Patients with inflammatory bowel disease (IBD), a chronic inflammatory disease of the colon, have an increased incidence of colon cancer. This has led to the hypothesis that chronic inflammation causes malignant transformation and promotes tumor progression. However, an alternative hypothesis can be made that everything starts with early malignant lesions, which activate innate but not adaptive immunity thus driving chronic inflammation. This imbalance between the innate and the adaptive immunity at the intestinal site may speed up colon cancer progression. To test this hypothesis we are examining development of colonic inflammation and associated colon cancer from the perspective of de novo expression of the tumor antigen MUC1 in both settings and innate and adaptive immune responses against it.
We have created an animal model that recapitulates de novo MUC1 expression in human IBD by crossing IL10-/- mice that develop IBD and colon cancer, with human MUC1 transgenic mice that express MUC1 under its own promoter, thereby maintaining human tissue specific expression of this molecule. Mice were sacrificed at various time points and colonic tissue sections assessed for inflammatory and malignant changes and MUC1 expression. We found that, like in humans, expression of normal MUC1 as well as hypoglycosylated (tumor) MUC1 increases with the severity of inflammation in IBD. In other experiments, MUC1+/IL10-/- mice were vaccinated with TnMUC100mer, representing the hypoglycosylated (tumor) form of MUC1. MUC1-specific vaccination slows the progression to IBD as measured by rectal prolapse. Vaccinated animals, that develop rectal prolapse, have fewer tumors than unvaccinated animals. We have developed an animal model of MUC1+ IBD and colon cancer that mimics human disease. We show that MUC1-specific vaccination slows the progression to IBD and has a protective anti-tumor effect. We postulate that induction of MUC1-specific immunity, including effector and regulatory T-cells, restores the balance between adaptive and innate immunity, which resolves chronic inflammation and stops progression of premalignant lesions to cancer.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-07182006-113506 |
| Date | 04 August 2006 |
| Creators | Beatty, Pamela Lynn |
| Contributors | Russell Salter, Olivera J. Finn, Scott Plevy, Rebecca Hughey, William Chambers |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-07182006-113506/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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