A theoretical investigation of the effect of proliferation and\ud adhesion on monoclonal conversion in the colonic crypt

Abstract

Colorectal cancers are initiated by the accumulation of mutations in the colonic epithelium. Using a spatially structured cell-based model of a colonic crypt, we investigate the likelihood that the progeny of a mutated cell will dominate, or be sloughed out of, a crypt. Our approach is to perform multiple simulations, varying the spatial location of the initial mutation, and its proliferative and adhesive properties, to obtain statistical distributions for the probability of domination. Our simulations lead us to make a number of predictions. The process of monoclonal conversion always occurs, and does not require that the cell which initially gave rise to the population remains in the crypt. Mutations occurring more than one to two cells from the base of the crypt are unlikely to become the dominant clone. The probability of a mutant clone persisting in the crypt is sensitive to dysregulation of adhesion, and comparison with a one-dimensional model suggests that this is caused by competition directly at the base of the crypt.\ud We also predict that increases in the extent of the spatial domain in which the mutant cells proliferate cause counter-intuitive non-linear changes to the probability of its fixation, due to effects that cannot be captured in simpler models