Abstract
Synchrotron Microbeam Radiation Therapy (MRT) relies on the spatial fractionation of the synchrotron photon beam into parallel micro-beams applying several hundred of grays in their paths. Several works have reported the therapeutic interest of the radiotherapy modality at preclinical level, but biological mechanisms responsible for the described efficacy are not fully understood to date. The aim of this study was to identify the early transcriptomic responses of normal brain and glioma tissue in rats after MRT irradiation (400Gy). The transcriptomic analysis of similarly irradiated normal brain and tumor tissues was performed 6 hours after irradiation of 9 L orthotopically tumor-bearing rats. Pangenomic analysis revealed 1012 overexpressed and 497 repressed genes in the irradiated contralateral normal tissue and 344 induced and 210 repressed genes in tumor tissue. These genes were grouped in a total of 135 canonical pathways. More than half were common to both tissues with a predominance for immunity or inflammation (64 and 67% of genes for normal and tumor tissues, respectively). Several pathways involving HMGB1, toll-like receptors, C-type lectins and CD36 may serve as a link between biochemical changes triggered by irradiation and inflammation and immunological challenge. Most immune cell populations were involved: macrophages, dendritic cells, natural killer, T and B lymphocytes. Among them, our results highlighted the involvement of Th17 cell population, recently described in tumor. The immune response was regulated by a large network of mediators comprising growth factors, cytokines, lymphokines. In conclusion, early response to MRT is mainly based on inflammation and immunity which appear therefore as major contributors to MRT efficacy.
Highlights
Glioblastoma is the most aggressive form of brain tumor
Survival In order to obtain similar irradiation in tumor and normal contralateral brain tissue, we have adapted a configuration of microbeam radiation therapy (MRT) previously reported to have a high interest for 9 L brain tumors therapy [17]
This unilateral MRT irradiation significantly increased the Mean Survival Time (MST) of treated animals compared with the untreated group (33 versus 19 days respectively, p,0.0001)
Summary
Synchrotron microbeam radiation therapy (MRT), a new form of radiosurgery, has been applied to rodent brain tumors and composed a new hope of treatment [2,3]. The use of highly intense synchrotron X-ray beams, with a high energy, high flux and a negligible divergence allows spatial fractionation of an incident beam into arrays of few tens microns wide parallel microbeams, delivering high radiation doses (hGy) in their paths and separated by few hundred microns wide [4]. It has been shown that the sparing effect is supported by the radioresistance of normal brain vessels to MRT for doses up to 1,000Gy [14,15], while there is a denudation of the tumor endothelium and a decrease in tumor blood volume [16,17]. Due to the unique irradiation geometry and the extraordinary dose delivered by MRT, it is not reasonable to extrapolate data and biological molecular events from conventional radiotherapy studies without prior studies
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