Adèle De Arcangelis1,2,3,4, Hussein Hamade1,2,3,4,5, Fabien Alpy2,3,4,6,7, Sylvain Normand8, Emilie Bruyère9, Olivier Lefebvre4,6,10,11, Agnès Méchine-Neuville6,12,13, Stéphanie Siebert1,2,3,4, Véronique Pfister1,2,3,4, Patricia Lepage14, Patrice Laquerriere4,15, Doulaye Dembele1,2,3,4, Anne Delanoye-Crespin8, Sophie Rodius1,2,3,4,16, Sylvie Robine17,18, Michèle Kedinger4,6, Isabelle Van Seuningen9, Patricia Simon-Assmann4,6,10,11, Mathias Chamaillard8, Michel Labouesse1,2,3,4,19, Elisabeth Georges-Labouesse1,2,3,4. 1. Department of Development and Stem Cells, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, France. 2. Inserm, U964, Illkirch, France. 3. CNRS, UMR 7104, Illkirch, France. 4. Université de Strasbourg, Strasbourg, France. 5. Current address: F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California, USA. 6. Inserm, U1109, MNT3 Team, Strasbourg, France. 7. Current address: Department of Functional Genomics and Cancer, IGBMC, Illkirch, France. 8. CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Centre d'Infection et d'Immunité de Lille, Université de Lille, Lille, France. 9. Inserm, Université de Lille, CHRU Lille, UMR-S 1172-Jean-Pierre Aubert Research Center, Lille, France. 10. LabEx Medalis, Université de Strasbourg, Strasbourg, France. 11. Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France. 12. CHRU Strasbourg, Hôpital de Hautepierre, Service d'anatomo-pathologie, Strasbourg, France. 13. Current address: Département de Pathologie, Institut Bergonie, Bordeaux, France. 14. UMR1319-MICALIS Institute, INRA, AgroParisTech,Université Paris-Saclay, Jouy-en-Josas, France. 15. CNRS, UMR 7178, Institut Pluridisciplinaire Hubert Curien, Strasbourg, France. 16. Current address: NORLUX Neuro-Oncology Laboratory, CRP-Santé, Luxembourg. 17. Institut Curie, Paris, France. 18. CNRS, UMR 144, Paris, France. 19. Current address: UMR7622, IBPS, Université Pierre et Marie Curie, Paris, France.
Abstract
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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