Abstract
Colon cancer (CRC) is one of the most common cancer types in Norway and the world. Coupled with a high mortality rate, the need for studies on CRC is of great importance. However, to study CRC, the need for suitable and robust animal models arises. The A/J Min/+ model has previously been established as an exemplary model for the studies on hereditary and spontaneous CRC. However, as the A/J Min/+ model displayed increased sensitivity to chemical carcinogens compared to the conventional Min/+ model, a need for characterisation of the age-dependent sensitivity to chemical carcinogens such as the procarcinogen AOM was identified. Due to the novelty of the model, no previous studies have charted the underlying mechanistic pathways which relate to the observed increased sensitivity in the A/J Min/+ model. Mice were injected once with AOM (8 mg/kg), at different ages (neonatal to juvenile) to characterise age-dependent sensitivity and terminated at 13 weeks of age. Screening of selected CYP enzymes involved in the metabolism of AOM was performed with in vitro metabolism of hepatic S9 fraction on mice terminated 24h after AOM exposure. Additionally, hepatic and colonic protein profiles were mapped with a proteomics approach to explore possible pathway modulations associated with CRC. Our results show that exposure to AOM in neonatal mice (7 days old) had no significant effect on the number of intestinal lesions. However, two- and four-week-old mice displayed higher sensitivity than neonatal mice and control. Additionally, our results confirm the involvement of Cyp2e1 in the metabolism of AOM in the A/J Min/+ model. The proteomics approach revealed modulations of CRC related pathways, apoptosis and cytoskeleton alterations. This thesis has provided more in-depth insight into the age-dependent sensitivity to chemical carcinogens in the A/J Min/+ model. The analysis of enzymatic activity and proteomic changes undertaken here has expanded our knowledge on how mechanistic pathways may stimulate the increased sensitivity in the A/J Min/+ model. Nevertheless, further research is needed to accurately characterise the age-dependent sensitivity to AOM in the A/J Min/+ model.