Effect of feedback regulation on stem cell fractions in tissues and tumors: Understanding chemoresistance in cancer

JOURNAL OF THEORETICAL BIOLOGY

卷:509

Article

Weiss, Lora D.¹  van den Driessche, P.²  Lowengrub, John S.¹  Wodarz, Dominik^1,3  Komarova, Natalia L.¹ 

[1] Univ Calif Irvine, Dept Math, Irvine, CA 92697 USA

[2] Univ Victoria, Dept Math & Stat, Victoria, BC V8W 2Y2, Canada

[3] Univ Calif Irvine, Susan & Henry Samueli Coll Hlth Sci, Dept Populat Hlth & Dis Prevent, Program Publ Hlth, Irvine, CA 92697 USA

关键词: Mathematical modeling;    Lineages;    Hierarchical tissues;    Bladder cancer;    Feedback loops;   

DOI  :  10.1016/j.jtbi.2020.110499

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

Free