all glioblastoma cell lines tested, demonstrating a consistent and universal effect of hypothermia. We showed that hypothermia significantly inhibits cell proliferation and migration, which are key processes involved in tumor growth. Proliferation arrest could be explained by the accumulation of cells in the G2/M phase of the cell cycle.
Together, these results support hypothermia as a promising adjuvant therapy for glioblastoma patients. Indeed, combined with current treatments, moderate hypothermia applied at the resection margin could prevent tumor recurrence after surgical resection. There is a crucial need to propose innovative glioblastoma treatments, and hypothermia appears as a promising therapeutic way.
SUPPORT
This work received financial support through grants from the Groupement des Entreprises Françaises de Lutte contre le Cancer (GEFLUC Grenoble - Dauphiné - Savoie) and the Fonds de dotation Clinatec.
Downregulation of miR‑485‑3p promotes glioblastoma cell proliferation and migration via targeting RNF135
