Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1782436543844057088 |
---|---|
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. |
format | Online Article Text |
id | pubmed-4899869 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT ruhlandmegank stromalsenescenceestablishesanimmunosuppressivemicroenvironmentthatdrivestumorigenesis AT lozaandrewj stromalsenescenceestablishesanimmunosuppressivemicroenvironmentthatdrivestumorigenesis AT capiettoaudehelene stromalsenescenceestablishesanimmunosuppressivemicroenvironmentthatdrivestumorigenesis AT luoxianmin stromalsenescenceestablishesanimmunosuppressivemicroenvironmentthatdrivestumorigenesis AT knolhoffbrettl stromalsenescenceestablishesanimmunosuppressivemicroenvironmentthatdrivestumorigenesis AT flanagankevinc stromalsenescenceestablishesanimmunosuppressivemicroenvironmentthatdrivestumorigenesis AT beltbriana stromalsenescenceestablishesanimmunosuppressivemicroenvironmentthatdrivestumorigenesis AT alspachelise stromalsenescenceestablishesanimmunosuppressivemicroenvironmentthatdrivestumorigenesis AT leahykathleen stromalsenescenceestablishesanimmunosuppressivemicroenvironmentthatdrivestumorigenesis AT luojingqin stromalsenescenceestablishesanimmunosuppressivemicroenvironmentthatdrivestumorigenesis AT schafferandras stromalsenescenceestablishesanimmunosuppressivemicroenvironmentthatdrivestumorigenesis AT edwardsjohnr stromalsenescenceestablishesanimmunosuppressivemicroenvironmentthatdrivestumorigenesis AT longmoregregory stromalsenescenceestablishesanimmunosuppressivemicroenvironmentthatdrivestumorigenesis AT faccioroberta stromalsenescenceestablishesanimmunosuppressivemicroenvironmentthatdrivestumorigenesis AT denardodavidg stromalsenescenceestablishesanimmunosuppressivemicroenvironmentthatdrivestumorigenesis AT stewartsheilaa stromalsenescenceestablishesanimmunosuppressivemicroenvironmentthatdrivestumorigenesis |