Abstract
Glioblastoma (GBM) is a deadly brain tumor, with fast recurrence even after surgical intervention, radio- and chemotherapies. One of the reasons for relapse is the early invasion of surrounding brain parenchyma by GBM, rendering tumor eradication difficult. Recent studies demonstrate that, in addition to eliminate possible residual tumoral cells after surgery, radiation stimulates the infiltrative behavior of GBM cells. The intermediate conductance of Ca2+-activated potassium channels (KCa3.1) play an important role in regulating the migration of GBM. Here, we show that high dose radiation of patient-derived GBM cells increases their invasion, and induces the transcription of key genes related to these functions, including the IL-4/IL-4R pair. In addition, we demonstrate that radiation increases the expression of KCa3.1 channels, and that their pharmacological inhibition counteracts the pro-invasive phenotype induced by radiation in tumor cells. Our data describe a possible approach to treat tumor resistance that follows radiation therapy in GBM patients.
Highlights
Glioblastoma (GBM) is the most common and deadly primary brain tumor in adults [1]
We evaluated the functional activity of KCa3.1 channels in GBM cells, by electrophysiological recordings, 48–72 h after irradiation
All statistical analyses were done using Sigma Plot 11.0 software. Data reported in this manuscript demonstrate that GBM cells irradiated with a single high dose of 35 Gy to mimic the condition of stereotaxic radio-surgery performed in patients, increased the invasion ability, by increasing the transcription level of genes involved in invasion and other in transcription regulation
Summary
Despite the current standard multimodal treatment regimen, including surgery, and/or adjuvant chemo- and radiotherapy (RT), mean survival in GBM patients remains low (less than 15 months) [2,3]. This poor patient prognosis results from the high proliferation rate of GBM cells, and from the ability of these cells to spread into surrounding brain parenchyma, escaping surgical resection, with rapid appearance of new tumor masses. Invading GBM cells intrinsically show decreased susceptibility to apoptosis, making radiotherapy and chemotherapy, as well as radiation surgery, poorly effective [5,6] For all these reasons, new strategies to suppress
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