A novel mouse model of radiation-induced cancer survivorship diseases of the gut
Autor: | Cecilia Bull, Linda Persson, Yohanna Eriksson, Dilip Kumar Malipatlolla, Martina Boström, Fei Sjöberg, John Swanpalmer, Klas Blomgren, Thomas Björk-Eriksson, Pedram Sultanian, Marie Kalm, Eleftheria Alevronta, Agnes E. Wold, Rita Grandér, Gunnar Steineck |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Programmed cell death Pathology medicine.medical_specialty Neoplasms Radiation-Induced Cell Survival Physiology medicine.medical_treatment Crypt Biology Pelvis Mice 03 medical and health sciences 0302 clinical medicine Fibrosis Physiology (medical) medicine Animals Gastrointestinal tract Radiotherapy Hepatology Gastroenterology Dose fractionation medicine.disease Pathophysiology Gastrointestinal Tract Radiation therapy Disease Models Animal Radiation Injuries Experimental 030104 developmental biology 030220 oncology & carcinogenesis Dose Fractionation Radiation Radiation-induced cancer Colorectal Neoplasms |
Zdroj: | American Journal of Physiology-Gastrointestinal and Liver Physiology. 313:G456-G466 |
ISSN: | 1522-1547 0193-1857 |
Popis: | 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. NEW & NOTEWORTHY 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. |
Databáze: | OpenAIRE |
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