A novel mouse model of radiation-induced cancer survivorship diseases of the gut

Abstract

A deeper understanding of the radiation-induced pathophysiological processes that develop in the gut is imperative to prevent, alleviate, or eliminate cancer survivorship diseases after radiotherapy to the pelvic area. Most rodent models of high-dose gastrointestinal radiation injury are limited by high mortality. We therefore established a model that allows for the delivering of radiation in fractions at high doses while maintaining long-term survival. Adult male C57/BL6 mice were exposed to small-field irradiation, restricted to 1.5 cm of the colorectum using a linear accelerator. Each mouse received 6 or 8 Gy, two times daily in 12-h intervals in two, three, or four fractions. Acute cell death was examined at 4.5 h postirradiation and histological changes at 6 wk postirradiation. Another group was given four fractions of 8 Gy and followed over time for development of visible symptoms. Irradiation caused immediate cell death, mainly limited to the colorectum. At 6 wk postirradiation, several crypts displayed signs of radiation-induced degeneration. The degenerating crypts were seen alongside crypts that appeared perfectly healthy. Crypt survival was reduced after the fourth fraction regardless of dose, whereas the number of macrophages increased. Angiogenesis was induced, likely as a compensatory mechanism for hypoxia. Four months postirradiation, mice began to show radiation-induced symptoms, and histological examination revealed an extensive crypt loss and fibrosis. Our model is uniquely suitable for studying the long-term trajectory and underlying mechanisms of radiation-induced gastrointestinal injury. A novel mouse model for studying the long-term trajectory of radiation-induced gut injury. The method allows for the use of high doses and multiple fractions, with minor impact on animal health for at least 3 mo. Crypt loss and a slow progression of fibrosis is observed. Crypt degeneration is a process restricted to isolated crypts. Crypt degeneration is presented as a convenient proxy endpoint for long-term radiation-induced gut injury.

Dietary Oat Bran Reduces Systemic Inflammation in Mice Subjected to Pelvic Irradiation

“…With the advent of new technologies, a high dose of radiation can be delivered to the tumor site. Our experimental model of pelvic radiotherapy is unique in that we irradiated the mice with the same clinical linear accelerator (LINAC) that is used to irradiate cancer patients [ 41 ]. Thus, high-energy photons can be delivered to a highly defined area, thereby avoiding undesirable irradiation of non-target organs.…”

“…Thus, high-energy photons can be delivered to a highly defined area, thereby avoiding undesirable irradiation of non-target organs. Our previous study showed that irradiation with 8 Gy × 4 fractions was best suited for our model as it inflicted similar pathologic changes in the mouse intestinal mucosa, notably crypt degeneration, as seen in a cancer survivor’s intestinal mucosa irradiated at the pelvic region [ 41 , 42 ]. Furthermore, these mice appear to maintain their overall health and a normal lifespan despite having received high doses of irradiation.…”

Long-term mucosal injury and repair in a murine model of pelvic radiotherapy

“…The dose rate is identical to that used for patient treatments, and the radiation can be fractionated 8 . 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 . The model produces dose- and fraction-dependent effects on the mucosa that are similar to those seen in humans.…”

Animal models of mucositis: critical tools for advancing pathobiological understanding and identifying therapeutic targets

“…To overcome these limitations, a new model has been developed by Bull and colleagues, in which C57BL/6 mice are exposed to small-field radiation restricted to 1.5cm of the colorectum using a linear accelerator [95]. Each mouse receives 6-8 Gy, twice daily in two, three or four fractions.…”