Mitochondrial Genetics and Cancer (eBook)

Gabriel D. Dakubo is the founder of Mito-Onc Consultancy, a pioneer consulting firm that provides evidence-based advice on discovery, validation and regulatory submission of cancer biomarkers based on mitochondrial genomic alterations.

Preface 5
Contents 8
Chapter 1: Basic Mitochondrial Genetics, Bioenergetics, and Biogenesis 16
Introduction 16
The Mitochondrion 17
Contrasting Features of Mitochondrial and Nuclear Genetics 18
Mitochondrial Genomic Structure and Organization 26
Mitochondrial Microsatellites and D310 27
Mitochondrial Pseudogenes 28
The Respiratory Chain 29
The Electron Transport Chain 29
Coupling of the Proton Gradient with Oxidative Phosphorylation 34
The Respiratory Chain and Reactive Oxygen Species Production 34
Mitochondrial Biogenesis 35
Mitochondrial Genome Replication 35
Mitochondrial Genome Transcription 37
Mitochondrial Transcription Initiation Machinery 37
Mitochondrial Transcripts 38
Mitochondrial RNA Processing 38
Mitochondrial RNA Turnover 39
Translation of Mitochondrial Messenger RNAs 40
Control of Mitochondrial Biogenesis 41
Hormonal Control 41
Nuclear Respiratory Factors 42
Peroxisomal Proliferator Activator Receptor Gamma Co-Activator-1a 43
Regulation of PGC-1 43
PGC-1a-Related Coactivator 45
Myc Oncogene and Mitochondrial Biogenesis 45
Import of Nuclear-Encoded Proteins into Mitochondria 45
Mitochondrial Import of Cytosolic Transfer RNA 46
Conclusion 46
References 47
Chapter 2: The Warburg Phenomenon and Other Metabolic Alterations of Cancer Cells 52
Introduction 52
Bioenergetics of Normal Cells 53
The Crabtree Effect 53
The Warburg Phenomenon 55
Molecular Basis of the Warburg Phenomenon 59
HK and Glycolysis 61
The PI3K/AKT Signaling Pathway and Glycolysis 62
The MYC Oncogene and Glycolysis 63
Hypoxia-Inducible Factor Pathway and Glycolysis 64
Regulation of Hypoxia-Inducible Factor 64
Regulation of Glycolysis and Mitochondrial Functions by Hypoxia-Inducible Factor 66
P53 and Glycolysis 68
Glutamine Metabolism in Cancer Cells 69
Lipid Metabolism in Cancer Cells 70
Citrate Metabolism by Prostate Glandular Epithelial Cells 71
Clinical Implications of Altered PCa Metabolism 72
Diagnostic Imaging of PCa 73
Screening for PCa Using Biofluids 74
PCa Prevention and Treatment 74
Conclusion 75
References 75
Chapter 3: Mitochondrial Control of Apoptosis and Cancer 80
Introduction 80
Cell Death Processes: The Conundrum of Semantics 81
Physiologic Importance of Apoptosis 82
Caspase Cascade 82
The Intrinsic or Mitochondrial Apoptotic Pathway 83
Mitochondrial Membrane Permeabilization 83
BCL-2 Family Members and Regulation of Mitochondrial Membrane Permeabilization 85
The Execution of Mitochondrial Apoptosis 88
Viral Control of Mitochondrial Apoptosis 89
Regulation of Intrinsic Apoptosis by Signaling Pathways 90
Mitochondrial Fission and Apoptosis 93
The Extrinsic Apoptotic Pathway 93
Evasion of Apoptosis by Cancer Cells 94
Cancer as a Defect in Apoptosis 95
Intrinsic Apoptotic Pathway Alterations in Cancer 95
Extrinsic Apoptotic Pathway Alterations in Cancer 97
Mitochondrial Genetic Defects and Apoptosis 98
Conclusion 100
References 100
Chapter 4: Mitochondrial-to-Nuclear Communications in Cancer 106
Introduction 106
Succinate Dehydrogenase and Fumarate Hydratase Mutations and Cancer 107
SDH Mutations and Cancer 108
Paragangliomas 108
Genetics and Clinical Features of PGL 109
SDH Mutations in Other Cancers 113
Genetics and Clinical Features of Fumarate Hydratase Mutations 113
Fumarate Hydratase Mutations in Other Cancers 115
Genetic Testing and Counseling for SDH and FH Mutations 115
SDH Mutations 115
Fumarate Hydratase Mutations 117
Mechanism of Tumor Induction by SDH and Fumarate Hydratase Mutations 118
Mitochondria-to-Nuclear Stress Signaling in Cancer 121
Nuclear Integration of Mitochondrial Genome Fragments and Possible Oncogene Induction 123
Conclusion 124
References 125
Chapter 5: Types of Mitochondrial Genetic Alterations in Cancer 130
Introduction 130
Mitochondrial Haplotypes and Haplogroups 131
Mitochondrial DNA Polymorphisms and Somatic Mutations 132
Mitochondrial Microsatellites 134
Discovery of D310 Instability as a Mutational Hot-Spot in Cancer 134
Mechanism of mtMSI 135
Clinical Utility of mtMSI 135
Mitochondrial Genome Rearrangements 136
Mitochondrial DNA Copy Number (Content) Changes 138
Novel Mitochondrial Transcripts in Cancer 138
Pitfalls Associated with Scoring Mitochondrial DNA Mutations 140
Criticisms of Somatic Mitochondrial DNA Mutations in Cancer 141
Natural Selection Explains Mitochondrial DNA Mutations in Cancer 142
Conclusion 142
References 143
Chapter 6: Mitochondrial Genetic Alterations in Cancer I 146
Introduction 146
Skin Cancer 147
Melanoma 148
Nonmelanoma Skin Cancer 150
Head and Neck Cancer 150
Salivary Gland Cancer 153
Thyroid Cancer and Parathyroid Adenoma 153
Breast Cancer 156
Lung Cancer 160
Esophageal Cancer 161
Gastric Cancer 162
Colorectal Cancer 164
Pancreatic Cancer 167
Hepatocellular Carcinoma 168
Gallbladder Cancer 170
Conclusion 170
References 170
Chapter 7: Mitochondrial Genetic Alterations in Cancer II 177
Introduction 177
Renal Cancer 177
Bladder Cancer 180
Prostate Cancer 180
Ovarian Cancer 183
Endometrial Cancer 185
Cervical Cancer 186
Nervous System Tumors 187
Hematologic Malignancy 188
Connective Tissue Cancer 191
Conclusion 192
References 192
Chapter 8: Mitochondrial Genome Rearrangements and Copy Number Changes in Cancer 196
Introduction 196
Overview of mtDNA Deletion Disorders 197
Mitochondrial Genome Deletions in Cancer 197
Is the CD a Tumor Suppressor? 207
mtDNA Content Alterations in Cancer 207
Cancers with Increased mtDNA Content 208
Cancers with Reduced mtDNA Content 211
Possible Reasons for mtDNA Repletion or Depletion in Cancer 212
Increased mtDNA Copy Number 212
Decreased mtDNA Copy Number 213
Postulated Mechanisms of Deletion Formation 213
Control of mtDNA Deletions 215
Conclusion 216
References 216
Chapter 9: Functional Importance of Mitochondrial Genetic Alterations in Cancer 222
Introduction 222
Mitochondrial DNA Mutations in Cancer: Cause or Consequence? 223
Functional Consequences of Mitochondrial DNA Mutations on Mitochondrial Biogenesis in Cancer 224
Techniques Employed to Study the Contribution of Mitochondrial DNA Mutations in Cancer 226
Generating rho0 Cells 227
Producing Transmitochondrial Hybrids (Cybrids) 228
Nuclear Transfection of Mutant Mitochondrial DNA 229
Contribution of Mitochondrial DNA Changes to Cancer Biology 230
Cancer Risk Predisposition 230
Cancer Initiation 231
Cancer Cell Proliferation and Growth 233
Cancer Progression and Metastasis 235
Acquisition of Hormonal Independence and Chemoresistance by Cancer Cells 236
Contribution of Mitochondrial Genome Changes to the Development of Oncocytic Tumors 237
Mitochondrial Membrane Potential and Cancer 239
Collaborative Evidences from Clinical Studies 240
Conclusion 241
References 242
Chapter 10: The Role of Mitochondrial Reactive Oxygen Species in Cancer 246
Introduction 246
ROS Production by Mitochondria 247
Biomolecular Targets of ROS 250
Modulation of Intrinsic Apoptosis by ROS 251
ROS and Hypoxia-Inducible Factor Stabilization in Cancer 252
ROS and p53 Functions 253
ROS and Oncogenic Signaling Pathways 253
MAPK Pathway 254
PI3K/AKT Pathway 255
Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B cells Pathway 255
Activator Protein 1 256
Protein Kinase C 256
Myc Oncogene 257
ROS and Carcinogenesis 257
Ameliorating the Harmful Effects of ROS 259
Conclusion 261
References 261
Chapter 11: Mitochondrial DNA Measurement in Exfoliated Cells for Cancer Detection and Monitoring: The Copy Number Advantage 267
Introduction 267
Tumor Signatures in Biofluids 268
Mitochondrial Genome Changes in Biofluids of Cancer Patients 270
Blood (Serum and Plasma) 270
Salivary Rinses 273
BAL and Sputum 274
Nipple Aspirate Fluid and Ductal Lavage 274
Urine 275
Cerebrospinal Fluid 276
Other Biofluids 276
Exfoliated Skin Cells for Skin Cancer Detection 277
Clinical Utility of Mitochondrial DNA Changes in Biofluids 277
Conclusion 279
References 279
Chapter 12: Early Cancer Detection and Monitoring Using Changes in the Mitochondrial Genome as Biosensors 283
Introduction 283
Field Cancerization Demonstrated by Mitochondrial Genome Changes 286
Field Cancerization Is a General Carcinogenic Phenomenon: Evidence from Nuclear Genetic Markers 289
Clinical Importance of Cancer Field Molecular Signatures 296
Appropriateness of Control Tissue in Cancer Studies 297
Risk Assessment, Early Cancer Detection, Chemoprevention, and Disease Monitoring 297
Tumor Margins and Recurrences 299
Conclusion 299
References 300
Chapter 13: Analysis of Mitochondrial Genome Alterations in Cancer 305
Introduction 305
Preparation of Clinical Samples for Mitochondrial Genome Analysis in Cancer 306
Analysis of Mitochondrial Genome Point Mutations in Cancer 307
Diagnostic Approaches 307
Restriction Fragment Length Polymorphism 308
Allele-Specific Oligonucleotide 309
Single-Strand Conformation Polymorphism Analysis 309
Heteroduplex Assays 310
Denaturing High-Performance Liquid Chromatography 312
Microarray Resequencing of Mitochondrial DNA 314
DNA Sequencing by Synthesis-(Pyrosequencing) 316
Analysis of Mitochondrial Genome Deletions and Content Changes 317
Southern Blotting 318
Quantitative Polymerase Chase Reaction 318
Quality Assurance Issues in Mitochondrial DNA Analysis 325
Conclusion 326
References 326
Chapter 14: ``Mitocans´´: Agents Targeting Mitochondria to Kill Cancer Cells 328
Introduction 328
Chemotherapy Targets 329
The Intrinsic Apoptotic Pathway 329
Agents Targeting Mitochondrial PTPC 330
Agents Targeting Prosurvival BCL-2 Family Members 335
Targeting the Mediators of Apoptosis 338
Targeting Glycolysis to Kill Cancer Cells 339
Targets of Redox Homeostasis 342
Targeting Membrane Potential Changes 343
Cancer Mitochondrial DNA Depletion as a Strategy 343
Delivery of Toxic Compounds to Mitochondria Using Differential Receptor Expression by Cancer Cells 344
Conclusion 345
References 345
Index 352