The increased risk of tumour occurrence in patients with chronic inflammatory diseases has long been reported. NF-κB is a transcription factor triggered in response to pro-inflammatory cytokines; a stimulatory role of NF-κB in cancer has been suspected, but not conclusively proven. Now two papers have directly addressed the effect of NF-κB expression in tumorigenesis and describe related and intriguing findings.

Patients with the inflammatory bowel disease ulcerative colitis are treated with non-steroidal anti-inflammatory drugs (NSAIDs) to reduce both disease symptoms and the increased risk of colitis-associated cancer (CAC). Michael Karin and colleagues investigated the activation of NF-κB in a mouse model of CAC. NSAIDs reportedly inhibit the function of an NF-κB activator, IKKβ. So, Karin and colleagues used mice with tissue-specific deletion of IKKβ to inhibit NF-κB activation

To induce colonic tumours in these mice, the authors used a pro-carcinogen — azoxymethane — and three doses of the pro-inflammatory sodium salt dextran sulphate. Mice lacking IKKβ in their intestinal epithelial cells had a markedly reduced occurrence of tumours compared with controls, indicating that NF-κB is important for tumour initiation and/or promotion. What might be the underlying mechanism for this? The inflammatory response, which induced apoptosis in the epithelial cells, was more severe in mice with IKKβ-deficient epithelial cells and was highlighted by the increased incidence of apoptosis in these cells. As NF-κB is a potent anti-apoptotic transcription factor, the authors concluded that the decreased rate of tumour incidence in these mice is due to increased apoptosis resulting from a lack of active NF-κB.

But does NF-κB also contribute to tumorigenesis through the inflammatory response? To address this, the author's generated mice in which IKKβ was specifically absent in the myeloid/macrophage lineage and treated these mice with the same pro-carcinogen and pro-inflammatory regimen. Tumour incidence was reduced in mice with NF-κB-deficient macrophages and correlated with lower levels of inflammatory cytokines, resulting in substantially reduced proliferation of intestinal epithelial cells. Therefore, the authors conclude that NF-κB contributes to CAC through two mechanisms: through protecting intestinal epithelial cells against inflammation-driven apoptosis and by increasing epithelial-cell proliferation through the transcription of macrophage inflammatory cytokines.

Similar conclusions have been reached by Yinon Ben-Neriah and colleagues in their recent Nature paper. To investigate the contribution of NF-κB to tumorigenesis they used multidrug resistance 2 ( Mdr2 )-knockout mice, which spontaneously develop cholestatic hepatitis, leading to hepatocellular carcinoma, a model of inflammatory-associated cancer. Initially, the authors showed that the inflammatory cytokine tumour-necrosis factor-α (TNFα) is produced by the invading inflammatory cells and surrounding endothelial cells, and results in increased NF-κB expression in hepatocytes. To examine this further, the Mdr2-knockout mice were crossed with mice that have hepatocytes with regulatable NF-κB activity. This showed that active NF-κB in hepatocytes was not required to drive the inflammatory process or for the evident hepatocyte proliferation and hyperploidy — characteristics of cholestatic hepatitis — or the early pre-malignant dysplastic state. However, analyses of older mice demonstrated that hepatocellular carcinoma size and incidence was reduced when NF-κB was inactivated in dysplastic hepatocytes, correlating with a threefold increase in inflammatory-cytokine-induced apoptosis in these cells.

So, Ben-Neriah and colleagues also show that the expression of NF-κB contributes to tumorigenesis through suppression of apoptosis. Importantly, they also show that induction of apoptosis in dysplastic hepatocytes expressing NF-κB can be achieved in vivo through the administration of TNFα-neutralizing antibodies. Drugs that target TNFα are already used in clinical practice and the authors suggest that these might prove useful as chemopreventive agents in patients with chronic inflammatory diseases who are at an increased risk of developing cancer.