Background
Colorectal cancer (CRC) is one of the most commonly occurring cancer types in Norway and the world. The study of CRC pathogenesis requires the availability of a robust animal model that is suitable to determine causative, cancer-driving agents, e.g. in food. The APCMin/+ model using multiple intestinal neoplasia (Min) mice with mutations in the Adenomatous polyposis coli (APC) gene has been established to study the development of tumour genesis. Mice carrying the heterozygous mutation ApcMin/+ develop small intestinal polyps because of the truncated APC-protein. However, in the conventionally used C57BL/6 mouse APCMin/+ model tumours develop mostly in the small intestine, in contrast to human CRC pathology, where lesions are predominantly in the colon. The more recently established A/J mouse APCMin/+ model (Moen et al., 2016) has the advantage that colonic adenomas develop spontaneously in the colon and is thus apparently a better model for CRC. The A/J APCMin/+ mice show considerable sensitivity towards dietary chemical carcinogens such as azoxymethane (AOM). The underlying mechanistic pathways have not been described so far.
Moen, B. et al., 2016. Effect of dietary fibers on cecal microbiota and intestinal tumorigenesis in azoxymethane treated A/J Min/+ mice. PLoS One, 11: e0155402.
Aims
It was the aim of MetAct to study the age-dependent sensitivity to AOM in the A/J APCMin/+ mouse model by exploring the biotransformation capacity and hepatic and colonic protein profiles in neonatal to juvenile mice.
Funding NMBU; 2019 – 2020
Results
Exposure to AOM in neonatal mice (7 days old) had no significant effect on the number of intestinal lesions as compared to untreated control mice. However, two- and four-week-old mice showed an increased sensitivity to AOM. Additionally, our results confirmed the involvement of the hepatic biotransformation enzyme Cyp2E1 in the metabolism of AOM in A/J APCMin/+ mice. The proteomics analysis revealed modulations in the levels of proteins with physiological functions in CRC-related pathways, apoptosis and cytoskeleton alterations.
Murphy, S. L. M. (2020). Age sensitivity and effects in A/J APC Min/+ mice (Mus musculus) after exposure to Azoxymethane, a potent carcinogen (Master’s thesis). University of Oslo, Norway. http://urn.nb.no/URN:NBN:no-82705