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Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis

Age is a significant risk factor for the development of cancer. However, the mechanisms that drive age-related increases in cancer remain poorly understood. To determine if senescent stromal cells influence tumorigenesis, we develop a mouse model that mimics the aged skin microenvironment. Using thi...

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Autores principales: Ruhland, Megan K., Loza, Andrew J., Capietto, Aude-Helene, Luo, Xianmin, Knolhoff, Brett L., Flanagan, Kevin C., Belt, Brian A., Alspach, Elise, Leahy, Kathleen, Luo, Jingqin, Schaffer, Andras, Edwards, John R., Longmore, Gregory, Faccio, Roberta, DeNardo, David G., Stewart, Sheila A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899869/
https://www.ncbi.nlm.nih.gov/pubmed/27272654
http://dx.doi.org/10.1038/ncomms11762
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author Ruhland, Megan K.
Loza, Andrew J.
Capietto, Aude-Helene
Luo, Xianmin
Knolhoff, Brett L.
Flanagan, Kevin C.
Belt, Brian A.
Alspach, Elise
Leahy, Kathleen
Luo, Jingqin
Schaffer, Andras
Edwards, John R.
Longmore, Gregory
Faccio, Roberta
DeNardo, David G.
Stewart, Sheila A.
author_facet Ruhland, Megan K.
Loza, Andrew J.
Capietto, Aude-Helene
Luo, Xianmin
Knolhoff, Brett L.
Flanagan, Kevin C.
Belt, Brian A.
Alspach, Elise
Leahy, Kathleen
Luo, Jingqin
Schaffer, Andras
Edwards, John R.
Longmore, Gregory
Faccio, Roberta
DeNardo, David G.
Stewart, Sheila A.
author_sort Ruhland, Megan K.
collection PubMed
description Age is a significant risk factor for the development of cancer. However, the mechanisms that drive age-related increases in cancer remain poorly understood. To determine if senescent stromal cells influence tumorigenesis, we develop a mouse model that mimics the aged skin microenvironment. Using this model, here we find that senescent stromal cells are sufficient to drive localized increases in suppressive myeloid cells that contributed to tumour promotion. Further, we find that the stromal-derived senescence-associated secretory phenotype factor interleukin-6 orchestrates both increases in suppressive myeloid cells and their ability to inhibit anti-tumour T-cell responses. Significantly, in aged, cancer-free individuals, we find similar increases in immune cells that also localize near senescent stromal cells. This work provides evidence that the accumulation of senescent stromal cells is sufficient to establish a tumour-permissive, chronic inflammatory microenvironment that can shelter incipient tumour cells, thus allowing them to proliferate and progress unabated by the immune system.
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spelling pubmed-48998692016-06-22 Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis Ruhland, Megan K. Loza, Andrew J. Capietto, Aude-Helene Luo, Xianmin Knolhoff, Brett L. Flanagan, Kevin C. Belt, Brian A. Alspach, Elise Leahy, Kathleen Luo, Jingqin Schaffer, Andras Edwards, John R. Longmore, Gregory Faccio, Roberta DeNardo, David G. Stewart, Sheila A. Nat Commun Article Age is a significant risk factor for the development of cancer. However, the mechanisms that drive age-related increases in cancer remain poorly understood. To determine if senescent stromal cells influence tumorigenesis, we develop a mouse model that mimics the aged skin microenvironment. Using this model, here we find that senescent stromal cells are sufficient to drive localized increases in suppressive myeloid cells that contributed to tumour promotion. Further, we find that the stromal-derived senescence-associated secretory phenotype factor interleukin-6 orchestrates both increases in suppressive myeloid cells and their ability to inhibit anti-tumour T-cell responses. Significantly, in aged, cancer-free individuals, we find similar increases in immune cells that also localize near senescent stromal cells. This work provides evidence that the accumulation of senescent stromal cells is sufficient to establish a tumour-permissive, chronic inflammatory microenvironment that can shelter incipient tumour cells, thus allowing them to proliferate and progress unabated by the immune system. Nature Publishing Group 2016-06-08 /pmc/articles/PMC4899869/ /pubmed/27272654 http://dx.doi.org/10.1038/ncomms11762 Text en Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Ruhland, Megan K.
Loza, Andrew J.
Capietto, Aude-Helene
Luo, Xianmin
Knolhoff, Brett L.
Flanagan, Kevin C.
Belt, Brian A.
Alspach, Elise
Leahy, Kathleen
Luo, Jingqin
Schaffer, Andras
Edwards, John R.
Longmore, Gregory
Faccio, Roberta
DeNardo, David G.
Stewart, Sheila A.
Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis
title Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis
title_full Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis
title_fullStr Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis
title_full_unstemmed Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis
title_short Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis
title_sort stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899869/
https://www.ncbi.nlm.nih.gov/pubmed/27272654
http://dx.doi.org/10.1038/ncomms11762
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