Mirams, G R and Fletcher, A G and Maini, P. K. and Byrne, H. M. (2012) A theoretical investigation of the effect of proliferation & adhesion on monoclonal conversion in the colonic crypt. Journal of Theoretical Biology, 312 (2). pp. 143156.

PDF
1MB 
Abstract
The surface epithelium lining the intestinal tract renews itself rapidly by a coordinated programme of cell proliferation, migration and differentiation events that is initiated in the crypts of Lieberkühn. It is generally believed that colorectal cancer arises due to mutations that disrupt the normal cellular dynamics of the crypts. Using a spatially structured cellbased 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 the proliferative and adhesive properties of the mutant cells, to obtain statistical distributions for the probability of their 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. By comparing simulation results with those from a simple onedimensional stochastic model of population dynamics at the base of the crypt, we infer that this sensitivity is due to direct competition between wildtype and mutant cells at the base of the crypt. We also predict that increases in the extent of the spatial domain in which the mutant cells proliferate can give rise to counterintuitive, nonlinear changes to the probability of their fixation, due to effects that cannot be captured in simpler models.
Item Type:  Article 

Uncontrolled Keywords:  Mathematical model; Colorectal crypt; Stem cell; Mutation; Clonal expansion 
Subjects:  A  C > Biology and other natural sciences 
Research Groups:  Centre for Mathematical Biology 
ID Code:  1597 
Deposited By:  Philip Maini 
Deposited On:  06 Sep 2012 07:38 
Last Modified:  29 May 2015 19:17 
Repository Staff Only: item control page