The Dynamics and Modification of Hypoxia

......................................................................................................................... 7 ABBREVIATIONS ............................................................................................................. 9 LIST OF PUBLICATIONS.............................................................................................. 10 INTRODUCTION ............................................................................................................. 11 General background.......................................................................................................... 11 Tumor microenvironment................................................................................................. 12 Tumor vasculature................................................................................................... 13 Organization ...................................................................................................... 13 Prognostic value ................................................................................................ 14 Vascular targeting.............................................................................................. 14 Perfusion .................................................................................................................. 15 Proliferation ............................................................................................................. 16 Proliferation patterns and prognosis ................................................................. 17 Tumor hypoxia ........................................................................................................ 18 Definitions of hypoxia....................................................................................... 18 Radiobiological hypoxia ................................................................................... 19 Hypoxia and prognosis...................................................................................... 20 Assays for detection of hypoxia........................................................................ 21 Patho-physiology of hypoxia ............................................................................ 22 Dynamics of hypoxic cells ................................................................................ 24 Hypoxia and malignant progression ................................................................. 25 Cell loss, apoptosis and necrosis............................................................................. 27 Relation between proliferation, hypoxia and cell loss ........................................... 27 AIMS OF THE PRESENT STUDY ................................................................................ 29 MATERIAL AND METHODS ........................................................................................ 31 Tumor models.......................................................................................................... 31 Exogenous cell markers and administered drugs ................................................... 31 Immunohistochemistry............................................................................................ 34 Image acquisition..................................................................................................... 36 Resolution ................................................................................................................ 36