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

Abstract 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 hy...

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Autores principales:	Mark A. Hull, Richard J. Cuthbert, C. W. Stanley Ko, Daniel J. Scott, Elizabeth J. Cartwright, Gillian Hawcroft, Sarah L. Perry, Nicola Ingram, Ian M. Carr, Alexander F. Markham, Constanze Bonifer, P. Louise Coletta
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e481426f4bf8467fae7994ac44635d17
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spelling	oai:doaj.org-article:e481426f4bf8467fae7994ac44635d172021-12-02T16:07:43ZParacrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc Min/+ mouse model of intestinal tumorigenesis10.1038/s41598-017-06253-52045-2322https://doaj.org/article/e481426f4bf8467fae7994ac44635d172017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06253-5https://doaj.org/toc/2045-2322Abstract 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.Mark A. HullRichard J. CuthbertC. W. Stanley KoDaniel J. ScottElizabeth J. CartwrightGillian HawcroftSarah L. PerryNicola IngramIan M. CarrAlexander F. MarkhamConstanze BoniferP. Louise ColettaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mark A. Hull Richard J. Cuthbert C. W. Stanley Ko Daniel J. Scott Elizabeth J. Cartwright Gillian Hawcroft Sarah L. Perry Nicola Ingram Ian M. Carr Alexander F. Markham Constanze Bonifer P. Louise Coletta Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc Min/+ mouse model of intestinal tumorigenesis
description	Abstract 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.
format	article
author	Mark A. Hull Richard J. Cuthbert C. W. Stanley Ko Daniel J. Scott Elizabeth J. Cartwright Gillian Hawcroft Sarah L. Perry Nicola Ingram Ian M. Carr Alexander F. Markham Constanze Bonifer P. Louise Coletta
author_facet	Mark A. Hull Richard J. Cuthbert C. W. Stanley Ko Daniel J. Scott Elizabeth J. Cartwright Gillian Hawcroft Sarah L. Perry Nicola Ingram Ian M. Carr Alexander F. Markham Constanze Bonifer P. Louise Coletta
author_sort	Mark A. Hull
title	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_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_sort	paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the apc min/+ mouse model of intestinal tumorigenesis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/e481426f4bf8467fae7994ac44635d17
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Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc Min/+ mouse model of intestinal tumorigenesis

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