ABSTRACT

Hadron therapy by proton beams represents an advanced anti-cancer strategy due to its highly localized dose deposition allowing a greater sparing of normal tissue and/or organs at risk compared to photon/electron radiotherapy. However, it is not clear to what extent non-targeted effects such as transcriptional modulations produced along the beamline may diffuse and impact the surrounding tissue. In this work, we analyze the transcriptome of proton-irradiated mouse skin and choose two biomarker genes to trace their modulation at different distances from the beam’s target and at different doses and times from irradiation to understand to what extent and how far it may propagate, using RNA-Seq and quantitative RT-PCR. In parallel, assessment of lipids alteration is performed by FTIR spectroscopy as a measure of tissue damage. Despite the observed high individual variability of expression, we can show evidence of transcriptional modulation of two biomarker genes at considerable distance from the beam’s target where a simulation system predicts a significantly lower adsorbed dose. The results are compatible with a model involving diffusion of transcripts or regulatory molecules from high dose irradiated cells to distant tissue’s portions adsorbing a much lower fraction of radiation.

摘要

通过质子束进行的强子治疗代表了一种先进的抗癌策略，因为与光子/电子放射治疗相比，它具有高度局部的剂量沉积，可以更大程度地保护处于危险中的正常组织和/或器官。然而，目前尚不清楚非靶向效应（例如沿光束线产生的转录调制）可能扩散并影响周围组织的程度。在这项工作中，我们分析了质子照射小鼠皮肤的转录组，并选择了两个生物标志物基因来追踪它们在距光束目标不同距离以及照射后不同剂量和时间的调制，以了解它可以传播到什么程度和多远，使用 RNA-Seq 和定量 RT-PCR。同时，通过 FTIR 光谱法对脂质变化进行评估，作为组织损伤的衡量标准。尽管观察到表达的高个体变异性，但我们可以在距光束目标相当远的距离处显示两个生物标志物基因的转录调节的证据，其中模拟系统预测吸附剂量显着降低。结果与涉及转录本或调节分子从高剂量辐照细胞扩散到吸收低得多的辐射部分的远处组织部分的模型兼容。