Computer modeling implicates stem cell overproduction in colon cancer initiation

On the basis of our investigation of the premalignant crypt phenotype in fa milial adenomatous polyposis patients, the hypothesis is developed that tum or initiation in the colon is caused by crypt stem cell overproduction. A n ovel kinetic model for the colonic crypt was used to investigate how the ea rliest tissue abnormality (altered crypt labeling index) arises in these pa tients who have a mutant APC genotype. Only an increase in crypt stem cell number, not changes in the rate of cell cycle proliferation, differentiatio n, or apoptosis of the non-stem cell population, simulated this abnormality . This suggests that APC regulates the number of stem cells in the colonic crypt and when the cells become mutant, an expansion of the crypt stem cell population results.