Conventional radiotherapy using X-rays is one of the most widely used radiation modalities in the field of cancer treatment. However, the effectiveness of conventional X-ray irradiation is limited by the undesirable exposure of normal healthy tissues. This off-target toxicity can lead to the induction of senescence in normal cells as a cell response to sublethal doses of ionizing radiation. Senescent normal cells can adversely impact the safety and the effectiveness of radiotherapy through the establishment of a protumoral environment in the margin of the targeted tumor resulting in treatment complications, and ultimately to cancer relapse. Indeed, despite their permanent growth arrest, senescent cells remain metabolically active and secrete deleterious intrinsic factors in their cellular environment that could impact cancer treatment outcomes. However, alternatives to conventional X-ray irradiation have been developed to limit radiotherapy off-target toxicity. Conventional proton beam therapy is one of them and takes advantage of its inherent depth-dose distribution profile to offer a better targeting of the tumor site while limiting the toxicity to surrounding tissues. The use of ultra-high dose rate proton irradiation could also be an option to limit radiotherapy side effects through the sparing of normal cells while maintaining an effective tumor control. In this master thesis, we tested the propensity of proton irradiations at conventional and ultra-high dose rate to induce senescence in normal cells. For this purpose, a model of ionizing radiation-induced senescence based on an established X-ray irradiation protocol was first developed and validated in normal human dermal fibroblasts. This irradiation protocol for senescence induction was then adapted and used to investigate whether proton irradiations were also able to induce senescence in normal cells and to what extent. In order to achieve these objectives, a broad set of relevant senescence biomarkers was assessed several days post-irradiation in irradiated fibroblasts. After analysis of the different biomarkers studied, a substantial and comparable enrichment of senescent fibroblasts was measured several days after both X-ray and proton irradiations whatever the dose rate applied. In addition, this enrichment seemed to be more pronounced at ultra-high dose rate for proton irradiation. Therefore, these results suggest an induction of senescence following proton irradiation in normal fibroblasts, with a more marked impact of ultra-high dose rate irradiation modalities for the same total dose studied.
Impact of X-ray and proton irradiations on the induction of senescence in normal human dermal fibroblasts
PAULUS, H. (Auteur). 17 janv. 2023
Student thesis: Master types › Master en sciences biomédicales à finalité spécialisée en recherche préclinique