Computational Biology, Department of Computer Science, University of Oxford, Parks Road, Oxford OX1 3QD, UK.
J Theor Biol. 2012 Nov 7;312:143-56. doi: 10.1016/j.jtbi.2012.08.002. Epub 2012 Aug 10.
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 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.
肠道表面上皮通过细胞增殖、迁移和分化事件的协调计划迅速自我更新，这些事件始于李氏隐窝。人们普遍认为，结直肠癌是由于突变破坏了隐窝的正常细胞动力学而引起的。我们使用结肠隐窝的基于细胞的空间结构模型来研究突变细胞的后代是否会占据或脱落隐窝的可能性。我们的方法是进行多次模拟，改变初始突变的空间位置以及突变细胞的增殖和粘附特性，以获得其主导的概率的统计分布。我们的模拟导致了一些预测。单克隆转化的过程总是会发生，并且不需要最初引起群体的细胞仍然存在于隐窝中。从隐窝底部起超过一个或两个细胞发生的突变不太可能成为优势克隆。突变克隆在隐窝中持续存在的概率对粘附失调很敏感。通过将模拟结果与隐窝底部简单的一维种群动态随机模型的结果进行比较，我们推断这种敏感性是由于隐窝底部野生型和突变型细胞之间的直接竞争所致。我们还预测，由于在更简单的模型中无法捕获的影响，突变细胞增殖的空间域的扩大可能会导致其固定的概率出现反直觉的非线性变化。
