Genomic Instability and Cancer Metastasis: Mechanisms, Emerging Themes, and Novel Therapeutic Strategies (Cancer Metastasis - Biology and Treatment Book 20)

Metastasis is the primary cause of mortality associated with cancer, and tumor genomic heterogeneity is a likely source for the cells that support cancer progression, resistance to therapy, and disease relapse. This book connects cancer metastasis with genomic instability in a comprehensive manner. Section 1 outlines the fundamental mechanisms responsible for these cellular and tissue phenotypes. Section 2 discusses in silico, in vitro, and in vivo models used for the experimental study of these processes. Section 3 reviews emerging themes (ex., microenvironment, mechanotransduction, and immunomodulation), and Section 4 highlights new therapeutic approaches to overcome the unique challenges presented by the heterogeneous and metastatic tumor. This book is intended for undergraduates and postgraduates with an interest in the areas of medicine, oncology, and cancer biology as well as for the content expert searching for thorough reviews of current knowledge in these areas. Preface 6 Contents 9 Chapter-1 11 Cancer Metastasis: Tracking and Attacking a Moving Target 11 Introduction 12 Introduction to Metastasis—The Clinical Problem 12 Clonal Heterogeneity and Evolution as a Hallmark of Cancer and Metastasis 15 Translating Heterogeneity into the Clinic: Tracking and Attacking a Moving Target 18 References 21 Chapter-2 24 The Generation, Detection, and Prevention of Genomic Instability During Cancer Progression and Metastasis 24 Introduction 25 Genomic Instability in Cancer 26 a. Nucleotide Instability (NIN) 26 b. Microsatellite Instability (MIN or MSI) 27 c. Chromosomal Instability (CIN) 27 Telomere Maintenance in Cancer 27 Epigenome Instability in Cancer 28 a. DNA Methylation in Cancer 28 b. Histone Modification in Cancer 29 c. Nucleosome Remodeling in Cancer 29 Crosstalk Between Genomic and Epigenomic Instability 30 Mechanisms for Genome and Epigenome Stability 30 a. Error-Free DNA Replication 30 b. Bipolar Spindle Assembly and Accurate Chromosome Segregation During Mitosis 31 c. Cell Cycle Checkpoints 33 Prevention, Detection, and Prognosis of Genome Instability 35 a. Non-Inherited Sources 35 b. Diagnosis of Genome Instability 36 b.i. Diagnosing Large Scale Aberrations 36 b. ii. Diagnosing Small Scale Aberrations 38 c. Genomic Instability and Cancer Prognosis 39 Genetic Changes and Cancer Evolution 39 References 40 Chapter-3 48 DNA Damage Response Pathways in Cancer Predisposition and Progression 48 Introduction 50 Mismatch Repair 51 Mismatch Repair, Monofunctional Alkylating Agent, and Therapy-Related Myeloid Neoplasms 54 Single-Strand Break Repair 55 Single-Strand Break Repair and Cancer 57 Double-Strand Break Repair 58 Homologous Recombination and Cancer 59 Non-Homologous End Joining 61 Non-Homologous End Joining and Cancer 62 Fanconi Anemia: A Cancer Predisposition Syndrome 63 Clinical Aspect of Fanconi Anemia 63 FA Pathway 64 Replication-Dependent Interstrand Crosslink Repair 64 Coordination of Other DNA Repair Pathways During Interstrand Cross Link Repair 66 Translesion Synthesis 67 Homologous Recombination 68 Another Replication-Dependent Pathway for Interstrand Crosslink Repair 68 Fanconi Anemia Pathway, Bifunctional Alkylating agent, and Therapy-Related Myeloid Neoplasms 68 References 69 Chapter-4 84 Mathematical Modeling for DNA Repair, Carcinogenesis and Cancer Detection 84 Introduction 85 Sources of DNA DSBs 85 DNA Double Strand Breaks Baseline Levels 87 Evaluating DSB Repair Kinetics with the RIF Assay 89 From DNA Damage to Cancer 90 Epidemiological Study: The A-Bomb Survivors 91 Modeling Cancer Using DNA Damage 92 Modeling Radiation-Induced Carcinogenesis 92 Using Foci Assay as Biomarkers for Cancer Risk and Cancer Detection 94 References 96 Chapter-5 103 Animal Models of Metastasis 103 Introduction 104 Zebrafish as a Model for Metastasis 105 History of Human Tumour Xenotransplantation (XT) in Zebrafish 106 A Tool for Mechanistic Metastasis Studies 107 Advantages and Disadvantages of Zebrafish XT as A Metastasis Model 109 Future Studies 109 Genetically Engineered Mouse Models of Metastatic Cancer 110 Breast Cancer 110 Prostate Cancer 112 Future Directions 113 Murine Xenograft Models 114 Implantation Sites and Artificial Models of Metastasis 114 Quantification of Metastatic Disease 116 Patient-Derived Xenografts 118 Implantation Sites 118 Metastatic PDX Models of Various Types of Cancer 119 Advantages and Major Applications of PDX Models 120 Application of PDX Models to the Study of Cancer Metastasis 120 PDXs for Drug and Biomarker Discovery 121 Personalized Cancer Therapy 121 Caveats and Future Prospects 122 Concluding Remarks 123 References 123 Chapter-6 132 Microenvironmental Control of Metastatic Progression 132 Introduction 133 Hypoxia-Induced Genomic Instability 135 Epigenetic Dysregulation 136 Immunomodulation 136 Mesenchymal Transformation 137 Mechanotransduction 139 Summary 139 References 140 Chapter-7 145 Mechanotransduction, Metastasis and Genomic Instability 145 Introduction 146 How Mechanotransduction Regulates Normal Cell Behavior 147 Extracellular Factors Affecting Mechanotransduction in Normal Cells 147 Intracellular Factors Affecting Mechanotransduction in Normal Cells 147 Mechanotransduction and Metastasis 149 Extracellular Factors Affecting Mechanotransduction in Tumors 150 Intracellular Factors Affecting Mechanotransduction in Tumors 151 Mechanotransduction and Genomic Instability 153 Mechanical Forces Affect Mitosis and Cell Cycle Progression 154 Mechanotransduction Regulates Biochemical Cues That Promote GIN 155 Restructuring of the Stroma Results in GIN 156 Synopsis and Outlook 156 References 157 Chapter-8 165 Immunomodulation and Genomic Instability 165 Introduction 166 Inflammation and Cancer 167 Inflammation and Genomic Instability 168 Immune Responses Against Cancer 170 Immune Recognition and Genomic Instability 171 Genomic Instability and Immune Editing 173 Conclusions 176 References 177 Chapter-9 184 Synthetic Genetic Approaches in Colorectal Cancer: Exploiting and Targeting Genome Instability 184 Introduction 185 Genome Instability and Its Role in Colorectal Cancer Development 186 Current Therapeutic Strategies to Combat Colorectal Cancer 190 Evolving Synthetic Genetic Approaches for Targeting Advanced Stage Colorectal Cancers 192 Conclusions—Evolution of Therapeutic Strategies at the Dawn of the Personalized Medicine Era 201 Acknowledgements 202 References 202 Chapter-10 210 Nanomedicine—Nanoparticles in Cancer Imaging and Therapy 210 Introduction 211 Nanoparticles with Medical Applications 212 Quantum Dots (QDs) 215 Liposomes 215 Dendrimers 215 Polymeric NPs 216 Iron Oxide NPs (IONPs) 216 Gold NPs (AuNPs) 216 Carbon Nanotubes 217 Nanoparticles as a Platform for Nanocarrier Design 217 Nanoscale Dimensions 217 Versatile Surface Chemistry 218 Polyethylene Glycol 218 Targeted Ligands 220 Nanoparticles for Cancer Imaging 221 Molecular Imaging 221 Optical Imaging 222 Radionuclide-Based Imaging 223 PET Imaging 224 64Cu-labeled NPs 224 18F-labeled NPs 225 SPECT Imaging 225 Molecular MRI 226 Non-Targeted MR Contrast Agents 226 Molecular MRI of Integrin Expression 227 Molecular MRI of Other Targets 227 Multimodality Imaging 228 Targeted Cancer Therapy 229 Drug Delivery 229 Polymer-Based Drug Nanocarriers 229 Polymeric NPs 230 Polymeric Micelles 230 Dendrimers 230 Lipid-Based Drug Nanocarriers 231 Liposomes 231 Metal-Based Drug Carriers 231 Gold Nanoparticles 231 Other Methods of Drug Delivery 232 Image-Guided Drug Delivery 232 Magnetic Drug Targeting 232 Thermal Therapy 233 Avoiding the Reticuloendothelial System (RES) 233 Passive Targeting 234 Active Targeting 234 Tumor-Specific Targeting 234 Targeting the Tumor Vasculature 235 Challenges and Future Outlook 236 References 240 Index 250 Metastasis is the primary cause of mortality associated with cancer, and tumor genomic heterogeneity is a likely source for the cells that support cancer progression, resistance to therapy, and disease relapse. This book connects cancer metastasis with genomic instability in a comprehensive manner. Section 1℗l outlines the fundamental mechanisms responsible for these cellular and tissue phenotypes. Section 2 discusses in silico, in vitro, and in vivo models used for the experimental study of these processes. Section 3 reviews emerging themes (ex., microenvironment, mechanotransduction, and immunomodulation), and Section 4 highlights new therapeutic approaches to overcome the unique challenges presented by the heterogeneous and metastatic tumor. This book is intended for undergraduates and postgraduates with an interest in the areas of medicine, oncology, and cancer biology as well as for the content expert searching for thorough reviews of current knowledge in these areas Front Matter....Pages i-x Cancer Metastasis: Tracking and Attacking a Moving Target....Pages 1-13 The Generation, Detection, and Prevention of Genomic Instability During Cancer Progression and Metastasis....Pages 15-38 DNA Damage Response Pathways in Cancer Predisposition and Progression....Pages 39-74 Mathematical Modeling for DNA Repair, Carcinogenesis and Cancer Detection....Pages 75-93 Animal Models of Metastasis....Pages 95-123 Microenvironmental Control of Metastatic Progression....Pages 125-137 Mechanotransduction, Metastasis and Genomic Instability....Pages 139-158 Immunomodulation and Genomic Instability....Pages 159-177 Synthetic Genetic Approaches in Colorectal Cancer: Exploiting and Targeting Genome Instability....Pages 179-204 Nanomedicine—Nanoparticles in Cancer Imaging and Therapy....Pages 205-244 Back Matter....Pages 245-247