Hemidesmosome integrity protects the colon against colitis and colorectal cancer

Adèle De Arcangelis, Hussein Hamade, Fabien Alpy, Sylvain Normand, Emilie Bruyère, Olivier Lefebvre, Agnès Méchine-Neuville, Stéphanie Siebert, Véronique Pfister, Patricia Lepage, Patrice Laquerriere, Doulaye Dembele, Anne Delanoye-Crespin, Sophie Rodius, Sylvie Robine, Michèle Kedinger, Isabelle Van Seuningen, Patricia Simon-Assmann, Mathias Chamaillard, Michel Labouesse*Elisabeth Georges-Labouesse

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

62 Citations (Scopus)


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 (α6IEC) or in adults (α6ΔIEC). Results Strikingly, all α6IEC 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 (α6 Î "IEC-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.

Original languageEnglish
Pages (from-to)1748-1760
Number of pages13
Issue number10
Publication statusPublished - 1 Oct 2017


  • IBD


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