Figure 3.

Schematic diagram illustrating a probable sequence of events resulting from exposure to high levels of hydrophobic bile acids (HBAs) that accompany a high-fat diet. This exposure leads to HBA-induced generation of ROS/RNS, activation of survival pathways (eg, autophagy, NF-κB), the generation of cells with genomic instability (eg, mutations, aneuploidy) and clonal selection of mutant cells with survival and proliferative advantages. The end results are the production of adenomas that progress to colon cancer. The epithelial cells of the colon of a person on a Western-style (high-fat/low vegetable/low micronutrient) diet are probably in a persistant “war zone” (bombardment with HBA-induced ROS/RNS, presence of food carcinogens, toxins, etc.). Cells in different stages of progression to malignancy are thus persistently receiving damages to their genome, resulting in clones of cells that are selected for survival in the adverse environment of the colon. While cells in the previous population, if receiving excessive DNA damage, underwent cell death altruistically for the overall benefit of the organism, the new clones of cells may behave selfishly. The new clones may acquire resistance to apoptosis and undergo clonal selection on the basis of their survival advantage, even when their DNA is damaged and after their genomes become unstable. This allows progression to adenomas and colon cancer.

Abbreviations: AA, arachidonic acid; COX, cyclooxygenase; LOX, lipoxygenase; PLA₂, phospholipiase A₂; NO, nitric oxide; ROS, reactive oxygen species; RNS, reactive nitrogen species.