Abstract
SUMMARY
Mutations in the tumour suppressor gene adenomatous polyposis coli (APC), resulting in truncated APC protein, are important in the development of both sporadic (> 80%) and inherited (familial adenomatous polyposis; FAP) colon cancer. Multiple intestinal neoplasia (Min) mice with heterozygous mutations in the Apc gene, a model for FAP, spontaneously develop hundreds of adenomas in the small intestine. Although the adenomas origin from the entherocytes in the intestinal epithelia, progression of the adenoma development may be affected by several additional factors such as changed function of other types of epithelial cells. Paneth cells are found in the bottom of the crypt in the small intestine. Their main function is to secrete antibacterial peptides into the intestine which participate in the regulation of the bacterial growth. It is previously shown that Min-mice have changes in the secretion from paneth cells, but the significance of this change on the adenoma growth in Min-mice is not known. Alterations in the bacterial growth in the intestine may also affect the metabolism of compounds in the intestine, and also of bioactivation of toxic compounds in food like heterocyclic amines (HA). We examined the effect of reduced development of paneth cells and consequently reduced secretion of antibacterial peptides on adenoma development in the small intestine of wild type (wt) mice and Min-mice. Additionally we studied whether the effect of the HA, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), on adenoma development in Min-mice increased as a function of reduced development of paneth cells. Min-mice were crossed with the transgenic Paneth-mice, which have delayed development of paneth cells caused by the transfection of a diphtheria toxin gene into paneth cells. The offspring was given a subcutaneous injection of PhIP. The results showed that delayed development of paneth cells had no significant effect on adenoma development neither in untreated wt mice nor in PhIP treated wt mice. Most interestingly the delayed paneth cell development significantly increased the number of adenomas in the Min-mice when treatment was not taken into account. We also found a strong tendency that reduced number of paneth cells increased the effect of PhIP on adenoma development in Min-mice, although the increase did not reach statistical significance. The conclusion is that delayed development of paneth cells increases the adenoma development in Min-mice as a function of heterozygous Apc mutation, and that it may increase the potency of PhIP as a mutagen in the intestine.