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

Abstract

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.

• Authors: Maximilian J Waldner, Stefan Wirtz, Christoph Becker, Daniel Seidel, Ingrid Tubbe, Kyra Cappel, Patricia S Hähnel, Peter R Galle, Martin Schuler, Markus F Neurath
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) Vol. 16 Issue 4 Pg. 559-67 (Apr 2010) ISSN: 1536-4844 [Electronic] England
• PMID: 19785028 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Pore Forming Cytotoxic Proteins
• perforin, mouse
• Dextran Sulfate

Topics

• Animals
• CD4-Positive T-Lymphocytes (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Chronic Disease
• Colitis (chemically induced, metabolism, pathology)
• Colonic Neoplasms (etiology, metabolism, pathology)
• Cytotoxicity, Immunologic
• Dextran Sulfate (toxicity)
• Disease Models, Animal
• Intestinal Mucosa (immunology)
• Killer Cells, Natural (immunology)
• Mice
• Mice, Inbred C57BL
• Pore Forming Cytotoxic Proteins (deficiency, physiology)
• Reverse Transcriptase Polymerase Chain Reaction
• Specific Pathogen-Free Organisms
• T-Lymphocytes (immunology)