Dissociation between predisposition to Colitis and development of Colitis-Associated Cancer in p110δ PI3K mice

The p110δ isoform of PI3K has attracted widespread attention for its role in allergy and inflammation and p110δ-specific inhibitors are currently being tested. Mice that express an inactivated p110δ PI3K isoform (p110δ) develop mild caecal and rectal colitis. p110δ mice were investigated for their propensity to inflammation and due to the causal link between inflammation and cancer also for their susceptibility to colorectal cancer in a colitis-associated cancer model. Here, we show that p110δ mice spontaneously develop colitis, but only in the presence of intestinal flora. Exposure to lipopolysaccharide leads to increased inflammatory cytokine secretion in p110δ colons. We show that p110δ mice have decreased numbers of peripheral CD4CD25 regulatory T cells and that these cells have a specific inability to migrate in response to the thymus exit chemokine sphingosine-1-phosphate, providing an additional explanation for the enhanced inflammatory phenotype. Finally, the absence of active p110δ PI3K results in aggravated inflammation but does not lead to more cancer in the colorectal cancer model. Also aged p110δ mice do not develop colorectal or other types of cancer. Thus our results reveal important new insight into the relation between colonic inflammation and cancer as the lack of active p110δ predisposes to colitis but does not carry increased risk of colitis-associated colon cancer, the latter probably as a consequence of a negative role for p110δ in colon tumour surveillance.