Inflammatory bowel diseases (IBD) are associated with an elevated risk of colorectal cancer that increases with disease duration and severity. Tumor necrosis factor (TNF) is a major therapeutic target in IBD, but long-term anti-TNF therapy is associated with increased risks of infection and lymphoma, therefore we asked whether TNF signaling through its receptors TNFR1 and TNFR2 could impact colitis and colitis-associated cancer (CAC). In acute dextran sulphate sodium (DSS)-colitis, no major inflammatory differences were found between wildtype (WT), TNFR1- and TNFR2-deficient mice, with the exception of reduced macrophage infiltration into inflamed tissue in TNFR1-/- mice. Chronic colitis and tumor development was assessed in these mice using the carcinogen azoxymethane and 4 cycles of DSS. TNFR1-/- mice were protected against colorectal tumor development compared to WT and TNFR2-/- mice, while inflammation was similar between strains. Hematopoietic TNFR1 deficiency resulted in reduced inflammation and tumor incidence, while stromal/epithelial TNFR1 deficiency reduced indices of cancer without affecting inflammation. 8-OHDG was significantly lower in TNFR1-/- mice compared to other strains, suggesting that TNF could contribute to oxidative stress within the colon. Mice lacking leukocyte NADPH oxidase were protected against clinical illness and CAC despite similar histological inflammation, indicating that inflammation-associated oxidative stress can play a role in CAC. In conclusion, TNF signaling through TNFR1 contributes significantly to the development of colorectal cancer in a model of CAC in a manner that involves both stromal/epithelial and hematopoietic TNFR1. This is significant because anti-TNF therapies may be effective at reducing CAC in the absence of a clinical reduction of IBD symptoms.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:NSHD.ca#10222/14393 |
| Date | 17 November 2011 |
| Creators | Stillie, RoseMarie |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
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