RT Journal Article
SR Electronic
T1 Hemidesmosome integrity protects the colon against colitis and colorectal cancer
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1748
OP 1760
DO 10.1136/gutjnl-2015-310847
VO 66
IS 10
A1 Adèle De Arcangelis
A1 Hussein Hamade
A1 Fabien Alpy
A1 Sylvain Normand
A1 Emilie Bruyère
A1 Olivier Lefebvre
A1 Agnès Méchine-Neuville
A1 Stéphanie Siebert
A1 Véronique Pfister
A1 Patricia Lepage
A1 Patrice Laquerriere
A1 Doulaye Dembele
A1 Anne Delanoye-Crespin
A1 Sophie Rodius
A1 Sylvie Robine
A1 Michèle Kedinger
A1 Isabelle Van Seuningen
A1 Patricia Simon-Assmann
A1 Mathias Chamaillard
A1 Michel Labouesse
A1 Elisabeth Georges-Labouesse
YR 2017
UL http://gut.bmj.com/content/66/10/1748.abstract
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.