IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer

The importance of mesenchymal cells in inflammation and/or neoplastic transformation is well recognized, but their role in the initiation of these processes, particularly in the intestine, remains elusive. Using mouse models of colorectal cancer, we show that IKK beta in intestinal mesenchymal cells (IMCs) is critically involved in colitis-associated, but not spontaneous tumorigenesis. We further demonstrate that IMC-specific IKK beta is involved in the initiation of colitis-associated cancer (CAC), as in its absence mice develop reduced immune cell infiltration, epithelial cell proliferation, and dysplasia at the early stages of the disease. At the molecular level, these effects are associated with decreased early production of proinflammatory and protumorigenic mediators, including IL-6, and reduced STAT3 activation. Ex vivo IKK beta-deficient IMCs show defective responses to innate immune stimuli such as LPS, as shown by decreased NF-kappa B signaling and reduced expression of important NF-kappa B target genes. Collectively, our results reveal a hitherto unknown role of mesenchymal IKK beta in driving inflammation and enabling carcinogenesis in the intestine.