期刊
JOURNAL OF THEORETICAL BIOLOGY
卷 312, 期 -, 页码 143-156出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jtbi.2012.08.002
关键词
Mathematical model; Colorectal crypt; Stem cell; Mutation; Clonal expansion
资金
- EPSRC
- Integrative Biology programme [GR/572023/01]
- GlaxoSmithKline Plc Grants
- Affiliates award
- Microsoft Research, Cambridge [EP/I017909/1]
- BBSRC [BB/D020190/1]
- Royal Society Wolfson Research Merit Award
- King Abdullah University of Science and Technology (KAUST) [KUK-C1-013-04]
- Biotechnology and Biological Sciences Research Council [BB/D020190/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/I017909/1] Funding Source: researchfish
- BBSRC [BB/D020190/1] Funding Source: UKRI
- EPSRC [EP/I017909/1] Funding Source: UKRI
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 Lieberkuhn. It is generally believed that colorectal cancer arises due to mutations that disrupt the normal cellular dynamics of the crypts. 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 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 one-dimensional stochastic model of population dynamics at the base of the crypt, we infer that this sensitivity is due to direct competition between wild-type 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 counter-intuitive, non-linear changes to the probability of their fixation, due to effects that cannot be captured in simpler models. (C) 2012 Elsevier Ltd. All rights reserved.
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