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ATRA modulates mechanical activation of TGF-β by pancreatic stellate cells
The hallmark of pancreatic ductal adenocarcinoma (PDAC) is abundant desmoplasia, which is orchestrated by pancreatic stellate cells (PSCs) and accounts for the majority of the stroma surrounding the tumour. Healthy PSCs are quiescent, but upon activation during disease progression, they adopt a myof...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931506/ https://www.ncbi.nlm.nih.gov/pubmed/27375161 http://dx.doi.org/10.1038/srep27639 |
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author | Sarper, Muge Cortes, Ernesto Lieberthal, Tyler J. del Río Hernández, Armando |
author_facet | Sarper, Muge Cortes, Ernesto Lieberthal, Tyler J. del Río Hernández, Armando |
author_sort | Sarper, Muge |
collection | PubMed |
description | The hallmark of pancreatic ductal adenocarcinoma (PDAC) is abundant desmoplasia, which is orchestrated by pancreatic stellate cells (PSCs) and accounts for the majority of the stroma surrounding the tumour. Healthy PSCs are quiescent, but upon activation during disease progression, they adopt a myofibroblast-contractile phenotype and secrete and concomitantly reorganise the stiff extracellular matrix (ECM). Transforming growth factor β (TGF-β) is a potent activator of PSCs, and its activation requires spatiotemporal organisation of cellular and extracellular cues to liberate it from an inactive complex with latent TGF-β binding protein (LTBP). Here we study the mechanical activation of TGF-β by PSCs in vitro by investigating LTBP-1 organisation with fibrillar fibronectin and show that all trans-retinoic acid (ATRA), which induces PSC quiescence, down-regulates the ability of PSCs to mechanically organise LTBP-1 and activate TGF-β through a mechanism involving myosin II dependent contractility. Therefore, ATRA inhibits the ability of PSCs to mechanically release active TGF-β, which might otherwise act in an autocrine manner to sustain PSCs in an active state and a tumour-favouring stiff microenvironment. |
format | Online Article Text |
id | pubmed-4931506 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-49315062016-07-06 ATRA modulates mechanical activation of TGF-β by pancreatic stellate cells Sarper, Muge Cortes, Ernesto Lieberthal, Tyler J. del Río Hernández, Armando Sci Rep Article The hallmark of pancreatic ductal adenocarcinoma (PDAC) is abundant desmoplasia, which is orchestrated by pancreatic stellate cells (PSCs) and accounts for the majority of the stroma surrounding the tumour. Healthy PSCs are quiescent, but upon activation during disease progression, they adopt a myofibroblast-contractile phenotype and secrete and concomitantly reorganise the stiff extracellular matrix (ECM). Transforming growth factor β (TGF-β) is a potent activator of PSCs, and its activation requires spatiotemporal organisation of cellular and extracellular cues to liberate it from an inactive complex with latent TGF-β binding protein (LTBP). Here we study the mechanical activation of TGF-β by PSCs in vitro by investigating LTBP-1 organisation with fibrillar fibronectin and show that all trans-retinoic acid (ATRA), which induces PSC quiescence, down-regulates the ability of PSCs to mechanically organise LTBP-1 and activate TGF-β through a mechanism involving myosin II dependent contractility. Therefore, ATRA inhibits the ability of PSCs to mechanically release active TGF-β, which might otherwise act in an autocrine manner to sustain PSCs in an active state and a tumour-favouring stiff microenvironment. Nature Publishing Group 2016-07-04 /pmc/articles/PMC4931506/ /pubmed/27375161 http://dx.doi.org/10.1038/srep27639 Text en Copyright © 2016, Macmillan Publishers Limited 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 Sarper, Muge Cortes, Ernesto Lieberthal, Tyler J. del Río Hernández, Armando ATRA modulates mechanical activation of TGF-β by pancreatic stellate cells |
title | ATRA modulates mechanical activation of TGF-β by pancreatic stellate cells |
title_full | ATRA modulates mechanical activation of TGF-β by pancreatic stellate cells |
title_fullStr | ATRA modulates mechanical activation of TGF-β by pancreatic stellate cells |
title_full_unstemmed | ATRA modulates mechanical activation of TGF-β by pancreatic stellate cells |
title_short | ATRA modulates mechanical activation of TGF-β by pancreatic stellate cells |
title_sort | atra modulates mechanical activation of tgf-β by pancreatic stellate cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931506/ https://www.ncbi.nlm.nih.gov/pubmed/27375161 http://dx.doi.org/10.1038/srep27639 |
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