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IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer

The importance of mesenchymal cells in inflammation and/or neoplastic transformation is well recognized, but their role in the initiation of these processes, particularly in the intestine, remains elusive. Using mouse models of colorectal cancer, we show that IKKβ in intestinal mesenchymal cells (IM...

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Detalles Bibliográficos
Autores principales: Koliaraki, Vasiliki, Pasparakis, Manolis, Kollias, George
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683996/
https://www.ncbi.nlm.nih.gov/pubmed/26621453
http://dx.doi.org/10.1084/jem.20150542
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author Koliaraki, Vasiliki
Pasparakis, Manolis
Kollias, George
author_facet Koliaraki, Vasiliki
Pasparakis, Manolis
Kollias, George
author_sort Koliaraki, Vasiliki
collection PubMed
description The importance of mesenchymal cells in inflammation and/or neoplastic transformation is well recognized, but their role in the initiation of these processes, particularly in the intestine, remains elusive. Using mouse models of colorectal cancer, we show that IKKβ in intestinal mesenchymal cells (IMCs) is critically involved in colitis-associated, but not spontaneous tumorigenesis. We further demonstrate that IMC-specific IKKβ is involved in the initiation of colitis-associated cancer (CAC), as in its absence mice develop reduced immune cell infiltration, epithelial cell proliferation, and dysplasia at the early stages of the disease. At the molecular level, these effects are associated with decreased early production of proinflammatory and protumorigenic mediators, including IL-6, and reduced STAT3 activation. Ex vivo IKKβ-deficient IMCs show defective responses to innate immune stimuli such as LPS, as shown by decreased NF-κB signaling and reduced expression of important NF-κB target genes. Collectively, our results reveal a hitherto unknown role of mesenchymal IKKβ in driving inflammation and enabling carcinogenesis in the intestine.
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spelling pubmed-46839962016-06-14 IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer Koliaraki, Vasiliki Pasparakis, Manolis Kollias, George J Exp Med Research Articles The importance of mesenchymal cells in inflammation and/or neoplastic transformation is well recognized, but their role in the initiation of these processes, particularly in the intestine, remains elusive. Using mouse models of colorectal cancer, we show that IKKβ in intestinal mesenchymal cells (IMCs) is critically involved in colitis-associated, but not spontaneous tumorigenesis. We further demonstrate that IMC-specific IKKβ is involved in the initiation of colitis-associated cancer (CAC), as in its absence mice develop reduced immune cell infiltration, epithelial cell proliferation, and dysplasia at the early stages of the disease. At the molecular level, these effects are associated with decreased early production of proinflammatory and protumorigenic mediators, including IL-6, and reduced STAT3 activation. Ex vivo IKKβ-deficient IMCs show defective responses to innate immune stimuli such as LPS, as shown by decreased NF-κB signaling and reduced expression of important NF-κB target genes. Collectively, our results reveal a hitherto unknown role of mesenchymal IKKβ in driving inflammation and enabling carcinogenesis in the intestine. The Rockefeller University Press 2015-12-14 /pmc/articles/PMC4683996/ /pubmed/26621453 http://dx.doi.org/10.1084/jem.20150542 Text en © 2015 Koliaraki et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Koliaraki, Vasiliki
Pasparakis, Manolis
Kollias, George
IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer
title IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer
title_full IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer
title_fullStr IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer
title_full_unstemmed IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer
title_short IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer
title_sort ikkβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683996/
https://www.ncbi.nlm.nih.gov/pubmed/26621453
http://dx.doi.org/10.1084/jem.20150542
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