Cargando…

Reduction of fibrosis and immune suppressive cells in ErbB2-dependent tumorigenesis by an LXR agonist

One of the central challenges for cancer therapy is the identification of factors in the tumor microenvironment that increase tumor progression and prevent immune surveillance. One such element associated with breast cancer is stromal fibrosis, a histopathologic criterion for invasive cancer and poo...

Descripción completa

Detalles Bibliográficos
Autores principales: Sheng, Gao, Yuan, Hongyan, Jin, Lu, Ranjit, Suman, Panov, Julia, Lu, Xun, Levi, Moshe, Glazer, Robert I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007044/
https://www.ncbi.nlm.nih.gov/pubmed/33780491
http://dx.doi.org/10.1371/journal.pone.0248996
_version_ 1783672419132637184
author Sheng, Gao
Yuan, Hongyan
Jin, Lu
Ranjit, Suman
Panov, Julia
Lu, Xun
Levi, Moshe
Glazer, Robert I.
author_facet Sheng, Gao
Yuan, Hongyan
Jin, Lu
Ranjit, Suman
Panov, Julia
Lu, Xun
Levi, Moshe
Glazer, Robert I.
author_sort Sheng, Gao
collection PubMed
description One of the central challenges for cancer therapy is the identification of factors in the tumor microenvironment that increase tumor progression and prevent immune surveillance. One such element associated with breast cancer is stromal fibrosis, a histopathologic criterion for invasive cancer and poor survival. Fibrosis is caused by inflammatory factors and remodeling of the extracellular matrix that elicit an immune tolerant microenvironment. To address the role of fibrosis in tumorigenesis, we developed NeuT/ATTAC transgenic mice expressing a constitutively active NeuT/erbB2 transgene, and an inducible, fat-directed caspase-8 fusion protein, which upon activation results in selective and partial ablation of mammary fat and its replacement with fibrotic tissue. Induction of fibrosis in NeuT/ATTAC mice led to more rapid tumor development and an inflammatory and fibrotic stromal environment. In an effort to explore therapeutic options that could reduce fibrosis and immune tolerance, mice were treated with the oxysterol liver X receptor (LXR) pan agonist, N,N-dimethyl-3-β-hydroxy-cholenamide (DMHCA), an agent known to reduce fibrosis in non-malignant diseases. DMHCA reduced tumor progression, tumor multiplicity and fibrosis, and improved immune surveillance by reducing infiltrating myeloid-derived suppressor cells and increasing CD4 and CD8 effector T cells. These effects were associated with downregulation of an LXR-dependent gene network related to reduced breast cancer survival that included Spp1, S100a9, Anxa1, Mfge8 and Cd14. These findings suggest that the use of DMHCA may be a potentially effective approach to reduce desmoplasia and immune tolerance and increase the efficacy of cancer therapy.
format Online
Article
Text
id pubmed-8007044
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-80070442021-04-07 Reduction of fibrosis and immune suppressive cells in ErbB2-dependent tumorigenesis by an LXR agonist Sheng, Gao Yuan, Hongyan Jin, Lu Ranjit, Suman Panov, Julia Lu, Xun Levi, Moshe Glazer, Robert I. PLoS One Research Article One of the central challenges for cancer therapy is the identification of factors in the tumor microenvironment that increase tumor progression and prevent immune surveillance. One such element associated with breast cancer is stromal fibrosis, a histopathologic criterion for invasive cancer and poor survival. Fibrosis is caused by inflammatory factors and remodeling of the extracellular matrix that elicit an immune tolerant microenvironment. To address the role of fibrosis in tumorigenesis, we developed NeuT/ATTAC transgenic mice expressing a constitutively active NeuT/erbB2 transgene, and an inducible, fat-directed caspase-8 fusion protein, which upon activation results in selective and partial ablation of mammary fat and its replacement with fibrotic tissue. Induction of fibrosis in NeuT/ATTAC mice led to more rapid tumor development and an inflammatory and fibrotic stromal environment. In an effort to explore therapeutic options that could reduce fibrosis and immune tolerance, mice were treated with the oxysterol liver X receptor (LXR) pan agonist, N,N-dimethyl-3-β-hydroxy-cholenamide (DMHCA), an agent known to reduce fibrosis in non-malignant diseases. DMHCA reduced tumor progression, tumor multiplicity and fibrosis, and improved immune surveillance by reducing infiltrating myeloid-derived suppressor cells and increasing CD4 and CD8 effector T cells. These effects were associated with downregulation of an LXR-dependent gene network related to reduced breast cancer survival that included Spp1, S100a9, Anxa1, Mfge8 and Cd14. These findings suggest that the use of DMHCA may be a potentially effective approach to reduce desmoplasia and immune tolerance and increase the efficacy of cancer therapy. Public Library of Science 2021-03-29 /pmc/articles/PMC8007044/ /pubmed/33780491 http://dx.doi.org/10.1371/journal.pone.0248996 Text en © 2021 Sheng et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Sheng, Gao
Yuan, Hongyan
Jin, Lu
Ranjit, Suman
Panov, Julia
Lu, Xun
Levi, Moshe
Glazer, Robert I.
Reduction of fibrosis and immune suppressive cells in ErbB2-dependent tumorigenesis by an LXR agonist
title Reduction of fibrosis and immune suppressive cells in ErbB2-dependent tumorigenesis by an LXR agonist
title_full Reduction of fibrosis and immune suppressive cells in ErbB2-dependent tumorigenesis by an LXR agonist
title_fullStr Reduction of fibrosis and immune suppressive cells in ErbB2-dependent tumorigenesis by an LXR agonist
title_full_unstemmed Reduction of fibrosis and immune suppressive cells in ErbB2-dependent tumorigenesis by an LXR agonist
title_short Reduction of fibrosis and immune suppressive cells in ErbB2-dependent tumorigenesis by an LXR agonist
title_sort reduction of fibrosis and immune suppressive cells in erbb2-dependent tumorigenesis by an lxr agonist
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007044/
https://www.ncbi.nlm.nih.gov/pubmed/33780491
http://dx.doi.org/10.1371/journal.pone.0248996
work_keys_str_mv AT shenggao reductionoffibrosisandimmunesuppressivecellsinerbb2dependenttumorigenesisbyanlxragonist
AT yuanhongyan reductionoffibrosisandimmunesuppressivecellsinerbb2dependenttumorigenesisbyanlxragonist
AT jinlu reductionoffibrosisandimmunesuppressivecellsinerbb2dependenttumorigenesisbyanlxragonist
AT ranjitsuman reductionoffibrosisandimmunesuppressivecellsinerbb2dependenttumorigenesisbyanlxragonist
AT panovjulia reductionoffibrosisandimmunesuppressivecellsinerbb2dependenttumorigenesisbyanlxragonist
AT luxun reductionoffibrosisandimmunesuppressivecellsinerbb2dependenttumorigenesisbyanlxragonist
AT levimoshe reductionoffibrosisandimmunesuppressivecellsinerbb2dependenttumorigenesisbyanlxragonist
AT glazerroberti reductionoffibrosisandimmunesuppressivecellsinerbb2dependenttumorigenesisbyanlxragonist