Inflammation-Associated Polyposis

 

Clinical Background

The formation of polyps in the colon is common and can arise for a variety of reasons ranging from lifestyle choices, including diet and obesity, to genetic predispositions. Polyps are typically detected upon routine endoscopy and the percentage of adults presenting with one or more polyps increases significantly above the age of 50. Polyps can be benign or malignant and in some cases, if left untreated, polyps lead to colorectal cancer. Exposure of animals to the carcinogen Azoxymethane (AOM) results in a somatic inactivating mutation in a Wnt pathway kinase responsible for targeting b catenin for proteasomal degradation rendering the pathway constitutively active. This mutation leads to the generation of spontaneous cancerous colorectal polyps that are similar to those observed in human patients and therefore provide a physiologically relevant animal model for spontaneous colorectal cancer. In addition, a combination of DSS treatment and AOM results in production of colitis associated colon cancer due to added damage to the mucosal layer and concomitant inflammation of the GI tract which exacerbates the insult of AOM exposure. Similar to patient population where colonoscopy is used to assess the presence of polyposis, our animal models utilized video endoscopy to detect and quantify the extent of polyposis.

Preclinical Models

Model Description Length Endpoints
Dextran sodium sulfate (DSS) & azoxymethane (AOM) induced polyposis
Administration of DSS and AOM resulting in colitis, aberrant crypt foci (ACF) formation, and polyposis 49+ days Video endoscopy, polyp score, diarrhea, bloody stool, colon length/weight, histology

 

Dextran sodium sulfate (DSS) & azoxymethane (AOM) induced polyposis

Mice are administered a single injection of AOM followed by seven days of exposure to DSS-treated drinking water. The colon is then examined for number and size of polyps using video endoscopy on days 14, 21, 28, 35, 42, and 49. Video endoscopy allows multiple in vivo assessments within subjects and provides a visual record of disease progression. Endoscopy images of polyposis are scored by a blinded observer using Biomodels validated scoring scale. At the time of sacrifice, the colon is dissected, weighed, its length measured, photographed, and examined using traditional histology methods.

 

Endoscopic Assessment

polyposis_1

 

Adenomatous Polyp

polyposis_2

 

Cross section of an H&E stained colon with polyp.H&E Stained Epithelium at 60x

polyposis_3

Normal epithelium

 

polyposis_4

Adenomatous Polyp