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Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc(Min/+) mouse model of intestinal tumorigenesis

Genetic deletion or pharmacological inhibition of cyclooxygenase (COX)-2 abrogates intestinal adenoma development at early stages of colorectal carcinogenesis. COX-2 is localised to stromal cells (predominantly macrophages) in human and mouse intestinal adenomas. Therefore, we tested the hypothesis...

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Autores principales: Hull, Mark A., Cuthbert, Richard J., Ko, C. W. Stanley, Scott, Daniel J., Cartwright, Elizabeth J., Hawcroft, Gillian, Perry, Sarah L., Ingram, Nicola, Carr, Ian M., Markham, Alexander F., Bonifer, Constanze, Coletta, P. Louise
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519705/
https://www.ncbi.nlm.nih.gov/pubmed/28729694
http://dx.doi.org/10.1038/s41598-017-06253-5
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author Hull, Mark A.
Cuthbert, Richard J.
Ko, C. W. Stanley
Scott, Daniel J.
Cartwright, Elizabeth J.
Hawcroft, Gillian
Perry, Sarah L.
Ingram, Nicola
Carr, Ian M.
Markham, Alexander F.
Bonifer, Constanze
Coletta, P. Louise
author_facet Hull, Mark A.
Cuthbert, Richard J.
Ko, C. W. Stanley
Scott, Daniel J.
Cartwright, Elizabeth J.
Hawcroft, Gillian
Perry, Sarah L.
Ingram, Nicola
Carr, Ian M.
Markham, Alexander F.
Bonifer, Constanze
Coletta, P. Louise
author_sort Hull, Mark A.
collection PubMed
description Genetic deletion or pharmacological inhibition of cyclooxygenase (COX)-2 abrogates intestinal adenoma development at early stages of colorectal carcinogenesis. COX-2 is localised to stromal cells (predominantly macrophages) in human and mouse intestinal adenomas. Therefore, we tested the hypothesis that paracrine Cox-2-mediated signalling from macrophages drives adenoma growth and progression in vivo in the Apc (Min/+) mouse model of intestinal tumorigenesis. Using a transgenic C57Bl/6 mouse model of Cox-2 over-expression driven by the chicken lysozyme locus (cLys-Cox-2), which directs integration site-independent, copy number-dependent transgene expression restricted to macrophages, we demonstrated that stromal macrophage Cox-2 in colorectal (but not small intestinal) adenomas from cLys-Cox-2 x Apc (Min/+) mice was associated with significantly increased tumour size (P = 0.025) and multiplicity (P = 0.025), compared with control Apc (Min/+) mice. Transgenic macrophage Cox-2 expression was associated with increased dysplasia, epithelial cell Cox-2 expression and submucosal tumour invasion, as well as increased nuclear β-catenin translocation in dysplastic epithelial cells. In vitro studies confirmed that paracrine macrophage Cox-2 signalling drives catenin-related transcription in intestinal epithelial cells. Paracrine macrophage Cox-2 activity drives growth and progression of Apc (Min/+) mouse colonic adenomas, linked to increased epithelial cell β-catenin dysregulation. Stromal cell (macrophage) gene regulation and signalling represent valid targets for chemoprevention of colorectal cancer.
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spelling pubmed-55197052017-07-26 Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc(Min/+) mouse model of intestinal tumorigenesis Hull, Mark A. Cuthbert, Richard J. Ko, C. W. Stanley Scott, Daniel J. Cartwright, Elizabeth J. Hawcroft, Gillian Perry, Sarah L. Ingram, Nicola Carr, Ian M. Markham, Alexander F. Bonifer, Constanze Coletta, P. Louise Sci Rep Article Genetic deletion or pharmacological inhibition of cyclooxygenase (COX)-2 abrogates intestinal adenoma development at early stages of colorectal carcinogenesis. COX-2 is localised to stromal cells (predominantly macrophages) in human and mouse intestinal adenomas. Therefore, we tested the hypothesis that paracrine Cox-2-mediated signalling from macrophages drives adenoma growth and progression in vivo in the Apc (Min/+) mouse model of intestinal tumorigenesis. Using a transgenic C57Bl/6 mouse model of Cox-2 over-expression driven by the chicken lysozyme locus (cLys-Cox-2), which directs integration site-independent, copy number-dependent transgene expression restricted to macrophages, we demonstrated that stromal macrophage Cox-2 in colorectal (but not small intestinal) adenomas from cLys-Cox-2 x Apc (Min/+) mice was associated with significantly increased tumour size (P = 0.025) and multiplicity (P = 0.025), compared with control Apc (Min/+) mice. Transgenic macrophage Cox-2 expression was associated with increased dysplasia, epithelial cell Cox-2 expression and submucosal tumour invasion, as well as increased nuclear β-catenin translocation in dysplastic epithelial cells. In vitro studies confirmed that paracrine macrophage Cox-2 signalling drives catenin-related transcription in intestinal epithelial cells. Paracrine macrophage Cox-2 activity drives growth and progression of Apc (Min/+) mouse colonic adenomas, linked to increased epithelial cell β-catenin dysregulation. Stromal cell (macrophage) gene regulation and signalling represent valid targets for chemoprevention of colorectal cancer. Nature Publishing Group UK 2017-07-20 /pmc/articles/PMC5519705/ /pubmed/28729694 http://dx.doi.org/10.1038/s41598-017-06253-5 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Hull, Mark A.
Cuthbert, Richard J.
Ko, C. W. Stanley
Scott, Daniel J.
Cartwright, Elizabeth J.
Hawcroft, Gillian
Perry, Sarah L.
Ingram, Nicola
Carr, Ian M.
Markham, Alexander F.
Bonifer, Constanze
Coletta, P. Louise
Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc(Min/+) mouse model of intestinal tumorigenesis
title Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc(Min/+) mouse model of intestinal tumorigenesis
title_full Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc(Min/+) mouse model of intestinal tumorigenesis
title_fullStr Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc(Min/+) mouse model of intestinal tumorigenesis
title_full_unstemmed Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc(Min/+) mouse model of intestinal tumorigenesis
title_short Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc(Min/+) mouse model of intestinal tumorigenesis
title_sort paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the apc(min/+) mouse model of intestinal tumorigenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519705/
https://www.ncbi.nlm.nih.gov/pubmed/28729694
http://dx.doi.org/10.1038/s41598-017-06253-5
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