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A model for the intrinsic limit of cancer therapy: Duality of treatment-induced cell death and treatment-induced stemness

Intratumor cellular heterogeneity and non-genetic cell plasticity in tumors pose a recently recognized challenge to cancer treatment. Because of the dispersion of initial cell states within a clonal tumor cell population, a perturbation imparted by a cytocidal drug only kills a fraction of cells. Du...

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Autores principales: Angelini, Erin, Wang, Yue, Zhou, Joseph Xu, Qian, Hong, Huang, Sui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9352192/
https://www.ncbi.nlm.nih.gov/pubmed/35877695
http://dx.doi.org/10.1371/journal.pcbi.1010319
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author Angelini, Erin
Wang, Yue
Zhou, Joseph Xu
Qian, Hong
Huang, Sui
author_facet Angelini, Erin
Wang, Yue
Zhou, Joseph Xu
Qian, Hong
Huang, Sui
author_sort Angelini, Erin
collection PubMed
description Intratumor cellular heterogeneity and non-genetic cell plasticity in tumors pose a recently recognized challenge to cancer treatment. Because of the dispersion of initial cell states within a clonal tumor cell population, a perturbation imparted by a cytocidal drug only kills a fraction of cells. Due to dynamic instability of cellular states the cells not killed are pushed by the treatment into a variety of functional states, including a “stem-like state” that confers resistance to treatment and regenerative capacity. This immanent stress-induced stemness competes against cell death in response to the same perturbation and may explain the near-inevitable recurrence after any treatment. This double-edged-sword mechanism of treatment complements the selection of preexisting resistant cells in explaining post-treatment progression. Unlike selection, the induction of a resistant state has not been systematically analyzed as an immanent cause of relapse. Here, we present a generic elementary model and analytical examination of this intrinsic limitation to therapy. We show how the relative proclivity towards cell death versus transition into a stem-like state, as a function of drug dose, establishes either a window of opportunity for containing tumors or the inevitability of progression following therapy. The model considers measurable cell behaviors independent of specific molecular pathways and provides a new theoretical framework for optimizing therapy dosing and scheduling as cancer treatment paradigms move from “maximal tolerated dose,” which may promote therapy induced-stemness, to repeated “minimally effective doses” (as in adaptive therapies), which contain the tumor and avoid therapy-induced progression.
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spelling pubmed-93521922022-08-05 A model for the intrinsic limit of cancer therapy: Duality of treatment-induced cell death and treatment-induced stemness Angelini, Erin Wang, Yue Zhou, Joseph Xu Qian, Hong Huang, Sui PLoS Comput Biol Research Article Intratumor cellular heterogeneity and non-genetic cell plasticity in tumors pose a recently recognized challenge to cancer treatment. Because of the dispersion of initial cell states within a clonal tumor cell population, a perturbation imparted by a cytocidal drug only kills a fraction of cells. Due to dynamic instability of cellular states the cells not killed are pushed by the treatment into a variety of functional states, including a “stem-like state” that confers resistance to treatment and regenerative capacity. This immanent stress-induced stemness competes against cell death in response to the same perturbation and may explain the near-inevitable recurrence after any treatment. This double-edged-sword mechanism of treatment complements the selection of preexisting resistant cells in explaining post-treatment progression. Unlike selection, the induction of a resistant state has not been systematically analyzed as an immanent cause of relapse. Here, we present a generic elementary model and analytical examination of this intrinsic limitation to therapy. We show how the relative proclivity towards cell death versus transition into a stem-like state, as a function of drug dose, establishes either a window of opportunity for containing tumors or the inevitability of progression following therapy. The model considers measurable cell behaviors independent of specific molecular pathways and provides a new theoretical framework for optimizing therapy dosing and scheduling as cancer treatment paradigms move from “maximal tolerated dose,” which may promote therapy induced-stemness, to repeated “minimally effective doses” (as in adaptive therapies), which contain the tumor and avoid therapy-induced progression. Public Library of Science 2022-07-25 /pmc/articles/PMC9352192/ /pubmed/35877695 http://dx.doi.org/10.1371/journal.pcbi.1010319 Text en © 2022 Angelini et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Angelini, Erin
Wang, Yue
Zhou, Joseph Xu
Qian, Hong
Huang, Sui
A model for the intrinsic limit of cancer therapy: Duality of treatment-induced cell death and treatment-induced stemness
title A model for the intrinsic limit of cancer therapy: Duality of treatment-induced cell death and treatment-induced stemness
title_full A model for the intrinsic limit of cancer therapy: Duality of treatment-induced cell death and treatment-induced stemness
title_fullStr A model for the intrinsic limit of cancer therapy: Duality of treatment-induced cell death and treatment-induced stemness
title_full_unstemmed A model for the intrinsic limit of cancer therapy: Duality of treatment-induced cell death and treatment-induced stemness
title_short A model for the intrinsic limit of cancer therapy: Duality of treatment-induced cell death and treatment-induced stemness
title_sort model for the intrinsic limit of cancer therapy: duality of treatment-induced cell death and treatment-induced stemness
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9352192/
https://www.ncbi.nlm.nih.gov/pubmed/35877695
http://dx.doi.org/10.1371/journal.pcbi.1010319
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