Impact of Hypoxia on Carbon Ion Therapy in Glioblastoma Cells: Modulation by LET and Hypoxia-Dependent Genes.

Samuel Valable,Elodie A. Pérès,Marine M. Leblond,Gaëlle Lambert,Edwige Petit,Jérôme Toutain,Karim Bordji,Myriam Bernaudin,Aurélie N. Gérault,Clément Anfray

doi:10.3390/cancers12082019

Abstract

Tumor hypoxia is known to limit the efficacy of ionizing radiations, a concept called oxygen enhancement ratio (OER). OER depends on physical factors such as pO2 and linear energy transfer (LET). Biological pathways, such as the hypoxia-inducible transcription factors (HIF), might also modulate the influence of LET on OER. Glioblastoma (GB) is resistant to low-LET radiation (X-rays), due in part to the hypoxic environment in this brain tumor. Here, we aim to evaluate in vitro whether high-LET particles, especially carbon ion radiotherapy (CIRT), can overcome the contribution of hypoxia to radioresistance, and whether HIF-dependent genes, such as erythropoietin (EPO), influence GB sensitivity to CIRT. Hypoxia-induced radioresistance was studied in two human GB cells (U251, GL15) exposed to X-rays or to carbon ion beams with various LET (28, 50, 100 keV/µm), and in genetically-modified GB cells with downregulated EPO signaling. Cell survival, radiobiological parameters, cell cycle, and ERK activation were assessed under those conditions. The results demonstrate that, although CIRT is more efficient than X-rays in GB cells, hypoxia can limit CIRT efficacy in a cell-type manner that may involve differences in ERK activation. Using high-LET carbon beams, or targeting hypoxia-dependent genes such as EPO might reduce the effects of hypoxia.

Highlights

Glioblastoma (GB), defined as a grade IV glioma based on the WHO classification, is the most common malignant primary brain tumor in adults, representing up to 46% of all gliomas and 16% of all primary brain tumors [1]
Many studies have shown that the relative biological effectiveness (RBE) of carbon ions enhances with linear energy transfer (LET) in many types of solid tumors, only a few addressed this issue in GB
We first investigated the biological response of GB cells to carbon ion radiotherapy (CIRT) at LET values ranging from 28 to 100 keV/μm to approximate those used in the clinics (Figure S1)

Summary

Introduction

Glioblastoma (GB), defined as a grade IV glioma based on the WHO classification, is the most common malignant primary brain tumor in adults, representing up to 46% of all gliomas and 16% of all primary brain tumors [1]. GB is one of the most aggressive tumors and has a poor prognosis, with a median overall survival from diagnosis of about 15–18 months and less than 10%. Of patients surviving more than five years [2]. The current standard of care for GB patients includes maximal tumor resection, postoperative external-beam radiation therapy (RT) (60 Gy in 2-Gy fractions) with concomitant temozolomide (TMZ, 75 mg/m2 ), followed by adjuvant TMZ (150–200 mg/m2 ) for six cycles. Tumor recurrence occurs early in the vast majority of patients (90%) [3]. The location of these tumors within the sensitive brain parenchyma along with their infiltrative and hypoxic patterns limit the use of aggressive local treatments, including conventional RT. It is known that GB is resistant to X-rays, in particular due to the presence of hypoxia in these brain tumors [4]

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