Cancer as a Metabolic Disease

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 xiiiPreface xv1. Images of Cancer 1How Cancer is Viewed 2References 132. Confusion Surrounds the Origin of Cancer 15The Oncogenic Paradox 18Hallmarks of Cancer 18Reassessment 26References 273. Cancer Models 31Problems with Some Cancer Models 31Animal Charges as a Major Impediment to Cancer Research 38Problems with Tumor Histological Classification 39Personal Perspective on Cancer 44References 454. Energetics of Normal Cells and Cancer Cells 47Metabolic Homeostasis 47The Constancy of the ∆G’ATP 54ATP Production in Normal Cells and Tumor Cells 55Energy Production Through Glucose Fermentation 57Glutaminolysis with or without Lactate Production 61Transamination Reactions 64TCA Cycle, Substrate-Level Phosphorylation 66Cholesterol Synthesis and Hypoxia 67Summary 67References 685. Respiratory Dysfunction in Cancer Cells 73Normal Mitochondria 74Morphological Defects in Tumor Cell Mitochondria 77Proteomic Abnormalities in Tumor Cell Mitochondria 79Lipidomic Abnormalities in Tumor Cell Mitochondria 81Cardiolipin: A Mitochondrial-Specific Lipid 83Cardiolipin and Abnormal Energy Metabolism in Tumor Cells 85Complicating Influence of the In Vitro Growth Environment on Cardiolipin Composition and Energy Metabolism 92Mitochondrial Uncoupling and Cancer 97Cancer Cell Heat Production and Uncoupled Mitochondria 98Personal Perspective 99Summary 100References 1016. The Warburg Dispute 107Sidney Weinhouse’s Criticisms of the Warburg Theory 108Alan Aisenberg’s Criticisms of the Warburg Theory 110Sidney Colowick’s Assessment of the Aisenberg Monograph 113Apples and Oranges 114References 1167. Is Respiration Normal in Cancer Cells? 119Pseudo-Respiration 119How Strong is the Scientific Evidence Showing that Tumor Cells can Produce Energy Through OxPhos? 124OxPhos Origin of ATP in Cancer Cells Reevaluated 124What About OxPhos Expression in Other Tumors? 127The Pedersen Review on Tumor Mitochondria and the Bioenergetics of Cancer Cells 128References 1298. Is Mitochondrial Glutamine Fermentation a Missing Link in the Metabolic Theory of Cancer? 133Amino Acid Fermentation can Maintain Cellular Energy Homeostasis During Anoxia 133Evidence Suggesting that Metastatic Mouse Cells Derive Energy from Glutamine Fermentation 134Fermentation Energy Pathways can Drive Cancer Cell Viability Under Hypoxia 138Competing Explanations for the Metabolic Origin of Cancer 141Chapter Summary 143References 1439. Genes, Respiration, Viruses, and Cancer 145Does Cancer have a Genetic Origin? 145Respiratory Insufficiency as the Origin of Cancer 150Germline Mutations, Damaged Respiration, and Cancer 154Somatic Mutations and Cancer 158Revisiting the Oncogene Theory 160Mitochondrial Mutations and the Absence or Presence of Cancer 163Viral Infection, Damaged Respiration, and the Origin of Cancer 165Summary 168References 16810. Respiratory Insufficiency, the Retrograde Response, and the Origin of Cancer 177The Retrograde (RTG) Response: An Epigenetic System Responsible for Nuclear Genomic Stability 177Inflammation Injures Cellular Respiration 181Hypoxia-Inducible Factor (HIF) Stability is Required for the Origin of Cancer 182Mitochondria and the Mutator Phenotype 183Calcium Homeostasis, Aneuploidy, and Mitochondrial Dysfunction 186Mitochondrial Dysfunction and Loss of Heterozygosity (LOH) 187Tissue Inflammation, Damaged Respiration, and Cancer 188References 18911. Mitochondria: The Ultimate Tumor Suppressor 195Mitochondrial Suppression of Tumorigenicity 195Normal Mitochondria Suppress Tumorigenesis in Cybrids 196Evidence from rho0 Cells 198Normal Mitochondria Suppress Tumorigenesis In Vivo 199Normal Mouse Cytoplasm Suppresses Tumorigenic Phenotypes 200Enhanced Differentiation and Suppressed Tumorigenicity in the Liver Microenvironment 202Summary of Nuclear-Cytoplasmic Transfer Experiments 203References 20412. Abnormalities in Growth Control, Telomerase Activity, Apoptosis, and Angiogenesis Linked to Mitochondrial Dysfunction 207Growth Signaling Abnormalities and Limitless Replicative Potential 208Linking Telomerase Activity to Cellular Energy and Cancer 209Evasion of Programmed Cell Death (Apoptosis) 209Sustained Vascularity (Angiogenesis) 210References 21113. Metastasis 215Metastasis Overview 215Cellular Origin of Metastasis 217Macrophages and Metastasis 221Carcinoma of Unknown Primary Origin 232Many Metastatic Cancers Express Multiple Macrophage Properties 233Linking Metastasis to Mitochondrial Dysfunction 233Revisiting the “Seed and Soil” Hypothesis of Metastasis 235Revisiting the Mesenchymal Epithelial Transition (MET) 236Genetic Heterogeneity in Cancer Metastases 237Transmissible Metastatic Cancers 240The Absence of Metastases in Crown-Gall Plant Tumors 240Chapter Summary 241References 24114. Mitochondrial Respiratory Dysfunction and the Extrachromosomal Origin of Cancer 253Connecting the Links 254Addressing the Oncogenic Paradox 255Is Cancer Many Diseases or a Singular Disease of Energy Metabolism? 258References 25815. Nothing in Cancer Biology Makes Sense Except in the Light of Evolution 261Revisiting Growth Advantage of Tumor Cells, Mutations, and Evolution 262Tumor Cell Fitness in Light of the Evolutionary Theory of Rick Potts 269Cancer Development and Lamarckian Inheritance 271Can Teleology Explain Cancer? 272References 27216. Cancer Treatment Strategies 277Current Status of Cancer Treatment 277The “Standard of Care” for Glioblastoma Management 280References 28517. Metabolic Management of Cancer 291Is it Dietary Content or Dietary Composition that Primarily Reduces Tumor Growth? 292Dietary Energy Reduction and Therapeutic Fasting in Rodents and Humans 294Ketogenic Diets 295Glucagon and Insulin 297Basal Metabolic Rate 298Ketones and Glucose 298Metabolic Management of Brain Cancer Using the KD 299Glucose Accelerates Tumor Growth! 301Glucose Regulates Blood Levels of Insulin and Insulin-Like Growth Factor 1 302Dietary Energy Reduction is Antiangiogenic 302Dietary Energy Reduction Targets Abnormal Tumor Vessels 307Dietary Energy Reduction is Proapoptotic 309Dietary Energy Reduction is Anti-Inflammatory 310Targeting Energy Metabolism in Advanced Cancer 314Differential Response of Normal Cells and Tumor Cells to Energy Stress 316Dietary Energy Reduction is Anti-Invasive in Experimental Glioblastoma 318Influence of Growth Site and Host on Tumor Progression 322Implications of Dietary Energy Reduction for Anticancer Therapeutics 324Targeting Glucose 325Metformin 326Synergistic Interaction of the Restricted Ketogenic Diet (KD-R) and 2-Deoxyglucose (2-DG) 327Can Synergy Occur with the KD-R and Hyperbaric Oxygen Therapy? 331Targeting Glutamine 333Glutamine Targeting Inhibits Systemic Metastasis 334Targeting Phagocytosis 339Targeting the Microenvironment 340Dietary Energy Reduction as a Mitochondrial Enhancement Therapy (MET) 341Summary 341References 34118. Patient Implementation of Metabolic Therapies for Cancer Management 355Introduction 355Guidelines for Implementing the Restricted Ketogenic Diet as a Treatment Strategy for Cancer 356Complicating Issues for Implementing the KD-R as a Treatment Strategy for Cancer 366Radiation and Chemotherapy is a Standard Treatment for Many Malignant Cancers 366Compliance 367Cancer as a Genetic Disease 367Mechanism of Action? 368Cachexia 368Summary 369References 37019. Cancer Prevention 375Cell Phones and Cancer 376Alzheimer’s Disease and Cancer Risk 377Ketone Metabolism Reduces Cancer Risk 378Mitochondrial Enhancement Therapy 379Therapeutic Fasting and Cancer Prevention 379Autophagy and Autolytic Cannibalism: A Thermodynamic Approach to Cancer Prevention 381Cancer Prevention by Following Restricted Ketogenic Diet 382References 38420. Case Studies and Personal Experiences in Using the Ketogenic Diet for Cancer Management 387Effects of a Ketogenic Diet on Tumor Metabolism and Nutritional Status in Pediatric Oncology Patients: Comments from Dr. Linda Nebeling 387Raffi’s Story: Comments from Miriam Kalamian 389Biological Plausibility that Cancer is a Metabolic Disease Dependent for Growth on Glucose and Glutamine: Comments from Dr. Bomar Herrin 395Using the Restricted Ketogenic Diet for Brain Cancer Management: Comments from Neuro-Oncologist, Dr. Kraig Moore 397The Ketogenic Diet for Brain Cancer Management: Comments from Beth Zupec-Kania 400Summary 402References 40321. Conclusions 405Major Conclusions 407References 408Index 409

“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)