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Study of Molecular and Immunological Factors That Determine the Sensitivity to the Antitumor Effect of Tumor Necrosis Factor

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Study of Molecular and Immunological Factors That Determine the Sensitivity to the Antitumor Effect of Tumor Necrosis Factor Study of molecular and immunological factors that determine the sensitivity to the antitumor effect of Tumor Necrosis Factor Leander Huyghe Thesis submitted in fulfillment of the requirements for the degree of DOCTOR IN SCIENCES: BIOTECHNOLOGY Promoter: Prof. Dr. Peter Brouckaert 2008 Ghent University, Faculty of Sciences VIB Department for Molecular Biomedical Research Cover pictures: C57BL/6 mouse, PECAM-1 stained tumor blood vessels, crystal structure of human Tumor Necrosis Factor (from Eck, M.J., Sprang, S.R. (1989) J. Biol. Chem. 264: 17595-605), May-Grünwald Giemsa stained blood smear showing lymphocyte and neutrophil, cultured B16Bl6 melanoma cells Study of molecular and immunological factors that determine the sensitivity to the antitumor effect of Tumor Necrosis Factor Leander Huyghe Thesis submitted in fulfillment of the requirements for the degree of DOCTOR IN SCIENCES: BIOTECHNOLOGY Promoter: Prof. Dr. Peter Brouckaert 2008 Ghent University, Faculty of Sciences VIB Department for Molecular Biomedical Research Examination committee: Reading committee: Prof. Dr. Peter Brouckaert 1 Prof. Dr. Dirk Elewaut 2 Prof. Dr. Olivier Feron 3 Prof. Dr. Bart Vanhaesebroeck 4 Other members: Prof. Dr. Johan Grooten (chair) 5 6 Prof. Dr. Georges Leclercq 1 Prof. Dr. Claude Libert 7 Dr. Jeroen Hostens 1 VIB Department for Molecular Biomedical Research, Ghent University, Ghent, Belgium 2 Department of Rheumatology, Ghent University Hospital, Ghent, Belgium 3 Unit of Pharmacology and Therapeutics, University of Louvain (UCL) Medical School, Brussels, Belgium 4 Centre for Cell Signaling, Institute of Cancer, Queen Mary University of London, London, UK 5 Department of Molecular Biology, Ghent University, Ghent, Belgium 6 Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital, Ghent, Belgium 7 Philip Morris Research Laboratories, Leuven, Belgium i TABLE OF CONTENTS LIST OF ABBREVIATIONS ..................................................................................... 1 OUTLINE OF THE THESIS ...................................................................................... 7 INTRODUCTION ....................................................................................................... 9 Chapter 1: Tumor Necrosis Factor ................................................................................. 9 Chapter foreword ....................................................................................................... 11 1.1. A brief history .................................................................................................. 11 1.2. TNF and its receptors ...................................................................................... 12 1.3. Regulation of TNF production .......................................................................... 15 1.4. TNF-R1 signaling ........................................................................................... 16 1.4.1. General aspects of TNF-R1 signaling ......................................................... 16 1.4.2. The NF-B pathway .................................................................................. 17 1.4.3. The MAPK pathway .................................................................................. 20 1.4.4. TNF-induced cell death ............................................................................. 24 1.4.5. Other TNF-induced pathways ..................................................................... 31 1.5. TNF-R2 signaling ........................................................................................... 35 1.6. TNF in inflammation and immunity .................................................................. 36 1.7. TNF in cancer therapy ...................................................................................... 43 1.8. References ...................................................................................................... 49 Chapter 2: Interferon- ............................................................................................... 69 2.1. IFN- and its receptor ...................................................................................... 71 2.2. IFN-R signaling ............................................................................................. 72 2.3. IFN- in immunity ........................................................................................... 75 2.4. Synergy with TNF ........................................................................................... 78 2.5. References ...................................................................................................... 82 Chapter 3: The PI3K/Akt pathway .............................................................................. 91 3.1. PI3K .............................................................................................................. 93 3.1.1. The PI3K family ........................................................................................ 93 3.1.2. Class I PI3Ks ............................................................................................ 96 3.2. Akt ............................................................................................................... 102 3.3. mTOR .......................................................................................................... 107 3.4. References .................................................................................................... 110 Chapter 4: Angiogenesis ............................................................................................ 121 4.1. Background and definitions ............................................................................ 123 4.2. Regulation of angiogenesis ............................................................................. 126 4.2.1. Positive regulators of angiogenesis ........................................................... 126 4.2.2. Negative regulators of angiogenesis .......................................................... 134 4.3. Tumor vascularization ................................................................................... 136 4.3.1. Tumor angiogenesis ................................................................................. 136 4.3.2. EPC recruitment ...................................................................................... 137 4.3.3. Vessel cooption ....................................................................................... 138 4.3.4. Mosaic vessels ........................................................................................ 139 4.3.5. Vasculogenic mimicry ............................................................................. 139 ii 4.3.6. Abnormalities in tumor blood vessels ....................................................... 140 4.4. References .................................................................................................... 141 Chapter 5: Vascular-targeting anticancer therapy .................................................... 151 5.1. Introduction .................................................................................................. 153 5.2. Angiogenesis inhibitors ................................................................................. 154 5.3. Vascular-disrupting agents ............................................................................. 156 5.3.1. Tubulin-binding agents ............................................................................ 156 5.3.2. TNF and TNF-inducing flavonoids ........................................................... 157 5.4. Ligand-directed vascular-targeting agents ....................................................... 159 5.5. References .................................................................................................... 161 Chapter 6: NKT cells ................................................................................................. 165 6.1. Definition ..................................................................................................... 167 6.2. Development ................................................................................................ 169 6.3. Function ....................................................................................................... 170 6.4. NKT cells in tumor immunity and cancer therapy ............................................ 172 6.5. References .................................................................................................... 175 CHAPTER 7: RESEARCH OBJECTIVES ......................................................... 179 EXPERIMENTAL WORK .................................................................................... 183 Chapter 8: Sensitization of the tumor vasculature to the vascular-disrupting effect of TNF by inhibition of the PI3K/Akt survival pathway ............................... 183 Abstract ................................................................................................................. 185 8.1. Introduction .................................................................................................. 186 8.2. Materials and methods ................................................................................... 187 8.2.1. Mice ...................................................................................................... 187 8.2.2. Cells ...................................................................................................... 188 8.2.3. Reagents ................................................................................................
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