Adenosine/TGFβ axis in regulation of mammary fibroblast functions.

Cancer associated fibroblasts (CAF) play a key role in cancer progression and metastasis. Diminished TGFβ response on CAF correlates with poor outcome and recurrence in cancer patients. Mechanisms behind lost TGFβ signaling on CAF are poorly understood, but, utilizing MMTV-PyMT mouse model, we have...

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Autores principales:	Georgii Vasiukov, Anna Menshikh, Philip Owens, Tatiana Novitskaya, Paula Hurley, Timothy Blackwell, Igor Feoktistov, Sergey V Novitskiy
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0288b858ed28440ca1eea1f6336daf90
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spelling	oai:doaj.org-article:0288b858ed28440ca1eea1f6336daf902021-12-02T20:10:59ZAdenosine/TGFβ axis in regulation of mammary fibroblast functions.1932-620310.1371/journal.pone.0252424https://doaj.org/article/0288b858ed28440ca1eea1f6336daf902021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0252424https://doaj.org/toc/1932-6203Cancer associated fibroblasts (CAF) play a key role in cancer progression and metastasis. Diminished TGFβ response on CAF correlates with poor outcome and recurrence in cancer patients. Mechanisms behind lost TGFβ signaling on CAF are poorly understood, but, utilizing MMTV-PyMT mouse model, we have previously demonstrated that in tumor microenvironment myeloid cells, producing adenosine, contribute to downregulated TGFβ signaling on CAFs. In the current work, we performed serial in vitro studies to investigate the role of adenosine/TGFβ axis in mouse mammary fibroblast functions, i.e., proliferation, protein expression, migration, and contractility. We found that adenosine analog NECA diminished TGFβ-induced CCL5 and MMP9 expression. Additionally, we discovered that NECA completely inhibited effect of TGFβ to upregulate αSMA, key protein of cytoskeletal rearrangements, necessary for migration and contractility of fibroblasts. Our results show that TGFβ increases contractility of mouse mammary fibroblasts and human fibroblast cell lines, and NECA attenuates theses effects. Using pharmacological approach and genetically modified animals, we determined that NECA effects on TGFβ pathway occur via A2A/A2B adenosine receptor-AC-PKA dependent manner. Using isolated CD11b+ cells from tumor tissue of CD73-KO and CD39-KO animals in co-culture experiments with ATP and AMP, we confirmed that myeloid cells can affect functions of mammary fibroblasts through adenosine signaling. Our data suggest a novel mechanism of interaction between adenosine and TGFβ signaling pathways that can impact phenotype of fibroblasts in a tumor microenvironment.Georgii VasiukovAnna MenshikhPhilip OwensTatiana NovitskayaPaula HurleyTimothy BlackwellIgor FeoktistovSergey V NovitskiyPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 6, p e0252424 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Georgii Vasiukov Anna Menshikh Philip Owens Tatiana Novitskaya Paula Hurley Timothy Blackwell Igor Feoktistov Sergey V Novitskiy Adenosine/TGFβ axis in regulation of mammary fibroblast functions.
description	Cancer associated fibroblasts (CAF) play a key role in cancer progression and metastasis. Diminished TGFβ response on CAF correlates with poor outcome and recurrence in cancer patients. Mechanisms behind lost TGFβ signaling on CAF are poorly understood, but, utilizing MMTV-PyMT mouse model, we have previously demonstrated that in tumor microenvironment myeloid cells, producing adenosine, contribute to downregulated TGFβ signaling on CAFs. In the current work, we performed serial in vitro studies to investigate the role of adenosine/TGFβ axis in mouse mammary fibroblast functions, i.e., proliferation, protein expression, migration, and contractility. We found that adenosine analog NECA diminished TGFβ-induced CCL5 and MMP9 expression. Additionally, we discovered that NECA completely inhibited effect of TGFβ to upregulate αSMA, key protein of cytoskeletal rearrangements, necessary for migration and contractility of fibroblasts. Our results show that TGFβ increases contractility of mouse mammary fibroblasts and human fibroblast cell lines, and NECA attenuates theses effects. Using pharmacological approach and genetically modified animals, we determined that NECA effects on TGFβ pathway occur via A2A/A2B adenosine receptor-AC-PKA dependent manner. Using isolated CD11b+ cells from tumor tissue of CD73-KO and CD39-KO animals in co-culture experiments with ATP and AMP, we confirmed that myeloid cells can affect functions of mammary fibroblasts through adenosine signaling. Our data suggest a novel mechanism of interaction between adenosine and TGFβ signaling pathways that can impact phenotype of fibroblasts in a tumor microenvironment.
format	article
author	Georgii Vasiukov Anna Menshikh Philip Owens Tatiana Novitskaya Paula Hurley Timothy Blackwell Igor Feoktistov Sergey V Novitskiy
author_facet	Georgii Vasiukov Anna Menshikh Philip Owens Tatiana Novitskaya Paula Hurley Timothy Blackwell Igor Feoktistov Sergey V Novitskiy
author_sort	Georgii Vasiukov
title	Adenosine/TGFβ axis in regulation of mammary fibroblast functions.
title_short	Adenosine/TGFβ axis in regulation of mammary fibroblast functions.
title_full	Adenosine/TGFβ axis in regulation of mammary fibroblast functions.
title_fullStr	Adenosine/TGFβ axis in regulation of mammary fibroblast functions.
title_full_unstemmed	Adenosine/TGFβ axis in regulation of mammary fibroblast functions.
title_sort	adenosine/tgfβ axis in regulation of mammary fibroblast functions.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/0288b858ed28440ca1eea1f6336daf90
work_keys_str_mv	AT georgiivasiukov adenosinetgfbaxisinregulationofmammaryfibroblastfunctions AT annamenshikh adenosinetgfbaxisinregulationofmammaryfibroblastfunctions AT philipowens adenosinetgfbaxisinregulationofmammaryfibroblastfunctions AT tatiananovitskaya adenosinetgfbaxisinregulationofmammaryfibroblastfunctions AT paulahurley adenosinetgfbaxisinregulationofmammaryfibroblastfunctions AT timothyblackwell adenosinetgfbaxisinregulationofmammaryfibroblastfunctions AT igorfeoktistov adenosinetgfbaxisinregulationofmammaryfibroblastfunctions AT sergeyvnovitskiy adenosinetgfbaxisinregulationofmammaryfibroblastfunctions
_version_	1718374923581259776

Adenosine/TGFβ axis in regulation of mammary fibroblast functions.

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