Ingham-Dempster Tim, Walker Dawn C, Corfe Bernard M
Insigneo Institute for in silico medicine, Pam Liversedge Building, University of Sheffield, Sir Frederick Mappin Building, Mappin Street, Sheffield S1 3JD, UK.
Department of Oncology and Metabolism, The Medical School, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK.
R Soc Open Sci. 2017 Apr 12;4(4):160858. doi: 10.1098/rsos.160858. eCollection 2017 Apr.
Colorectal cancer (CRC) is a major cause of cancer mortality. Colon crypts are multi-cellular flask-shaped invaginations of the colonic epithelium, with stem cells at their base which support the continual turnover of the epithelium with loss of cells by anoikis from the flat mucosa. Mutations in these stem cells can become embedded in the crypts, a process that is strongly implicated in CRC initiation. We describe a computational model which includes novel features, including an accurate representation of the geometry of the crypt mouth. Model simulations yield previously unseen emergent phenomena, such as localization of cell death to a small region of the crypt mouth which corresponds with that observed . A mechanism emerges in the model for regulation of crypt cellularity in response to changes in either cell proliferation rates or membrane adhesion strengths. We show that cell shape assumptions influence this behaviour, with cylinders recapitulating biology better than spheres. Potential applications of the model include determination of roles of mutations in neoplasia and exploring factors for altered crypt morphodynamics.
结直肠癌（CRC）是癌症死亡的主要原因。结肠隐窝是结肠上皮的多细胞烧瓶状内陷结构，其底部有干细胞，这些干细胞支持上皮细胞的持续更新，同时扁平黏膜上的细胞因失巢凋亡而脱落。这些干细胞中的突变可嵌入隐窝，这一过程与CRC的起始密切相关。我们描述了一个计算模型，该模型具有新颖的特征，包括对隐窝口几何形状的精确表示。模型模拟产生了以前未见的涌现现象，例如细胞死亡定位于隐窝口的一个小区域，这与观察到的情况相符。模型中出现了一种机制，用于响应细胞增殖率或膜黏附强度的变化来调节隐窝细胞数量。我们表明，细胞形状假设会影响这种行为，圆柱体比球体更能重现生物学现象。该模型的潜在应用包括确定突变在肿瘤形成中的作用以及探索隐窝形态动力学改变的因素。
