Cancer as a Metabolic Disease. on the Origin, Management, and Prevention of Cancer

Description

The book addresses controversies related to the origins of cancer and provides solutions to cancer management and prevention. It expands upon Otto Warburg's well-known theory that all cancer is a disease of energy metabolism. However, Warburg did not link his theory to the "hallmarks of cancer" and thus his theory was discredited. This book aims to provide evidence, through case studies, that cancer is primarily a metabolic disease requring metabolic solutions for its management and prevention. Support for this position is derived from critical assessment of current cancer theories. Brain cancer case studies are presented as a proof of principle for metabolic solutions to disease management, but similarities are drawn to other types of cancer, including breast and colon, due to the same cellular mutations that they demonstrate.

Table of Contents

• Foreword
• Preface

1. Images of Cancer
• How Cancer is Viewed
• References
2. Confusion Surrounds the Origin of Cancer
• The Oncogenic Paradox
• Hallmarks of Cancer
• Reassessment
• References
3. Cancer Models
• Problems with Some Cancer Models
• Animal Charges as a Major Impediment to Cancer Research
• Problems with Tumor Histological Classification
• Personal Perspective on Cancer
• References
4. Energetics of Normal Cells and Cancer Cells
• Metabolic Homeostasis
• The Constancy of the G ATP
• ATP Production in Normal Cells and Tumor Cells
• Energy Production Through Glucose Fermentation
• Glutaminolysis with or without Lactate Production
• Transamination Reactions
• TCA Cycle, Substrate-Level Phosphorylation
• Cholesterol Synthesis and Hypoxia
• Summary
• References
5. Respiratory Dysfunction in Cancer Cells
• Normal Mitochondria
• Morphological Defects in Tumor Cell Mitochondria
• Proteomic Abnormalities in Tumor Cell Mitochondria
• Lipidomic Abnormalities in Tumor Cell Mitochondria
• Cardiolipin: A Mitochondrial-Specific Lipid
• Cardiolipin and Abnormal Energy Metabolism in Tumor Cells
• Complicating Influence of the In Vitro Growth Environment on Cardiolipin Composition and Energy Metabolism
• Mitochondrial Uncoupling and Cancer
• Cancer Cell Heat Production and Uncoupled Mitochondria
• Personal Perspective
• Summary
• References
6. The Warburg Dispute
• Sidney Weinhouse’s Criticisms of the Warburg Theory
• Alan Aisenberg’s Criticisms of the Warburg Theory
• Sidney Colowick’s Assessment of the Aisenberg Monograph
• Apples and Oranges
• References
7. Is Respiration Normal in Cancer Cells?
• Pseudo-Respiration
• How Strong is the Scientific Evidence Showing that Tumor Cells can Produce Energy Through OxPhos?
• OxPhos Origin of ATP in Cancer Cells Reevaluated
• What About OxPhos Expression in Other Tumors?
• The Pedersen Review on Tumor Mitochondria and the Bioenergetics of Cancer Cells
• References
8. Is Mitochondrial Glutamine Fermentation a Missing Link in the Metabolic Theory of Cancer?
• Amino Acid Fermentation can Maintain Cellular Energy Homeostasis During Anoxia
• Evidence Suggesting that Metastatic Mouse Cells Derive Energy from Glutamine Fermentation
• Fermentation Energy Pathways can Drive Cancer Cell Viability Under Hypoxia
• Competing Explanations for the Metabolic Origin of Cancer
• Chapter Summary
• References
9. Genes, Respiration, Viruses, and Cancer
• Does Cancer have a Genetic Origin?
• Respiratory Insufficiency as the Origin of Cancer
• Germline Mutations, Damaged Respiration, and Cancer
• Somatic Mutations and Cancer
• Revisiting the Oncogene Theory
• Mitochondrial Mutations and the Absence or Presence of Cancer
• Viral Infection, Damaged Respiration, and the Origin of Cancer
• Summary
• References
10. Respiratory Insufficiency, the Retrograde Response, and the Origin of Cancer
• The Retrograde (RTG) Response: An Epigenetic System Responsible for Nuclear Genomic Stability
• Inflammation Injures Cellular Respiration
• Hypoxia-Inducible Factor (HIF) Stability is Required for the Origin of Cancer
• Mitochondria and the Mutator Phenotype
• Calcium Homeostasis, Aneuploidy, and Mitochondrial Dysfunction
• Mitochondrial Dysfunction and Loss of Heterozygosity (LOH)
• Tissue Inflammation, Damaged Respiration, and Cancer
• References
11. Mitochondria: The Ultimate Tumor Suppressor
• Mitochondrial Suppression of Tumorigenicity
• Normal Mitochondria Suppress Tumorigenesis in Cybrids
• Evidence from rho0 Cells
• Normal Mitochondria Suppress Tumorigenesis In Vivo
• Normal Mouse Cytoplasm Suppresses Tumorigenic Phenotypes
• Enhanced Differentiation and Suppressed Tumorigenicity in the Liver Microenvironment
• Summary of Nuclear-Cytoplasmic Transfer Experiments
• References
12. Abnormalities in Growth Control, Telomerase Activity, Apoptosis, and Angiogenesis Linked to Mitochondrial Dysfunction
• Growth Signaling Abnormalities and Limitless Replicative Potential
• Linking Telomerase Activity to Cellular Energy and Cancer
• Evasion of Programmed Cell Death (Apoptosis)
• Sustained Vascularity (Angiogenesis)
• References
13. Metastasis
• Metastasis Overview
• Cellular Origin of Metastasis
• Macrophages and Metastasis
• Carcinoma of Unknown Primary Origin
• Many Metastatic Cancers Express Multiple Macrophage Properties
• Linking Metastasis to Mitochondrial Dysfunction
• Revisiting the “Seed and Soil” Hypothesis of Metastasis
• Revisiting the Mesenchymal Epithelial Transition (MET)
• Genetic Heterogeneity in Cancer Metastases
• Transmissible Metastatic Cancers
• The Absence of Metastases in Crown-Gall Plant Tumors
• Chapter Summary
• References
14. Mitochondrial Respiratory Dysfunction and the Extrachromosomal Origin of Cancer
• Connecting the Links
• Addressing the Oncogenic Paradox
• Is Cancer Many Diseases or a Singular Disease of Energy Metabolism?
• References
15. Nothing in Cancer Biology Makes Sense Except in the Light of Evolution
• Revisiting Growth Advantage of Tumor Cells, Mutations, and Evolution
• Tumor Cell Fitness in Light of the Evolutionary Theory of Rick Potts
• Cancer Development and Lamarckian Inheritance
• Can Teleology Explain Cancer?
• References
16. Cancer Treatment Strategies
• Current Status of Cancer Treatment
• The “Standard of Care” for Glioblastoma Management
• References
17. Metabolic Management of Cancer
• Is it Dietary Content or Dietary Composition that Primarily Reduces Tumor Growth?
• Dietary Energy Reduction and Therapeutic Fasting in Rodents and Humans
• Ketogenic Diets
• Glucagon and Insulin
• Basal Metabolic Rate
• Ketones and Glucose
• Metabolic Management of Brain Cancer Using the KD
• Glucose Accelerates Tumor Growth!
• Glucose Regulates Blood Levels of Insulin and Insulin-Like Growth Factor 1
• Dietary Energy Reduction is Antiangiogenic
• Dietary Energy Reduction Targets Abnormal Tumor Vessels
• Dietary Energy Reduction is Proapoptotic
• Dietary Energy Reduction is Anti-Inflammatory
• Targeting Energy Metabolism in Advanced Cancer
• Differential Response of Normal Cells and Tumor Cells to Energy Stress
• Dietary Energy Reduction is Anti-Invasive in Experimental Glioblastoma
• Influence of Growth Site and Host on Tumor Progression
• Implications of Dietary Energy Reduction for Anticancer Therapeutics
• Targeting Glucose
• Metformin
• Synergistic Interaction of the Restricted Ketogenic Diet (KD-R) and 2-Deoxyglucose (2-DG)
• Can Synergy Occur with the KD-R and Hyperbaric Oxygen Therapy?
• Targeting Glutamine
• Glutamine Targeting Inhibits Systemic Metastasis
• Targeting Phagocytosis
• Targeting the Microenvironment
• Dietary Energy Reduction as a Mitochondrial Enhancement Therapy (MET)
• Summary
• References
18. Patient Implementation of Metabolic Therapies for Cancer Management
• Introduction
• Guidelines for Implementing the Restricted Ketogenic Diet as a Treatment Strategy for Cancer
• Complicating Issues for Implementing the KD-R as a Treatment Strategy for Cancer
• Radiation and Chemotherapy is a Standard Treatment for Many Malignant Cancers
• Compliance
• Cancer as a Genetic Disease
• Mechanism of Action?
• Cachexia
• Summary
• References
19. Cancer Prevention
• Cell Phones and Cancer
• Alzheimer’s Disease and Cancer Risk
• Ketone Metabolism Reduces Cancer Risk
• Mitochondrial Enhancement Therapy
• Therapeutic Fasting and Cancer Prevention
• Autophagy and Autolytic Cannibalism: A Thermodynamic Approach to Cancer Prevention
• Cancer Prevention by Following Restricted Ketogenic Diet
• References
20. Case Studies and Personal Experiences in Using the Ketogenic Diet for Cancer Management
• Effects of a Ketogenic Diet on Tumor Metabolism and Nutritional Status in Pediatric Oncology Patients: Comments from Dr. Linda Nebeling
• Raffi’s Story: Comments from Miriam Kalamian
• Biological Plausibility that Cancer is a Metabolic Disease Dependent for Growth on Glucose and Glutamine: Comments from Dr. Bomar Herrin
• Using the Restricted Ketogenic Diet for Brain Cancer Management: Comments from Neuro-Oncologist, Dr. Kraig Moore
• The Ketogenic Diet for Brain Cancer Management: Comments from Beth Zupec-Kania
• Summary
• References
21. Conclusions
• Major Conclusions
• References
• Index

Author Information

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.