1 Table of Contents 1 Table of Contents 5 2 Introduction 7 2.1 Preface 7 2.2 Aims and Objectives 10 3 Materials and Methods 12 3.1 Literature Review – Search Strategy 12 3.2 Mathematics and Programming 12 3.3 Validation Process 13 3.3.1 Balancing – Visual Validation 13 3.3.2 Regression Analysis – Statistical Validation 13 4 Results 14 4.1 The War on Cancer Revisited 14 4.1.1 The Concept of Carcinogenesis through the Ages 14 4.1.2 The Hallmarks of Cancer (Hanahan and Weinberg) 21 4.1.2.1 Hallmark Capabilities 22 4.1.2.2 Enabling Characteristics 30 4.1.3 The Genetic Hallmarks of Cancer – Gene Expression Hallmarks 31 4.1.4 Principles of Evolution and Entropy – Cancer as an evolutionary disease 36 4.1.4.1 Evolution 36 4.1.4.2 Entropy 44 4.1.4.3 Probability and Chance 47 4.1.5 Principles of Cancer Treatment 51 4.1.5.1 Surgery 51 4.1.5.2 Radiation 51 4.1.5.3 Chemotherapy 52 4.1.5.4 Hormone Therapy 53 4.1.5.5 Immunotherapy 53 4.1.5.6 Targeted Therapy 54 4.1.6 Recent Research Strategies 54 4.1.7 The Cancer Hallmarks – A Synthesis 56 4.2 Modeling and Simulation 57 4.2.1 In Silico Research 57 4.2.1.1 General 57 4.2.1.2 Analytical versus Simulating Models 58 4.2.1.3 Machine Learning 59 4.2.1.4 Bioinformatics in Evolutionary Biology 59 4.2.1.5 Bioinformatics in Oncology 61 4.2.2 Towards Simulating Carcinogenesis 64 4.2.2.1 Approaches – Primary Models 64 4.2.2.2 Simulating Cancer Treatment Response 64 4.2.2.3 Simulating Carcinogenesis based on the “Hallmarks of Cancer” 71 4.2.3 Towards Simulating Hematopoiesis and Acute Myeloid Leukemia 91 4.2.3.1 Establishing Physiological Hematopoiesis after Transplantation: Tissue Homeostasis 92 4.2.3.2 Simulating Leukemogenesis: Acute Myeloid Leukemia 99 4.3 The Hallmark Concept Revisited 111 5 Discussion 115 6 Summary 119 7 Zusammenfassung 121 8 References 123 9 Table of Figures 129 10 Table of Tables 132 11 Acknowledgement 133 12 Curriculum Vitae 134 13 Appendix 137 13.1 Full Simulation Codes 137 13.2 Ridge Regression – Standard Deviations 158 13.3 Eidesstattliche Versicherung 163 13.4 Publikationsverzeichnis 164