Turner C, Kohandel M
Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1.
J Theor Biol. 2010 Aug 7;265(3):329-35. doi: 10.1016/j.jtbi.2010.05.024.
Under the cancer stem cell (CSC) hypothesis, sustained metastatic growth requires the dissemination of a CSC from the primary tumour followed by its re-establishment in a secondary site. The epithelial-mesenchymal transition (EMT), a differentiation process crucial to normal development, has been implicated in conferring metastatic ability on carcinomas. Balancing these two concepts has led researchers to investigate a possible link between EMT and the CSC phenotype-indeed, recent evidence indicates that, following induction of EMT in human breast cancer and related cell lines, stem cell activity increased, as judged by the presence of cells displaying the CD44(high)/CD24(low) phenotype and an increase in the ability of cells to form mammospheres. We mathematically investigate the nature of this increase in stem cell activity. A stochastic model is used when small number of cells are under consideration, namely in simulating the mammosphere assay, while a related continuous model is used to probe the dynamics of larger cell populations. Two scenarios of EMT-mediated CSC enrichment are considered. In the first, differentiated cells re-acquire a CSC phenotype-this model implicates fully mature cells as key subjects of de-differentiation and entails a delay period of several days before de-differentiation occurs. In the second, pre-existing CSCs experience accelerated division and increased proportion of self-renewing divisions; a lack of perfect CSC biomarkers and cell sorting techniques requires that this model be considered, further emphasizing the need for better characterization of the mammary (cancer) stem cell hierarchy. Additionally, we suggest the utility of comparing mammosphere data to computational mammosphere simulations in elucidating the growth characteristics of mammary (cancer) stem cells.
在癌症干细胞（CSC）假说中，转移性肿瘤的持续生长需要癌症干细胞从原发肿瘤中播散出来，并在继发部位重新形成。上皮-间质转化（EMT）是正常发育过程中至关重要的分化过程，与赋予癌细胞转移能力有关。平衡这两个概念促使研究人员探究EMT与CSC表型之间可能存在的联系——事实上，最近的证据表明，在人乳腺癌及相关细胞系中诱导EMT后，干细胞活性增加，这可通过具有CD44(高)/CD24(低)表型的细胞的存在以及细胞形成乳腺球能力的增强来判断。我们从数学角度研究这种干细胞活性增加的本质。当考虑少量细胞时，即模拟乳腺球实验时，使用随机模型，而使用相关的连续模型来探究较大细胞群体的动力学。我们考虑了EMT介导的CSC富集的两种情况。第一种情况是，分化细胞重新获得CSC表型——该模型认为完全成熟的细胞是去分化的关键主体，并且在去分化发生前需要几天的延迟期。第二种情况是，预先存在的CSC经历加速分裂以及自我更新分裂比例增加；由于缺乏完善的CSC生物标志物和细胞分选技术，需要考虑该模型，这进一步强调了更好地表征乳腺（癌）干细胞层次结构的必要性。此外，我们建议在阐明乳腺（癌）干细胞的生长特性时，将乳腺球数据与计算乳腺球模拟进行比较。
