Department of Mathematics, University of California Irvine, Irvine, CA 92697, United States.
Department of Mathematics and Statistics, University of Victoria, Victoria, BC V8W 2Y2, Canada.
J Theor Biol. 2021 Jan 21;509:110499. doi: 10.1016/j.jtbi.2020.110499. Epub 2020 Oct 29.
While resistance mutations are often implicated in the failure of cancer therapy, lack of response also occurs without such mutants. In bladder cancer mouse xenografts, repeated chemotherapy cycles have resulted in cancer stem cell (CSC) enrichment, and consequent loss of therapy response due to the reduced susceptibility of CSCs to drugs. A particular feedback loop present in the xenografts has been shown to promote CSC enrichment in this system. Yet, many other regulatory loops might also be operational and might promote CSC enrichment. Their identification is central to improving therapy response. Here, we perform a comprehensive mathematical analysis to define what types of regulatory feedback loops can and cannot contribute to CSC enrichment, providing guidance to the experimental identification of feedback molecules. We derive a formula that reveals whether or not the cell population experiences CSC enrichment over time, based on the properties of the feedback. We find that negative feedback on the CSC division rate or positive feedback on differentiated cell death rate can lead to CSC enrichment. Further, the feedback mediators that achieve CSC enrichment can be secreted by either CSCs or by more differentiated cells. The extent of enrichment is determined by the CSC death rate, the CSC self-renewal probability, and by feedback strength. Defining these general characteristics of feedback loops can guide the experimental screening for and identification of feedback mediators that can promote CSC enrichment in bladder cancer and potentially other tumors. This can help understand and overcome the phenomenon of CSC-based therapy resistance.
虽然耐药突变常与癌症治疗失败有关，但在没有这些突变的情况下也会出现无应答。在膀胱癌小鼠异种移植模型中，反复的化疗周期导致了癌症干细胞（CSC）的富集，并且由于 CSCs 对药物的敏感性降低，导致治疗反应丧失。在该系统中，已经证明异种移植物中存在的一个特定反馈回路会促进 CSC 的富集。然而，许多其他调节回路可能也在起作用，并可能促进 CSC 的富集。识别它们是提高治疗反应的关键。在这里，我们进行了全面的数学分析，以确定哪些类型的调节反馈回路可以或不能促进 CSC 的富集，为实验鉴定反馈分子提供指导。我们推导出了一个公式，该公式基于反馈的特性，揭示了细胞群体是否会随着时间的推移经历 CSC 的富集。我们发现，CSC 分裂率的负反馈或分化细胞死亡率的正反馈可以导致 CSC 的富集。此外，实现 CSC 富集的反馈介质可以由 CSCs 或更分化的细胞分泌。富集的程度取决于 CSC 的死亡率、CSC 的自我更新概率和反馈强度。定义这些反馈回路的一般特征可以指导实验筛选和鉴定可促进膀胱癌和潜在其他肿瘤中 CSC 富集的反馈介质。这有助于理解和克服基于 CSC 的治疗耐药现象。
