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首页> 外文期刊>Journal of Theoretical Biology >Effect of feedback regulation on stem cell fractions in tissues and tumors: Understanding chemoresistance in cancer
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Effect of feedback regulation on stem cell fractions in tissues and tumors: Understanding chemoresistance in cancer

机译：反馈调节对组织和肿瘤干细胞分数的影响：了解癌症中的化学抑制

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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. (C) 2020 Elsevier Ltd. All rights reserved.
机译：虽然耐药突变通常与癌症治疗的失败有关，但在没有这种突变的情况下也会出现缺乏反应。在膀胱癌小鼠异种移植物中，重复化疗周期导致肿瘤干细胞（CSC）富集，并由于CSC对药物的敏感性降低而导致治疗反应的丧失。异种移植物中存在一个特殊的反馈回路，可以促进该系统中CSC的富集。然而，许多其他监管循环可能也在运行，并可能促进CSC浓缩。他们的识别对改善治疗反应至关重要。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和不能有助于CSC富集，为反馈分子的实验鉴定提供指导。根据反馈的性质，我们推导出一个公式，揭示细胞群体是否随着时间的推移经历CSC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导致CSC富集。此外，实现CSC富集的反馈介质可由CSC或更多分化细胞分泌。富集程度由CSC死亡率、CSC自我更新概率和反馈强度决定。定义反馈回路的这些一般特征可以指导实验筛选和识别反馈介质，这些介质可以促进膀胱癌和潜在的其他肿瘤中CSC的富集。这有助于理解和克服基于CSC的治疗抵抗现象。（C） 2020爱思唯尔有限公司版权所有。

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