title: Possible mechanisms relating diet and risk of colon cancer.
abstract: Two recent developments in cancer epidemiology and experimental carcinogenesis provide the basis for two possible mechanisms relating diet and colon cancer risk. The first development is the accumulating epidemiological evidence for an association between insulin resistance and colonic adenomas and cancers. This evidence suggests the following mechanism: the consumption of excess dietary energy results in the development of insulin resistance with increased circulating levels of insulin, triglycerides, and non-esterified fatty acids. These circulating factors subject colonic epithelial cells to a proliferative stimulus and also expose them to reactive oxygen intermediates. These long-term exposures result in the promotion of colon cancer. The second development is the continuing identification of agents that significantly inhibit experimental colon carcinogenesis. These observations suggest the following mechanism: focal loss of epithelial barrier function resulting from a failure of terminal differentiation results in the "leak" of a presently undefined toxin and a focal inflammatory response characterized by evidence of the activation of the COX-2 enzyme and an oxidative stress with the release of reactive oxygen intermediates. The resulting focal proliferation and mutagenesis give rise to aberrant crypt foci and adenomas. The process is inhibited by: (a) demulcents confined to the colonic lumen that "repair" the surface; (b) anti-inflammatory agents; or (c) antioxidants. The two mechanisms, i.e., insulin resistance acting throughout the body and focal epithelial barrier failure acting locally, can describe most of the known relationships between diet and colon cancer risk.
authors.affiliation: Department of Nutritional Sciences, University of Toronto, Ontario, Canada. wr.bruce@utoronto.ca
authors.forename: W R
authors.initials: WR
authors.lastname: Bruce
authors.forename: A
authors.initials: A
authors.lastname: Giacca
authors.forename: A
authors.initials: A
authors.lastname: Medline
mesh_terms: D002273:Carcinogens / Q000009:adverse effects*; D003110:Colonic Neoplasms / Q000209:etiology*; D051546:Cyclooxygenase 2; D004032:Diet / Q000009:adverse effects*; D002149:Energy Intake; D004790:Enzyme Induction; D006801:Humans; D007333:Insulin Resistance; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D017382:Reactive Oxygen Species; D012306:Risk
chemical_list: D002273:Carcinogens; D007527:Isoenzymes; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases