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Cancer as a Metabolic Disease
On the Origin, Management, and Prevention of Cancer
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This book offers a refreshing perspective for anyone wanting to get a comprehensive background on the newer emerging interest in targeting cancer metabolism for therapy. (Doody s, 11 January 2013) For the first time, an entire issue is being devoted to a review article based on a recent medical book. This is a departure from our usual format, but I think you will agree that this topic warrants the detailed treatment we have given it ...This book should be required reading for all scientifically literate people who are involved in the cancer problem. (Advances in Cancer Treatment, 1 October 2012)
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THOMAS N. SEYFRIED, PhD, has taught and conducted research in the fields of neurogenetics, neurochemistry, and cancer for more than twenty-five years at Yale University and Boston College. He has published more than 150 scientific articles and book chapters and is on the editorial boards of Nutrition & Metabolism, Journal of Lipid Research, Neurochemical Research, and ASN Neuro.
Forword xiii Preface xv 1. Images of Cancer 1 How Cancer is Viewed 2 References 13 2. Confusion Surrounds the Origin of Cancer 15 The Oncogenic Paradox 18 Hallmarks of Cancer 18 Reassessment 26 References 27 3. Cancer Models 31 Problems with Some Cancer Models 31 Animal Charges as a Major Impediment to Cancer Research 38 Problems with Tumor Histological Classification 39 Personal Perspective on Cancer 44 References 45 4. Energetics of Normal Cells and Cancer Cells 47 Metabolic Homeostasis 47 The Constancy of the G ATP 54 ATP Production in Normal Cells and Tumor Cells 55 Energy Production Through Glucose Fermentation 57 Glutaminolysis with or without Lactate Production 61 Transamination Reactions 64 TCA Cycle, Substrate-Level Phosphorylation 66 Cholesterol Synthesis and Hypoxia 67 Summary 67 References 68 5. Respiratory Dysfunction in Cancer Cells 73 Normal Mitochondria 74 Morphological Defects in Tumor Cell Mitochondria 77 Proteomic Abnormalities in Tumor Cell Mitochondria 79 Lipidomic Abnormalities in Tumor Cell Mitochondria 81 Cardiolipin: A Mitochondrial-Specific Lipid 83 Cardiolipin and Abnormal Energy Metabolism in Tumor Cells 85 Complicating Influence of the In Vitro Growth Environment on Cardiolipin Composition and Energy Metabolism 92 Mitochondrial Uncoupling and Cancer 97 Cancer Cell Heat Production and Uncoupled Mitochondria 98 Personal Perspective 99 Summary 100 References 101 6. The Warburg Dispute 107 Sidney Weinhouse s Criticisms of the Warburg Theory 108 Alan Aisenberg s Criticisms of the Warburg Theory 110 Sidney Colowick s Assessment of the Aisenberg Monograph 113 Apples and Oranges 114 References 116 7. Is Respiration Normal in Cancer Cells? 119 Pseudo-Respiration 119 How Strong is the Scientific Evidence Showing that Tumor Cells can Produce Energy Through OxPhos? 124 OxPhos Origin of ATP in Cancer Cells Reevaluated 124 What About OxPhos Expression in Other Tumors? 127 The Pedersen Review on Tumor Mitochondria and the Bioenergetics of Cancer Cells 128 References 129 8. Is Mitochondrial Glutamine Fermentation a Missing Link in the Metabolic Theory of Cancer? 133 Amino Acid Fermentation can Maintain Cellular Energy Homeostasis During Anoxia 133 Evidence Suggesting that Metastatic Mouse Cells Derive Energy from Glutamine Fermentation 134 Fermentation Energy Pathways can Drive Cancer Cell Viability Under Hypoxia 138 Competing Explanations for the Metabolic Origin of Cancer 141 Chapter Summary 143 References 143 9. Genes, Respiration, Viruses, and Cancer 145 Does Cancer have a Genetic Origin? 145 Respiratory Insufficiency as the Origin of Cancer 150 Germline Mutations, Damaged Respiration, and Cancer 154 Somatic Mutations and Cancer 158 Revisiting the Oncogene Theory 160 Mitochondrial Mutations and the Absence or Presence of Cancer 163 Viral Infection, Damaged Respiration, and the Origin of Cancer 165 Summary 168 References 168 10. Respiratory Insufficiency, the Retrograde Response, and the Origin of Cancer 177 The Retrograde (RTG) Response: An Epigenetic System Responsible for Nuclear Genomic Stability 177 Inflammation Injures Cellular Respiration 181 Hypoxia-Inducible Factor (HIF) Stability is Required for the Origin of Cancer 182 Mitochondria and the Mutator Phenotype 183 Calcium Homeostasis, Aneuploidy, and Mitochondrial Dysfunction 186 Mitochondrial Dysfunction and Loss of Heterozygosity (LOH) 187 Tissue Inflammation, Damaged Respiration, and Cancer 188 References 189 11. Mitochondria: The Ultimate Tumor Suppressor 195 Mitochondrial Suppression of Tumorigenicity 195 Normal Mitochondria Suppress Tumorigenesis in Cybrids 196 Evidence from rho0 Cells 198 Normal Mitochondria Suppress Tumorigenesis In Vivo 199 Normal Mouse Cytoplasm Suppresses Tumorigenic Pheno