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Pro and Anti Tumorigenic Effect of Proteinases in Intestinal Tumorigenesis

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Pro and Anti Tumorigenic Effect of Proteinases in Intestinal Tumorigenesis PRO AND ANTI TUMORIGENIC EFFECT OF PROTEINASES IN INTESTINAL TUMORIGENESIS By Mark Jason Sinnamon Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Cancer Biology May, 2008 Nashville, Tennessee Approved: Professor Lynn M. Matrisian Professor Barbara Fingleton Professor Ambra Pozzi Professor Simon W. Hayward Professor Kevin G. Osteen CANCER BIOLOGY PRO AND ANTI TUMORIGENIC EFFECT OF PROTEINASES IN INTESTINAL TUMORIGENESIS MARK JASON SINNAMON Dissertation under the direction of Professor Lynn M. Matrisian 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. Approved_____________________________________________Date:______________ ORIGINAL PUBLICATIONS Acuff, H.B., Sinnamon, M., Fingleton, B., Boone, B., Levy, S.E., Chen, X., Pozzi, A., Carbone, D.P., Schwartz, D.R., Moin, K., Sloane, B.F., Matrisian, L.M. (2006) Analysis of host- and tumor-derived proteinases using a custom dual species microarray reveals a protective role for stromal matrix metalloproteinase-12 in non-small cell lung cancer. Cancer Res. 2006 Aug 15;66(16):7968-75. Schwartz, D.R., Moin, K., Yao, B., Matrisian, L.M., Coussens, L.M., Bugge, T.H., Fingleton, B., Acuff, H.B., Sinnamon, M., Nassar, H., Platts, A.E., Krawetz, S.A., Linebaugh, B.E., Sloane, B.F. (2007) Hu/Mu ProtIn oligonucleotide microarray: dual- species array for profiling protease and protease inhibitor gene expression in tumors and their microenvironment. Mol Cancer Res. May;5(5):443-54. Sinnamon, M.J., Carter, K.J., Sims, L.P., Lafleur, B., Fingleton, B., Matrisian, L.M. (2007) A protective role for mast cells in intestinal tumorigenesis. Carcinogenesis. 2008 Feb 6; (in press) Sinnamon, M.J., Carter, K.J., Fingleton, B., Matrisian, L.M. Effect of stromal MMP ablation on tumorigenesis in the Min model system. (in preparation) iii ACKNOWLEDGEMENTS Firstly, I would firstly like to thank my mentor, Dr. Lynn Matrisian, for her support, guidance, and confidence throughout the course of this thesis project. I would like to thank the current and former members of my dissertation committee for their guidance and assistance: Dr. Kevin Osteen, Dr. Barbara Fingleton, Dr. Simon Hayward, Dr. Ambra Pozzi, and Dr. Robert Whitehead. I would especially like to acknowledge those researchers who have contributed reagents and technical expertise critical for assays needed to complete this work, namely Dr. Hayward, Dr. Pozzi, and Dr. Jamie Lee. Additionally, I would like to acknowledge past and current members of the Matrisian Laboratory including Dr. Howard Crawford, Dr. Tracy Vargo-Gogola, Dr. Rebecca Wagenaar-Miller, Dr. Mark Gustavson, Dr. Permila Harrell, Dr. Heath Acuff, Dr. Oliver McIntyre, Dr. Conor Lynch, Dr. Michael Van Saun, Dr. Michelle Martin, Dr. Lee Gorden, Kathy Carter, Sophie Thiolloy, and Randy Scherer. I would like to especially acknowledge Dr. Barbara Fingleton and Dr. Lisa McCawley for their continued support whether it be constructing a talk, proofreading a paper, or listening to me talk myself out of that day’s “greatest idea ever”. Lastly, I truly appreciate the support and encouragement from my family and friends throughout this process. iv TABLE OF CONTENTS Page ACKNOWLEDGEMENTS ............................................................................................... iv LIST OF FIGURES ......................................................................................................... viii LIST OF TABLES ...............................................................................................................x LIST OF ABBREVIATIONS ............................................................................................ xi Chapter I. INTRODUCTION ..................................................................................................1 Colorectal Cancer .........................................................................................1 General Characteristics, Staging, Pathology, Genetics ..........................1 The Min Mouse as a Model Organism of Intestinal Tumorigenesis .....8 MMPs and Cancer ......................................................................................11 The Matrix Metalloproteinase Family .................................................11 Regulation of MMP Activity ...............................................................17 MMPs in Tumorigenesis and Cancer Progression ...............................20 II. MATERIALS AND METHODS ...........................................................................26 Mice Breeding and Genotyping .................................................................26 Preparation of Genomic DNA .............................................................26 Min Mice ..............................................................................................26 Generation of MMP-2-/- Min Mice ......................................................27 Generation of MMP-2-/-; MMP-7-/- Min Mice .....................................28 v Generation of MMP-9-/- Min Mice .......................................................28 Generation of MMP-12-/- Min Mice ....................................................30 Generation of MMP-19-/- Min Mice ....................................................30 Generation of c-kitW-sh/W-sh Min Mice ..................................................31 Tissue Collection, Processing, and Tumor Measurements ........................32 Tissue Collection and Tumor Measurements ......................................32 RNA Isolation, Microarray Analysis, and Real-Time PCR .......................32 RNA Isolation ......................................................................................32 cDNA Microarray Construction ..........................................................33 Affymetrix Hu/Mu ProtIn Array Construction ....................................48 Real Time PCR Analysis .....................................................................49 Histochemical and Immunohistochemical Analyses .................................49 Chloroacetate Reaction (CAE) to Demonstrate Mast Cells .................49 Immunohistochemistry ........................................................................50 Visualization of Proliferation and Apoptosis .......................................50 Demonstration of Leukocyte Populations ............................................51 MMP-9 and von Willebrand Factor IHC .............................................52 Immunohistochemical Quantification ..................................................53 Immunofluorescent Co-localization of MMP-9 ...................................53 III. RESULTS .............................................................................................................55 MMPs in Mouse Models of Colon Cancer ................................................55 Microarray Profiling of Intestinal Adenomas ......................................55 Analysis of Heterogeneity of MMP Expression in Tumors .................61 The Role of MMP-2 in Intestinal Tumorigenesis ......................................65 The Role of MMP-12 in Intestinal Tumorigenesis ....................................68 The Role of MMP-19 in Intestinal Tumorigenesis ....................................71 vi The Role of MMP-9 in Intestinal Tumorigenesis ......................................73 IV. AN ANTI-TUMORIGENIC ROLE FOR MAST CELLS ...................................78 Introduction ................................................................................................78 Results ........................................................................................................79
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