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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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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. |
format | Online Article Text |
id | pubmed-9352192 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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