Phosphatidylinositol 3-Kinase γ Inhibition Ameliorates Inflammation and Tumor Growth in a Model of Colitis-Associated Cancer

Abstract

Background & Aims: A large body of evidence supports a correlation between inflammation and cancer, although the molecular mechanisms that govern this process are incompletely understood. Phosphatidylinositol 3-kinase (PI3K) is an enzyme that regulates the immune response and contributes to cell transformation in several tumor types. Here, we address the role of the PI3Kγ isoform in inflammatory bowel disease and in the development of colitis-associated cancer. Methods: PI3Kγ-/- and control mice were repeatedly treated with dextran sulfate sodium to induce chronic colitis and colitis-associated cancer. Colorectal tumor burden and colon inflammation were evaluated in these mice. Leukocyte populations in colon were characterized by flow cytometry analysis. Results: PI3Kγ-deficient mice had a lower incidence of colitis-associated tumors, as well as reduced tumor multiplicity and smaller tumor size compared with controls. Reduced tumor development paralleled less colon inflammation in PI3Kγ-deficient mice. Analysis of leukocyte populations in the colon of PI3Kγ-deficient mice showed defective activation and infiltration of myeloid cells and defective recruitment of T cells to the colon compared with controls. Conclusions: PI3Kγ regulates the innate immune response in a murine model of ulcerative colitis, thereby controlling colon inflammation and tumor formation. © 2010 AGA Institute.