Forsøksdyr: Underlying mechanisms of dietary exposure to processed meat on colorectal cancer development, and potential preventive effects of novel processed meat products added vegetables.

Godkjenningsdato 23.03.2020

Godkjenningsperiode 23.03.2020-22.03.2024

The present study aims to investigate carcinogenic potential and underlying mechanisms of processed meat on intestinal, cancerous lesions in A/J APC Min/+ mouse model. The study group have long experience using this model to address various aspects of colorectal cancer initiation, promotion, and progression (see attachments 3-6).

To reduce the experimental period, Azoxymethane (AOM) and Dextran Sulfate Sodium (DSS) will be used to enhance the intestinal tumor load, and will also be used as initiator and promotor, respectively, to assess the initiating and/or promoting effects of the processed meat products. The AOM/DSS approach is a common chemical carcinogenesis model. The carcinogenic potential of processed meat products is determined by scoring the number, size and spatial distribution of small lesions and tumors. In addition, underlying mechanisms revealed through enzyme activities, proteomic and metabolomic profiles may indicate the molecular events behind the carcinogenic potential.

This mouse line is characterized by development of intestinal lesions spontaneously. The lesions normally do not affect the well-being of the animals within the experimental study period. Although the AOM/DSS enhances the prevalence of intestinal lesions, and the unknown effects from additional exposure to processed meat products, it is not expected that the wellbeing of the animals will be affected. The animals are closely monitored, and if the lesions become severe and animals develop clinical symptoms (rectal bleeding, discomfort), the animals will be euthanized. The diets will be available ad libitum. Handling of the animals will be kept to a minimum, only allowing ear-marking, weaning, weighing and moving when the cages are cleaned. Blood sampling may be performed three times during the experimental period, from 6 weeks of age, with 3 weeks interval.

The expected scientific and societal value of this study are the increased knowledge of underlying mechanisms and relations between consumption of processed meat and carcinogenesis in A/J APC (Min/+) mouse model, which is highly relevant for understanding human colorectal cancer. In addition, this study contributes to the knowledge of biomarkers of early cancerous events, which may enable early detection of precancerous colorectal lesions as well as revealing mechanistic interactions between immune system, microbiota and carcinogenic compounds from processed meat.

In total, 880 A/J (Min/+) mice and 840 A/J wildtype mice are included.

The A/J APC (Min/+) mouse model is well suited to study the susceptibility for formation of intestinal lesions, as well as tumor distribution. Due to the similarity between the gene defect in this mouse model and in human sporadic colorectal cancer, the model is used for studying carcinogenesis in colorectal cancer in humans. Although in vitro studies are helpful tools within cancer research, such studies do not enable reliable predictions regarding carcinogenesis from dietary exposure, which are the main endpoints in these studies. After careful consideration, the performance of animal experiments provide the only possibility to include the entirety of physiological processes.