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Title page for ETD etd-03312008-145158

Type of Document Dissertation
Author Sinnamon, Mark J
Author's Email Address mark.sinnamon@vanderbilt.edu
URN etd-03312008-145158
Title Pro and anti tumorigenic effect of proteinases in intestinal tumorigenesis
Degree PhD
Department Cancer Biology
Advisory Committee
Advisor Name Title
Lynn M. Matrisian Committee Chair
Ambra Pozzi Committee Member
Barbara Fingleton Committee Member
Kevin G. Osteen Committee Member
Simon W. Hayward Committee Member
  • Intestines -- Cancer
  • Cancer
  • MMP
  • Mast
  • Proteinase
  • Tumorigenesis
  • Carcinogenesis
Date of Defense 2008-03-07
Availability unrestricted
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.
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