PT  - JOURNAL ARTICLE
AU  - Adèle De Arcangelis
AU  - Hussein Hamade
AU  - Fabien Alpy
AU  - Sylvain Normand
AU  - Emilie Bruyère
AU  - Olivier Lefebvre
AU  - Agnès Méchine-Neuville
AU  - Stéphanie Siebert
AU  - Véronique Pfister
AU  - Patricia Lepage
AU  - Patrice Laquerriere
AU  - Doulaye Dembele
AU  - Anne Delanoye-Crespin
AU  - Sophie Rodius
AU  - Sylvie Robine
AU  - Michèle Kedinger
AU  - Isabelle Van Seuningen
AU  - Patricia Simon-Assmann
AU  - Mathias Chamaillard
AU  - Michel Labouesse
AU  - Elisabeth Georges-Labouesse
TI  - Hemidesmosome integrity protects the colon against colitis and colorectal cancer
AID  - 10.1136/gutjnl-2015-310847
DP  - 2017 Oct 01
TA  - Gut
PG  - 1748--1760
VI  - 66
IP  - 10
4099  - http://gut.bmj.com/content/66/10/1748.short
4100  - http://gut.bmj.com/content/66/10/1748.full
SO  - Gut2017 Oct 01; 66
AB  - Objective Epidemiological and clinical data indicate that patients suffering from IBD with long-standing colitis display a higher risk to develop colorectal high-grade dysplasia. Whereas carcinoma invasion and metastasis rely on basement membrane (BM) disruption, experimental evidence is lacking regarding the potential contribution of epithelial cell/BM anchorage on inflammation onset and subsequent neoplastic transformation of inflammatory lesions. Herein, we analyse the role of the α6β4 integrin receptor found in hemidesmosomes that attach intestinal epithelial cells (IECs) to the laminin-containing BM.Design We developed new mouse models inducing IEC-specific ablation of α6 integrin either during development (α6ΔIEC) or in adults (α6ΔIEC-TAM).Results Strikingly, all α6ΔIEC mutant mice spontaneously developed long-standing colitis, which degenerated overtime into infiltrating adenocarcinoma. The sequence of events leading to disease onset entails hemidesmosome disruption, BM detachment, IL-18 overproduction by IECs, hyperplasia and enhanced intestinal permeability. Likewise, IEC-specific ablation of α6 integrin induced in adult mice (α6ΔIEC-TAM) resulted in fully penetrant colitis and tumour progression. Whereas broad-spectrum antibiotic treatment lowered tissue pathology and IL-1β secretion from infiltrating myeloid cells, it failed to reduce Th1 and Th17 response. Interestingly, while the initial intestinal inflammation occurred independently of the adaptive immune system, tumourigenesis required B and T lymphocyte activation.Conclusions We provide for the first time evidence that loss of IECs/BM interactions triggered by hemidesmosome disruption initiates the development of inflammatory lesions that progress into high-grade dysplasia and carcinoma. Colorectal neoplasia in our mouse models resemble that seen in patients with IBD, making them highly attractive for discovering more efficient therapies.