A theoretical investigation of the effect of proliferation and adhesion on monoclonal conversion in the colonic crypt
KAUST Grant NumberKUK-C1-013-04
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AbstractThe 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 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. © 2012 Elsevier Ltd.
CitationMirams GR, Fletcher AG, Maini PK, Byrne HM (2012) A theoretical investigation of the effect of proliferation and adhesion on monoclonal conversion in the colonic crypt. Journal of Theoretical Biology 312: 143–156. Available: http://dx.doi.org/10.1016/j.jtbi.2012.08.002.
SponsorsThe authors gratefully acknowledge financial support from the EPSRC awarded to AGF and GRM as part of the Integrative Biology programme (GR/572023/01). GRM is supported by a GlaxoSmithKline Plc Grants and Affiliates award. AGF is funded by the EPSRC and Microsoft Research, Cambridge through Grant EP/I017909/1 (www.2020science.net). AGF and PKM acknowledge support from the BBSRC through grant BB/D020190/1. PKM was partially supported by a Royal Society Wolfson Research Merit Award. This publication was based on work supported in part by Award no. KUK-C1-013-04, made by King Abdullah University of Science and Technology (KAUST).
JournalJournal of Theoretical Biology
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