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Inhibition of TLR4 Signaling Impedes Tumor Growth in Colitis-Associated Colon Cancer

Patients suffering from ulcerative colitis are at increased risk of developing colorectal cancer. Although the exact underlying mechanisms of inflammation-associated carcinogenesis remain unknown, the intestinal microbiota as well as pathogenic bacteria are discussed as contributors to inflammation...

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Autores principales: Pastille, Eva, Faßnacht, Tabea, Adamczyk, Alexandra, Ngo Thi Phuong, Nhi, Buer, Jan, Westendorf, Astrid M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138317/
https://www.ncbi.nlm.nih.gov/pubmed/34025672
http://dx.doi.org/10.3389/fimmu.2021.669747
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author Pastille, Eva
Faßnacht, Tabea
Adamczyk, Alexandra
Ngo Thi Phuong, Nhi
Buer, Jan
Westendorf, Astrid M.
author_facet Pastille, Eva
Faßnacht, Tabea
Adamczyk, Alexandra
Ngo Thi Phuong, Nhi
Buer, Jan
Westendorf, Astrid M.
author_sort Pastille, Eva
collection PubMed
description Patients suffering from ulcerative colitis are at increased risk of developing colorectal cancer. Although the exact underlying mechanisms of inflammation-associated carcinogenesis remain unknown, the intestinal microbiota as well as pathogenic bacteria are discussed as contributors to inflammation and colitis-associated colon cancer (CAC). In the present study, we analyzed the impact of TLR4, the receptor for Gram-negative bacteria derived lipopolysaccharides, on intestinal inflammation and tumorigenesis in a murine model of CAC. During the inflammatory phases of CAC development, we observed a strong upregulation of Tlr4 expression in colonic tissues. Blocking of TLR4 signaling by a small-molecule-specific inhibitor during the inflammatory phases of CAC strongly diminished the development and progression of colonic tumors, which was accompanied by decreased numbers of infiltrating macrophages and reduced colonic pro-inflammatory cytokine levels compared to CAC control mice. Interestingly, inhibiting bacterial signaling by antibiotic treatment during the inflammatory phases of CAC also protected mice from severe intestinal inflammation and almost completely prevented tumor growth. Nevertheless, application of antibiotics involved rapid and severe body weight loss and might have unwanted side effects. Our results indicate that bacterial activation of TLR4 on innate immune cells in the colon triggers inflammation and promotes tumor growth. Thus, the inhibition of the TLR4 signaling during intestinal inflammation might be a novel approach to impede CAC development.
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spelling pubmed-81383172021-05-22 Inhibition of TLR4 Signaling Impedes Tumor Growth in Colitis-Associated Colon Cancer Pastille, Eva Faßnacht, Tabea Adamczyk, Alexandra Ngo Thi Phuong, Nhi Buer, Jan Westendorf, Astrid M. Front Immunol Immunology Patients suffering from ulcerative colitis are at increased risk of developing colorectal cancer. Although the exact underlying mechanisms of inflammation-associated carcinogenesis remain unknown, the intestinal microbiota as well as pathogenic bacteria are discussed as contributors to inflammation and colitis-associated colon cancer (CAC). In the present study, we analyzed the impact of TLR4, the receptor for Gram-negative bacteria derived lipopolysaccharides, on intestinal inflammation and tumorigenesis in a murine model of CAC. During the inflammatory phases of CAC development, we observed a strong upregulation of Tlr4 expression in colonic tissues. Blocking of TLR4 signaling by a small-molecule-specific inhibitor during the inflammatory phases of CAC strongly diminished the development and progression of colonic tumors, which was accompanied by decreased numbers of infiltrating macrophages and reduced colonic pro-inflammatory cytokine levels compared to CAC control mice. Interestingly, inhibiting bacterial signaling by antibiotic treatment during the inflammatory phases of CAC also protected mice from severe intestinal inflammation and almost completely prevented tumor growth. Nevertheless, application of antibiotics involved rapid and severe body weight loss and might have unwanted side effects. Our results indicate that bacterial activation of TLR4 on innate immune cells in the colon triggers inflammation and promotes tumor growth. Thus, the inhibition of the TLR4 signaling during intestinal inflammation might be a novel approach to impede CAC development. Frontiers Media S.A. 2021-05-07 /pmc/articles/PMC8138317/ /pubmed/34025672 http://dx.doi.org/10.3389/fimmu.2021.669747 Text en Copyright © 2021 Pastille, Faßnacht, Adamczyk, Ngo Thi Phuong, Buer and Westendorf https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Pastille, Eva
Faßnacht, Tabea
Adamczyk, Alexandra
Ngo Thi Phuong, Nhi
Buer, Jan
Westendorf, Astrid M.
Inhibition of TLR4 Signaling Impedes Tumor Growth in Colitis-Associated Colon Cancer
title Inhibition of TLR4 Signaling Impedes Tumor Growth in Colitis-Associated Colon Cancer
title_full Inhibition of TLR4 Signaling Impedes Tumor Growth in Colitis-Associated Colon Cancer
title_fullStr Inhibition of TLR4 Signaling Impedes Tumor Growth in Colitis-Associated Colon Cancer
title_full_unstemmed Inhibition of TLR4 Signaling Impedes Tumor Growth in Colitis-Associated Colon Cancer
title_short Inhibition of TLR4 Signaling Impedes Tumor Growth in Colitis-Associated Colon Cancer
title_sort inhibition of tlr4 signaling impedes tumor growth in colitis-associated colon cancer
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138317/
https://www.ncbi.nlm.nih.gov/pubmed/34025672
http://dx.doi.org/10.3389/fimmu.2021.669747
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