Perforin deficiency attenuates inflammation and tumor growth in colitis-associated cancer

✍ Scribed by Maximilian J. Waldner; Stefan Wirtz; Christoph Becker; Daniel Seidel; Ingrid Tubbe; Kyra Cappel; Patricia S. Hähnel; Peter R. Galle; Martin Schuler; Markus F. Neurath

• Book ID: 102861518
• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: English
• Weight: 782 KB
• Volume: 16
• Category: Article
• ISSN: 1078-0998
• DOI: 10.1002/ibd.21107

✦ Synopsis

Background:

Patients with inflammatory bowel disease (ibd) have a markedly increased risk to develop colon cancer, but there are only limited data about the host antitumor response in such colitis-associated cancer. in the present study we aimed at assessing the role of perforin-dependent effector mechanisms in the immune response in a murine model of colitis-associated colon cancer.

Methods:

Wildtype and perforin-deficient mice were analyzed in a mouse model of colitis-associated colon cancer using azoxymethane (aom) and dextran sodium sulfate (dss).

Results:

Tumors of wildtype mice showed infiltration of cd4+, cd8+ t cells, natural killer (nk) cells, high numbers of apoptotic cells, and expression of the transcription factor eomesodermin and cytotoxic effector proteins, suggesting a potential role of the antitumor immune response in aom/dss tumorigenesis. furthermore, perforin deficiency resulted in reduced apoptosis of epithelial cells as compared to wildtype mice, whereas tumor infiltration by nk cells, cd8+, and cd4+ t cells was unchanged. however, perforin-deficient mice surprisingly developed significantly fewer tumors than wildtype mice. subsequent studies identified an important role of perforin in regulating colitis activity, as perforin deficiency caused a significant reduction of dss colitis activity and proinflammatory cytokine production as compared to wildtype controls.

Conclusions:

Perforin is involved in both the antitumor immune response and the regulation of activity of mucosal inflammation in colitis-associated cancer. our data emphasize the possible consequences for therapeutic strategies targeting colitis-associated colon cancer.