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Radiation-Induced Reprogramming of Pre-Senescent Mammary Epithelial Cells Enriches Putative CD44(+)/CD24(−/low) Stem Cell Phenotype

The enrichment of putative CD44(+)/CD24(−/low) breast stem cell populations following exposure to ionizing radiation (IR) has been ascribed to their inherent radioresistance and an elevated frequency of symmetric division during repopulation. However, recent studies demonstrating radiation-induced p...

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Autores principales: Gao, Xuefeng, Sishc, Brock J., Nelson, Christopher B., Hahnfeldt, Philip, Bailey, Susan M., Hlatky, Lynn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905979/
https://www.ncbi.nlm.nih.gov/pubmed/27379202
http://dx.doi.org/10.3389/fonc.2016.00138
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author Gao, Xuefeng
Sishc, Brock J.
Nelson, Christopher B.
Hahnfeldt, Philip
Bailey, Susan M.
Hlatky, Lynn
author_facet Gao, Xuefeng
Sishc, Brock J.
Nelson, Christopher B.
Hahnfeldt, Philip
Bailey, Susan M.
Hlatky, Lynn
author_sort Gao, Xuefeng
collection PubMed
description The enrichment of putative CD44(+)/CD24(−/low) breast stem cell populations following exposure to ionizing radiation (IR) has been ascribed to their inherent radioresistance and an elevated frequency of symmetric division during repopulation. However, recent studies demonstrating radiation-induced phenotypic reprogramming (the transition of non-CD44(+)/CD24(−/low) cells into the CD44(+)/CD24(−/low) phenotype) as a potential mechanism of CD44(+)/CD24(−/low) cell enrichment have raised the question of whether a higher survival and increased self-renewal of existing CD44(+)/CD24(−/low) cells or induced reprogramming is an additional mode of enrichment. To investigate this question, we combined a cellular automata model with in vitro experimental data using both MCF-10A non-tumorigenic human mammary epithelial cells and MCF-7 breast cancer cells, with the goal of identifying the mechanistic basis of CD44(+)/CD24(−/low) stem cell enrichment in the context of radiation-induced cellular senescence. Quantitative modeling revealed that incomplete phenotypic reprogramming of pre-senescent non-stem cells (reprogramming whereby the CD44(+)/CD24(−/low) phenotype is conveyed, along with the short-term proliferation capacity of the original cell) could be an additional mode of enriching the CD44(+)/CD24(−/low) subpopulation. Furthermore, stem cell enrichment in MCF-7 cells occurs both at lower doses and earlier time points, and has longer persistence, than that observed in MCF-10A cells, suggesting that phenotypic plasticity appears to be less regulated in breast cancer cells. Taken together, these results suggest that reprogramming of pre-senescent non-stem cells may play a significant role in both cancer and non-tumorigenic mammary epithelial populations following exposure to IR, a finding with important implications for both radiation therapy and radiation carcinogenesis.
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spelling pubmed-49059792016-07-04 Radiation-Induced Reprogramming of Pre-Senescent Mammary Epithelial Cells Enriches Putative CD44(+)/CD24(−/low) Stem Cell Phenotype Gao, Xuefeng Sishc, Brock J. Nelson, Christopher B. Hahnfeldt, Philip Bailey, Susan M. Hlatky, Lynn Front Oncol Oncology The enrichment of putative CD44(+)/CD24(−/low) breast stem cell populations following exposure to ionizing radiation (IR) has been ascribed to their inherent radioresistance and an elevated frequency of symmetric division during repopulation. However, recent studies demonstrating radiation-induced phenotypic reprogramming (the transition of non-CD44(+)/CD24(−/low) cells into the CD44(+)/CD24(−/low) phenotype) as a potential mechanism of CD44(+)/CD24(−/low) cell enrichment have raised the question of whether a higher survival and increased self-renewal of existing CD44(+)/CD24(−/low) cells or induced reprogramming is an additional mode of enrichment. To investigate this question, we combined a cellular automata model with in vitro experimental data using both MCF-10A non-tumorigenic human mammary epithelial cells and MCF-7 breast cancer cells, with the goal of identifying the mechanistic basis of CD44(+)/CD24(−/low) stem cell enrichment in the context of radiation-induced cellular senescence. Quantitative modeling revealed that incomplete phenotypic reprogramming of pre-senescent non-stem cells (reprogramming whereby the CD44(+)/CD24(−/low) phenotype is conveyed, along with the short-term proliferation capacity of the original cell) could be an additional mode of enriching the CD44(+)/CD24(−/low) subpopulation. Furthermore, stem cell enrichment in MCF-7 cells occurs both at lower doses and earlier time points, and has longer persistence, than that observed in MCF-10A cells, suggesting that phenotypic plasticity appears to be less regulated in breast cancer cells. Taken together, these results suggest that reprogramming of pre-senescent non-stem cells may play a significant role in both cancer and non-tumorigenic mammary epithelial populations following exposure to IR, a finding with important implications for both radiation therapy and radiation carcinogenesis. Frontiers Media S.A. 2016-06-14 /pmc/articles/PMC4905979/ /pubmed/27379202 http://dx.doi.org/10.3389/fonc.2016.00138 Text en Copyright © 2016 Gao, Sishc, Nelson, Hahnfeldt, Bailey and Hlatky. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Gao, Xuefeng
Sishc, Brock J.
Nelson, Christopher B.
Hahnfeldt, Philip
Bailey, Susan M.
Hlatky, Lynn
Radiation-Induced Reprogramming of Pre-Senescent Mammary Epithelial Cells Enriches Putative CD44(+)/CD24(−/low) Stem Cell Phenotype
title Radiation-Induced Reprogramming of Pre-Senescent Mammary Epithelial Cells Enriches Putative CD44(+)/CD24(−/low) Stem Cell Phenotype
title_full Radiation-Induced Reprogramming of Pre-Senescent Mammary Epithelial Cells Enriches Putative CD44(+)/CD24(−/low) Stem Cell Phenotype
title_fullStr Radiation-Induced Reprogramming of Pre-Senescent Mammary Epithelial Cells Enriches Putative CD44(+)/CD24(−/low) Stem Cell Phenotype
title_full_unstemmed Radiation-Induced Reprogramming of Pre-Senescent Mammary Epithelial Cells Enriches Putative CD44(+)/CD24(−/low) Stem Cell Phenotype
title_short Radiation-Induced Reprogramming of Pre-Senescent Mammary Epithelial Cells Enriches Putative CD44(+)/CD24(−/low) Stem Cell Phenotype
title_sort radiation-induced reprogramming of pre-senescent mammary epithelial cells enriches putative cd44(+)/cd24(−/low) stem cell phenotype
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905979/
https://www.ncbi.nlm.nih.gov/pubmed/27379202
http://dx.doi.org/10.3389/fonc.2016.00138
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