Matrix metalloproteinases (MMPs) are classically associated with late stage metastases, though previous work by our lab and others have expanded the role of MMPs to all stages of tumor development. Using a genetic model of intestinal tumorigenesis, the Min (multiple intestinal neoplasia) mouse, we previously demonstrated a role for MMPs, in particular MMP-7, in the development of intestinal adenomas. To further explore the role of proteinases in the development of intestinal neoplasia, I created a novel microarray to examine more than 500 proteases for differential expression in intestinal tumors. Relative microarray analysis found that MMPs-10, -13, and -14 have the highest fold change in expression in tumor compared to normal samples, while absolute microarray analysis indicated that MMPs-9, -12, -15 and -19 are present in tumor samples but not normal intestine. As a result of this screen, I generated Min mice genetically deficient for various proteinases that were differentially detected in Min adenomas (MMP-2, -9, -12, and -19). Genetic ablation of MMP-2, -12, or -19 did not affect tumor number or size, however, MMP-9 deficient Min mice developed 25% fewer tumors than littermate controls. Further, in the context of intestinal tumors, the major cellular source of MMP-9 is neutrophils thus suggesting a pro-tumorigenic role of inflammation in early tumorigenesis. Additionally, our screen detected several mast cell produced proteinases in tumor tissue that were absent from normal intestine. To examine the effect of mast cell proteinases in tumorigenesis, I generated mast cell-deficient Min mice. Surprisingly, these mice developed 50% more tumors than mast cell Min mice, thus indicating that mast cells function in an anti-tumorigenic role early during intestinal tumorigenesis. Thus, these studies demonstrate that proteinases and infiltrating inflammatory cells function in both pro- and anti-tumorigenic roles during early intestinal tumor development.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03312008-145158 |
| Date | 22 April 2008 |
| Creators | Sinnamon, Mark J |
| Contributors | Lynn M. Matrisian, Barbara Fingleton, Kevin G. Osteen, Simon W. Hayward, Ambra Pozzi |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03312008-145158/ |
| 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 Vanderbilt University 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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