Abstract
Chronic intestinal injury after pelvic radiotherapy affects countless cancer survivors worldwide. A comprehensive understanding of the long-term injury dynamics is prevented in available animal models. With linear accelerators that are used to treat cancer in patients, we irradiated a small volume encompassing the colorectum in mice with four fractions of 8 Gy per fraction. We then determined the long-term dynamics of mucosal injury, repair, and the duration of inflammation. We show that crypt fission, not cell proliferation, is the main long-term mechanism for rescuing crypt density after irradiation, and provides a potentially wide window for clinical interventions. Persisting macrophage aggregations indicate a chronic mucosal inflammation. A better understanding as to how crypt fission is triggered and why it fails to repair fully the mucosa may help restore bowel health after pelvic radiotherapy. Moreover, anti-inflammatory interventions, even if implemented long after completed radiotherapy, could promote bowel health in pelvic cancer survivors.
Highlights
Chronic intestinal injury after pelvic radiotherapy affects countless cancer survivors worldwide
We have recently developed a model of fractionated irradiation of the mouse colorectum using linear accelerators, whereby we deliver clinically relevant doses to the gut mucosa while safeguarding animal survival[9]
Our model shows that infiltrating macrophages do not appear in the mucosal tissue until several weeks after the initial injury
Summary
Chronic intestinal injury after pelvic radiotherapy affects countless cancer survivors worldwide. Patients who survive cancer through the help of pelvic radiotherapy have a life-long risk of sequelae that result from radiation-induced injury to the intestines. The long-term trajectory of radiation-induced intestinal injury is difficult to study, since most of the models that simulate clinically relevant doses kill the animal within a week or two[7]. We have recently developed a model of fractionated irradiation of the mouse colorectum using linear accelerators, whereby we deliver clinically relevant doses to the gut mucosa while safeguarding animal survival[9]. We used the model to determine the dynamics of radiation-induced injury to the colorectal mucosa up to 30 weeks after tissue irradiation, with special emphasis on the repair processes and inflammatory activities. The validity of the murine model was examined in rectal biopsies from patients treated with pelvic radiotherapy
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