Mouse Models of Colitis-Associated Cancer Link Inflammation with Tumorigenesis

Michael Karin, Ph.D.
University of California San Diego
NIEHS Grant P42ES10337

Background: The relationship between cancer and inflammation due to chronic infection has been suspected but never proven for centuries. Citing evidence comparing the inflammatory response to the wound healing response, researchers have gone as far as to say that tumors were wounds that would not heal. However, now NIEHS-supported scientists at the University of California, San Diego have shown the first evidence of the molecular link between inflammation and cancer.

These researchers had previously described the interaction of an inhibitory enzyme, known as I-kappa-B kinase (IKKβ), with a transcription factor known as nuclear factor kappa B (NF-κB). IKKβ is a pro-inflammatory protein that is required for the activation of NF-κB. NF-κB acts as a master switch to turn on inflammation in response to bacterial or viral infections. In epithelial cells, IKKβ has been shown to promote cancer by inhibiting a cell-killing process called apoptosis. NF-κB causes the expression of pro-inflammatory molecules that stimulate the division of epithelial cells and thereby increases tumor size.

Advance: The researchers chose a mouse model of colitis-associated cancer (CAC) as their model for study. People suffering from colitis are at high risk of developing CAC. Two types of transgenic mice were used; both lacking IKKβ in either intestinal epithelial cells or myeloid cells. The researchers found that in mice lacking IKKβ in their intestinal epithelial cells, chemical induction of inflammation occurred even without activation of NF-κB. However, tumor incidence decreased by 80% as compared to normal mice. Further tissue analysis demonstrated that stimulation of apoptosis had decreased cancer development.

In the myeloid cells, the research team found that lacking IKKβ reduced the expression of many genes that contribute to the inflammatory process. When NF-κB was not activated, there was a 50% reduction in chemically induced tumors as compared to the normal animals and the tumors that did grow were significantly smaller.

Implication: These results show that blocking the inflammatory response set in motion by the activation of NF-κB by IKKβ, significantly reduces the size and number of tumors in these mouse models and proves that this pathway is a key molecular mechanism linking chronic inflammation to cancer. The authors conclude that the results "suggest that specific pharmacological inhibition of IKKβ may be very effecting in prevention of colitis associated cancer."

Citation: Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, Kagnoff MF, Karin M. IKK beta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 2004 Aug 6;118(3):285-96.