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 disruption, experimental evidence is lacking regarding the potential contribution of epithelial cell/basement membrane anchorage on inflammation onset and subsequent neoplastic transformation of inflammatory lesions.
Dr Adèle De Arcangelis and colleagues from France analyzed the role of the α6β4 integrin receptor found in hemidesmosomes that attach intestinal epithelial cells to the laminin-containing basement membrane.
The researchers developed new mouse models inducing intestinal epithelial cell-pecific ablation of α6 integrin either during development or in adults.
Strikingly, all α6ΔIEC mutant mice spontaneously developed long-standing colitis, which degenerated overtime into infiltrating adenocarcinoma.
|Tumourigenesis required B and T lymphocyte activation |
The sequence of events leading to disease onset entails hemidesmosome disruption, basement membrane detachment, IL-18 overproduction by intestinal epithelial cells, hyperplasia and enhanced intestinal permeability.
The researchers found that intestinal epithelial cells-specific ablation of α6 integrin induced in adult mice resulted in fully penetrant colitis and tumor 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.
The team noted that while the initial intestinal inflammation occurred independently of the adaptive immune system, tumourigenesis required B and T lymphocyte activation.
Dr De Arcangelis' team comments, "We provide for the first time evidence that loss of intestinal epithelial cells/basement membrane 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."