Cargando…

The Cdx2 homeobox gene suppresses intestinal tumorigenesis through non–cell-autonomous mechanisms

Developmental genes contribute to cancer, as reported for the homeobox gene Cdx2 playing a tumor suppressor role in the gut. In this study, we show that human colon cancers exhibiting the highest reduction in CDX2 expression belong to the serrated subtype with the worst evolution. In mice, mosaic kn...

Descripción completa

Detalles Bibliográficos
Autores principales: Balbinot, Camille, Armant, Olivier, Elarouci, Nabila, Marisa, Laetitia, Martin, Elisabeth, De Clara, Etienne, Onea, Alina, Deschamps, Jacqueline, Beck, Felix, Freund, Jean-Noël, Duluc, Isabelle
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839756/
https://www.ncbi.nlm.nih.gov/pubmed/29439001
http://dx.doi.org/10.1084/jem.20170934
_version_ 1783304455394951168
author Balbinot, Camille
Armant, Olivier
Elarouci, Nabila
Marisa, Laetitia
Martin, Elisabeth
De Clara, Etienne
Onea, Alina
Deschamps, Jacqueline
Beck, Felix
Freund, Jean-Noël
Duluc, Isabelle
author_facet Balbinot, Camille
Armant, Olivier
Elarouci, Nabila
Marisa, Laetitia
Martin, Elisabeth
De Clara, Etienne
Onea, Alina
Deschamps, Jacqueline
Beck, Felix
Freund, Jean-Noël
Duluc, Isabelle
author_sort Balbinot, Camille
collection PubMed
description Developmental genes contribute to cancer, as reported for the homeobox gene Cdx2 playing a tumor suppressor role in the gut. In this study, we show that human colon cancers exhibiting the highest reduction in CDX2 expression belong to the serrated subtype with the worst evolution. In mice, mosaic knockout of Cdx2 in the adult intestinal epithelium induces the formation of imperfect gastric-type metaplastic lesions. The metaplastic knockout cells do not spontaneously become tumorigenic. However, they induce profound modifications of the microenvironment that facilitate the tumorigenic evolution of adjacent Cdx2-intact tumor-prone cells at the surface of the lesions through NF-κB activation, induction of inducible nitric oxide synthase, and stochastic loss of function of Apc. This study presents a novel paradigm in that metaplastic cells, generally considered as precancerous, can induce tumorigenesis from neighboring nonmetaplastic cells without themselves becoming cancerous. It unveils the novel property of non–cell-autonomous tumor suppressor gene for the Cdx2 gene in the gut.
format Online
Article
Text
id pubmed-5839756
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-58397562018-09-05 The Cdx2 homeobox gene suppresses intestinal tumorigenesis through non–cell-autonomous mechanisms Balbinot, Camille Armant, Olivier Elarouci, Nabila Marisa, Laetitia Martin, Elisabeth De Clara, Etienne Onea, Alina Deschamps, Jacqueline Beck, Felix Freund, Jean-Noël Duluc, Isabelle J Exp Med Research Articles Developmental genes contribute to cancer, as reported for the homeobox gene Cdx2 playing a tumor suppressor role in the gut. In this study, we show that human colon cancers exhibiting the highest reduction in CDX2 expression belong to the serrated subtype with the worst evolution. In mice, mosaic knockout of Cdx2 in the adult intestinal epithelium induces the formation of imperfect gastric-type metaplastic lesions. The metaplastic knockout cells do not spontaneously become tumorigenic. However, they induce profound modifications of the microenvironment that facilitate the tumorigenic evolution of adjacent Cdx2-intact tumor-prone cells at the surface of the lesions through NF-κB activation, induction of inducible nitric oxide synthase, and stochastic loss of function of Apc. This study presents a novel paradigm in that metaplastic cells, generally considered as precancerous, can induce tumorigenesis from neighboring nonmetaplastic cells without themselves becoming cancerous. It unveils the novel property of non–cell-autonomous tumor suppressor gene for the Cdx2 gene in the gut. Rockefeller University Press 2018-03-05 /pmc/articles/PMC5839756/ /pubmed/29439001 http://dx.doi.org/10.1084/jem.20170934 Text en © 2018 Balbinot et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/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 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Balbinot, Camille
Armant, Olivier
Elarouci, Nabila
Marisa, Laetitia
Martin, Elisabeth
De Clara, Etienne
Onea, Alina
Deschamps, Jacqueline
Beck, Felix
Freund, Jean-Noël
Duluc, Isabelle
The Cdx2 homeobox gene suppresses intestinal tumorigenesis through non–cell-autonomous mechanisms
title The Cdx2 homeobox gene suppresses intestinal tumorigenesis through non–cell-autonomous mechanisms
title_full The Cdx2 homeobox gene suppresses intestinal tumorigenesis through non–cell-autonomous mechanisms
title_fullStr The Cdx2 homeobox gene suppresses intestinal tumorigenesis through non–cell-autonomous mechanisms
title_full_unstemmed The Cdx2 homeobox gene suppresses intestinal tumorigenesis through non–cell-autonomous mechanisms
title_short The Cdx2 homeobox gene suppresses intestinal tumorigenesis through non–cell-autonomous mechanisms
title_sort cdx2 homeobox gene suppresses intestinal tumorigenesis through non–cell-autonomous mechanisms
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839756/
https://www.ncbi.nlm.nih.gov/pubmed/29439001
http://dx.doi.org/10.1084/jem.20170934
work_keys_str_mv AT balbinotcamille thecdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms
AT armantolivier thecdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms
AT elaroucinabila thecdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms
AT marisalaetitia thecdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms
AT martinelisabeth thecdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms
AT declaraetienne thecdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms
AT oneaalina thecdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms
AT deschampsjacqueline thecdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms
AT beckfelix thecdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms
AT freundjeannoel thecdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms
AT dulucisabelle thecdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms
AT balbinotcamille cdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms
AT armantolivier cdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms
AT elaroucinabila cdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms
AT marisalaetitia cdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms
AT martinelisabeth cdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms
AT declaraetienne cdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms
AT oneaalina cdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms
AT deschampsjacqueline cdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms
AT beckfelix cdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms
AT freundjeannoel cdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms
AT dulucisabelle cdx2homeoboxgenesuppressesintestinaltumorigenesisthroughnoncellautonomousmechanisms