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

Waldner, Maximilian J. MD1,2; Wirtz, Stefan PhD1; Becker, Christoph PhD1; Seidel, Daniel1; Tubbe, Ingrid1; Cappel, Kyra1; Hähnel, Patricia S. MD3; Galle, Peter R. MD, PhD4; Schuler, Martin MD, PhD3; Neurath, Markus F. MD, PhD1,2,*

doi: 10.1002/ibd.21107
Original Basic Science Articles

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. (Inflamm Bowel Dis 2009;)

1Institute of Molecular Medicine, University of Mainz, Mainz, Germany

2I. Department of Medicine, University of Erlangen, Erlangen, Germany

3Department of Medicine (Cancer Research), West German Cancer Center, University Duisburg-Essen, Essen, Germany

4I. Department of Medicine, University of Mainz, Mainz, Germany

*Reprints: I. Department of Medicine, University of Erlangen-Nürnberg, Ulmenweg 18, D-91054 Erlangen, Erlangen Germany

Email: markus.neurath@uk-erlangen.de

Received for publication 15 July 2009; Accepted 6 August 2009.

Published online 25 September 2009 in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: DFG within the Graduiertenkolleg; Grant Number: GK 1043; Grant sponsor: DFG; Grant Number: SCHU1541/3-1) within the FOR527; Grant sponsor: Geninca Project within the Seventh Framework Programme.

© Crohn's & Colitis Foundation of America, Inc.
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