Colorectal cancer (CRC) is the third most common type of cancer in humans, and incidences in Norwegian women were, in 2012, found to be the highest in the world. CRC develops as a result of several genetic and epigenetic changes that cause a transformation of intestinal epithelium from normal tissue, via benign neoplasms, into carcinoma. The disease is slowly progressing and influenced by factors such as diet and gut microbiota.
Mutation in the APC gene is apparent in around 80% of sporadic CRC cases. This mutation occurs in the multiple intestinal neoplasia (Min/+) in mouse, suggesting that Min/+ mice would be a suitable model for human CRC. In this strain, multiple adenomas develop from a heterozygous nonsense mutation at codon 850 of the APC gene. Such a mutation reduces the rate of β-catenin degradation, thereby activating the Wnt signal transduction pathway at unfit times. In addition, a properly functioning APC gene is an essential component of adherent junctions, cell adhesion and the microtubule cytoskeleton. The Min/+ mouse model based on the A/J strain (A/J Min/+) develops extensive amounts of colonic lesions. It also displays a continuous transition from early lesions to carcinomas suggesting that it closely reflects human colorectal carcinogenesis.
The aim of the main study is to investigate effects of a mixture of POPs relevant to human exposure on the development of colorectal cancer. The study will be conducted using both the A/J Min/+ mouse model for human CRC and an APC mutated in vitro murine intestinal stem cell model. Tumors developed as a result of POPs exposure will be used for mechanistic studies. To continue in the direction towards human CRC, an in vitro intestinal stem cell model with mutations in the APC gene will be exposed to the same POP mixture. This will enable a better interpretation of the results in accordance to colorectal carcinogenesis in humans.
We hypothesize that exposure to environmental hazardous contaminants can act individually or combined, through different mechanistic pathways to contribute to cancer development. In particular, we want to explore mechanisms that may lead to cellular effects altering intestinal epithelium development and predispose individuals to colorectal cancer.
The master project will form part of the main study. The student will be supervised by Erik Ropstad, Steven Verhaegen, Ketil Hylland, Gunn ?stby