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A groundbreaking new approach to understanding, preventing, and treating cancer Supported by evidence from more than 1,000 scientific and clinical studies, this groundbreaking book demonstrates that cancer is a metabolic disease and, more importantly, that it can be more effectively managed and prevented when it is recognized as such. Moreover, the book provides detailed evidence that the traditional view of cancer as a genetic disease has been largely responsible for the failure to develop effective therapies and preventive strategies. Cancer as a Metabolic Disease reevaluates the origins of…mehr
A groundbreaking new approach to understanding, preventing, and treating cancer
Supported by evidence from more than 1,000 scientific and clinical studies, this groundbreaking book demonstrates that cancer is a metabolic disease and, more importantly, that it can be more effectively managed and prevented when it is recognized as such. Moreover, the book provides detailed evidence that the traditional view of cancer as a genetic disease has been largely responsible for the failure to develop effective therapies and preventive strategies.
Cancer as a Metabolic Disease reevaluates the origins of cancer based on the latest research findings as well as several decades of studies exploring the defects in tumor cell energy metabolism. Author Thomas Seyfried is a biochemical geneticist who has been investigating the lipid biochemistry of cancer for thirty years. In this book, he carefully establishes why approaching cancer as a metabolic disease leads to better understanding and management of all aspects of the disease, including inflammation, vascularization, cell death, drug resistance, and genomic instability. In addition, the book explores:
Origin of metastasis
New treatment strategies that target tumor cell energy metabolism, including the ketogenic diet
More effective prevention strategies in light of the metabolic origin of cancer
Case studies and perspectives from the point of view of physicians, patients, and caregivers
Throughout the book, tables, figures, and graphs summarize key information and clarify complex concepts. In addition, the renowned cancer biochemist Peter Pedersen from Johns Hopkins Medical School also provides a historical perspective on the importance of the information presented in his foreward to the book.
Cancer as a Metabolic Disease is essential reading for all cancer researchers and clinicians as well as public health professionals. By treating cancer as a metabolic disease, the book sets readers on a new, more promising path to understanding the origins of cancer and developing new, more effective strategies to treat and prevent it.
Supported by evidence from more than 1,000 scientific and clinical studies, this groundbreaking book demonstrates that cancer is a metabolic disease and, more importantly, that it can be more effectively managed and prevented when it is recognized as such. Moreover, the book provides detailed evidence that the traditional view of cancer as a genetic disease has been largely responsible for the failure to develop effective therapies and preventive strategies.
Cancer as a Metabolic Disease reevaluates the origins of cancer based on the latest research findings as well as several decades of studies exploring the defects in tumor cell energy metabolism. Author Thomas Seyfried is a biochemical geneticist who has been investigating the lipid biochemistry of cancer for thirty years. In this book, he carefully establishes why approaching cancer as a metabolic disease leads to better understanding and management of all aspects of the disease, including inflammation, vascularization, cell death, drug resistance, and genomic instability. In addition, the book explores:
Origin of metastasis
New treatment strategies that target tumor cell energy metabolism, including the ketogenic diet
More effective prevention strategies in light of the metabolic origin of cancer
Case studies and perspectives from the point of view of physicians, patients, and caregivers
Throughout the book, tables, figures, and graphs summarize key information and clarify complex concepts. In addition, the renowned cancer biochemist Peter Pedersen from Johns Hopkins Medical School also provides a historical perspective on the importance of the information presented in his foreward to the book.
Cancer as a Metabolic Disease is essential reading for all cancer researchers and clinicians as well as public health professionals. By treating cancer as a metabolic disease, the book sets readers on a new, more promising path to understanding the origins of cancer and developing new, more effective strategies to treat and prevent it.
Produktdetails
- Produktdetails
- Verlag: Wiley & Sons
- Artikelnr. des Verlages: 14558492000
- 1. Auflage
- Erscheinungstermin: 27. Juli 2012
- Englisch
- Abmessung: 250mm x 167mm x 30mm
- Gewicht: 800g
- ISBN-13: 9780470584927
- ISBN-10: 0470584920
- Artikelnr.: 34549227
- Verlag: Wiley & Sons
- Artikelnr. des Verlages: 14558492000
- 1. Auflage
- Erscheinungstermin: 27. Juli 2012
- Englisch
- Abmessung: 250mm x 167mm x 30mm
- Gewicht: 800g
- ISBN-13: 9780470584927
- ISBN-10: 0470584920
- Artikelnr.: 34549227
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 Phenotypes 200 Enhanced Differentiation and
Suppressed Tumorigenicity in the Liver Microenvironment 202 Summary of
Nuclear-Cytoplasmic Transfer Experiments 203 References 204 12.
Abnormalities in Growth Control, Telomerase Activity, Apoptosis, and
Angiogenesis Linked to Mitochondrial Dysfunction 207 Growth Signaling
Abnormalities and Limitless Replicative Potential 208 Linking Telomerase
Activity to Cellular Energy and Cancer 209 Evasion of Programmed Cell Death
(Apoptosis) 209 Sustained Vascularity (Angiogenesis) 210 References 211 13.
Metastasis 215 Metastasis Overview 215 Cellular Origin of Metastasis 217
Macrophages and Metastasis 221 Carcinoma of Unknown Primary Origin 232 Many
Metastatic Cancers Express Multiple Macrophage Properties 233 Linking
Metastasis to Mitochondrial Dysfunction 233 Revisiting the "Seed and Soil"
Hypothesis of Metastasis 235 Revisiting the Mesenchymal Epithelial
Transition (MET) 236 Genetic Heterogeneity in Cancer Metastases 237
Transmissible Metastatic Cancers 240 The Absence of Metastases in
Crown-Gall Plant Tumors 240 Chapter Summary 241 References 241 14.
Mitochondrial Respiratory Dysfunction and the Extrachromosomal Origin of
Cancer 253 Connecting the Links 254 Addressing the Oncogenic Paradox 255 Is
Cancer Many Diseases or a Singular Disease of Energy Metabolism? 258
References 258 15. Nothing in Cancer Biology Makes Sense Except in the
Light of Evolution 261 Revisiting Growth Advantage of Tumor Cells,
Mutations, and Evolution 262 Tumor Cell Fitness in Light of the
Evolutionary Theory of Rick Potts 269 Cancer Development and Lamarckian
Inheritance 271 Can Teleology Explain Cancer? 272 References 272 16. Cancer
Treatment Strategies 277 Current Status of Cancer Treatment 277 The
"Standard of Care" for Glioblastoma Management 280 References 285 17.
Metabolic Management of Cancer 291 Is it Dietary Content or Dietary
Composition that Primarily Reduces Tumor Growth? 292 Dietary Energy
Reduction and Therapeutic Fasting in Rodents and Humans 294 Ketogenic Diets
295 Glucagon and Insulin 297 Basal Metabolic Rate 298 Ketones and Glucose
298 Metabolic Management of Brain Cancer Using the KD 299 Glucose
Accelerates Tumor Growth! 301 Glucose Regulates Blood Levels of Insulin and
Insulin-Like Growth Factor 1 302 Dietary Energy Reduction is Antiangiogenic
302 Dietary Energy Reduction Targets Abnormal Tumor Vessels 307 Dietary
Energy Reduction is Proapoptotic 309 Dietary Energy Reduction is
Anti-Inflammatory 310 Targeting Energy Metabolism in Advanced Cancer 314
Differential Response of Normal Cells and Tumor Cells to Energy Stress 316
Dietary Energy Reduction is Anti-Invasive in Experimental Glioblastoma 318
Influence of Growth Site and Host on Tumor Progression 322 Implications of
Dietary Energy Reduction for Anticancer Therapeutics 324 Targeting Glucose
325 Metformin 326 Synergistic Interaction of the Restricted Ketogenic Diet
(KD-R) and 2-Deoxyglucose (2-DG) 327 Can Synergy Occur with the KD-R and
Hyperbaric Oxygen Therapy? 331 Targeting Glutamine 333 Glutamine Targeting
Inhibits Systemic Metastasis 334 Targeting Phagocytosis 339 Targeting the
Microenvironment 340 Dietary Energy Reduction as a Mitochondrial
Enhancement Therapy (MET) 341 Summary 341 References 341 18. Patient
Implementation of Metabolic Therapies for Cancer Management 355
Introduction 355 Guidelines for Implementing the Restricted Ketogenic Diet
as a Treatment Strategy for Cancer 356 Complicating Issues for Implementing
the KD-R as a Treatment Strategy for Cancer 366 Radiation and Chemotherapy
is a Standard Treatment for Many Malignant Cancers 366 Compliance 367
Cancer as a Genetic Disease 367 Mechanism of Action? 368 Cachexia 368
Summary 369 References 370 19. Cancer Prevention 375 Cell Phones and Cancer
376 Alzheimer's Disease and Cancer Risk 377 Ketone Metabolism Reduces
Cancer Risk 378 Mitochondrial Enhancement Therapy 379 Therapeutic Fasting
and Cancer Prevention 379 Autophagy and Autolytic Cannibalism: A
Thermodynamic Approach to Cancer Prevention 381 Cancer Prevention by
Following Restricted Ketogenic Diet 382 References 384 20. Case Studies and
Personal Experiences in Using the Ketogenic Diet for Cancer Management 387
Effects of a Ketogenic Diet on Tumor Metabolism and Nutritional Status in
Pediatric Oncology Patients: Comments from Dr. Linda Nebeling 387 Raffi's
Story: Comments from Miriam Kalamian 389 Biological Plausibility that
Cancer is a Metabolic Disease Dependent for Growth on Glucose and
Glutamine: Comments from Dr. Bomar Herrin 395 Using the Restricted
Ketogenic Diet for Brain Cancer Management: Comments from Neuro-Oncologist,
Dr. Kraig Moore 397 The Ketogenic Diet for Brain Cancer Management:
Comments from Beth Zupec-Kania 400 Summary 402 References 403 21.
Conclusions 405 Major Conclusions 407 References 408 Index 409
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 Phenotypes 200 Enhanced Differentiation and
Suppressed Tumorigenicity in the Liver Microenvironment 202 Summary of
Nuclear-Cytoplasmic Transfer Experiments 203 References 204 12.
Abnormalities in Growth Control, Telomerase Activity, Apoptosis, and
Angiogenesis Linked to Mitochondrial Dysfunction 207 Growth Signaling
Abnormalities and Limitless Replicative Potential 208 Linking Telomerase
Activity to Cellular Energy and Cancer 209 Evasion of Programmed Cell Death
(Apoptosis) 209 Sustained Vascularity (Angiogenesis) 210 References 211 13.
Metastasis 215 Metastasis Overview 215 Cellular Origin of Metastasis 217
Macrophages and Metastasis 221 Carcinoma of Unknown Primary Origin 232 Many
Metastatic Cancers Express Multiple Macrophage Properties 233 Linking
Metastasis to Mitochondrial Dysfunction 233 Revisiting the "Seed and Soil"
Hypothesis of Metastasis 235 Revisiting the Mesenchymal Epithelial
Transition (MET) 236 Genetic Heterogeneity in Cancer Metastases 237
Transmissible Metastatic Cancers 240 The Absence of Metastases in
Crown-Gall Plant Tumors 240 Chapter Summary 241 References 241 14.
Mitochondrial Respiratory Dysfunction and the Extrachromosomal Origin of
Cancer 253 Connecting the Links 254 Addressing the Oncogenic Paradox 255 Is
Cancer Many Diseases or a Singular Disease of Energy Metabolism? 258
References 258 15. Nothing in Cancer Biology Makes Sense Except in the
Light of Evolution 261 Revisiting Growth Advantage of Tumor Cells,
Mutations, and Evolution 262 Tumor Cell Fitness in Light of the
Evolutionary Theory of Rick Potts 269 Cancer Development and Lamarckian
Inheritance 271 Can Teleology Explain Cancer? 272 References 272 16. Cancer
Treatment Strategies 277 Current Status of Cancer Treatment 277 The
"Standard of Care" for Glioblastoma Management 280 References 285 17.
Metabolic Management of Cancer 291 Is it Dietary Content or Dietary
Composition that Primarily Reduces Tumor Growth? 292 Dietary Energy
Reduction and Therapeutic Fasting in Rodents and Humans 294 Ketogenic Diets
295 Glucagon and Insulin 297 Basal Metabolic Rate 298 Ketones and Glucose
298 Metabolic Management of Brain Cancer Using the KD 299 Glucose
Accelerates Tumor Growth! 301 Glucose Regulates Blood Levels of Insulin and
Insulin-Like Growth Factor 1 302 Dietary Energy Reduction is Antiangiogenic
302 Dietary Energy Reduction Targets Abnormal Tumor Vessels 307 Dietary
Energy Reduction is Proapoptotic 309 Dietary Energy Reduction is
Anti-Inflammatory 310 Targeting Energy Metabolism in Advanced Cancer 314
Differential Response of Normal Cells and Tumor Cells to Energy Stress 316
Dietary Energy Reduction is Anti-Invasive in Experimental Glioblastoma 318
Influence of Growth Site and Host on Tumor Progression 322 Implications of
Dietary Energy Reduction for Anticancer Therapeutics 324 Targeting Glucose
325 Metformin 326 Synergistic Interaction of the Restricted Ketogenic Diet
(KD-R) and 2-Deoxyglucose (2-DG) 327 Can Synergy Occur with the KD-R and
Hyperbaric Oxygen Therapy? 331 Targeting Glutamine 333 Glutamine Targeting
Inhibits Systemic Metastasis 334 Targeting Phagocytosis 339 Targeting the
Microenvironment 340 Dietary Energy Reduction as a Mitochondrial
Enhancement Therapy (MET) 341 Summary 341 References 341 18. Patient
Implementation of Metabolic Therapies for Cancer Management 355
Introduction 355 Guidelines for Implementing the Restricted Ketogenic Diet
as a Treatment Strategy for Cancer 356 Complicating Issues for Implementing
the KD-R as a Treatment Strategy for Cancer 366 Radiation and Chemotherapy
is a Standard Treatment for Many Malignant Cancers 366 Compliance 367
Cancer as a Genetic Disease 367 Mechanism of Action? 368 Cachexia 368
Summary 369 References 370 19. Cancer Prevention 375 Cell Phones and Cancer
376 Alzheimer's Disease and Cancer Risk 377 Ketone Metabolism Reduces
Cancer Risk 378 Mitochondrial Enhancement Therapy 379 Therapeutic Fasting
and Cancer Prevention 379 Autophagy and Autolytic Cannibalism: A
Thermodynamic Approach to Cancer Prevention 381 Cancer Prevention by
Following Restricted Ketogenic Diet 382 References 384 20. Case Studies and
Personal Experiences in Using the Ketogenic Diet for Cancer Management 387
Effects of a Ketogenic Diet on Tumor Metabolism and Nutritional Status in
Pediatric Oncology Patients: Comments from Dr. Linda Nebeling 387 Raffi's
Story: Comments from Miriam Kalamian 389 Biological Plausibility that
Cancer is a Metabolic Disease Dependent for Growth on Glucose and
Glutamine: Comments from Dr. Bomar Herrin 395 Using the Restricted
Ketogenic Diet for Brain Cancer Management: Comments from Neuro-Oncologist,
Dr. Kraig Moore 397 The Ketogenic Diet for Brain Cancer Management:
Comments from Beth Zupec-Kania 400 Summary 402 References 403 21.
Conclusions 405 Major Conclusions 407 References 408 Index 409
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 Phenotypes 200 Enhanced Differentiation and
Suppressed Tumorigenicity in the Liver Microenvironment 202 Summary of
Nuclear-Cytoplasmic Transfer Experiments 203 References 204 12.
Abnormalities in Growth Control, Telomerase Activity, Apoptosis, and
Angiogenesis Linked to Mitochondrial Dysfunction 207 Growth Signaling
Abnormalities and Limitless Replicative Potential 208 Linking Telomerase
Activity to Cellular Energy and Cancer 209 Evasion of Programmed Cell Death
(Apoptosis) 209 Sustained Vascularity (Angiogenesis) 210 References 211 13.
Metastasis 215 Metastasis Overview 215 Cellular Origin of Metastasis 217
Macrophages and Metastasis 221 Carcinoma of Unknown Primary Origin 232 Many
Metastatic Cancers Express Multiple Macrophage Properties 233 Linking
Metastasis to Mitochondrial Dysfunction 233 Revisiting the "Seed and Soil"
Hypothesis of Metastasis 235 Revisiting the Mesenchymal Epithelial
Transition (MET) 236 Genetic Heterogeneity in Cancer Metastases 237
Transmissible Metastatic Cancers 240 The Absence of Metastases in
Crown-Gall Plant Tumors 240 Chapter Summary 241 References 241 14.
Mitochondrial Respiratory Dysfunction and the Extrachromosomal Origin of
Cancer 253 Connecting the Links 254 Addressing the Oncogenic Paradox 255 Is
Cancer Many Diseases or a Singular Disease of Energy Metabolism? 258
References 258 15. Nothing in Cancer Biology Makes Sense Except in the
Light of Evolution 261 Revisiting Growth Advantage of Tumor Cells,
Mutations, and Evolution 262 Tumor Cell Fitness in Light of the
Evolutionary Theory of Rick Potts 269 Cancer Development and Lamarckian
Inheritance 271 Can Teleology Explain Cancer? 272 References 272 16. Cancer
Treatment Strategies 277 Current Status of Cancer Treatment 277 The
"Standard of Care" for Glioblastoma Management 280 References 285 17.
Metabolic Management of Cancer 291 Is it Dietary Content or Dietary
Composition that Primarily Reduces Tumor Growth? 292 Dietary Energy
Reduction and Therapeutic Fasting in Rodents and Humans 294 Ketogenic Diets
295 Glucagon and Insulin 297 Basal Metabolic Rate 298 Ketones and Glucose
298 Metabolic Management of Brain Cancer Using the KD 299 Glucose
Accelerates Tumor Growth! 301 Glucose Regulates Blood Levels of Insulin and
Insulin-Like Growth Factor 1 302 Dietary Energy Reduction is Antiangiogenic
302 Dietary Energy Reduction Targets Abnormal Tumor Vessels 307 Dietary
Energy Reduction is Proapoptotic 309 Dietary Energy Reduction is
Anti-Inflammatory 310 Targeting Energy Metabolism in Advanced Cancer 314
Differential Response of Normal Cells and Tumor Cells to Energy Stress 316
Dietary Energy Reduction is Anti-Invasive in Experimental Glioblastoma 318
Influence of Growth Site and Host on Tumor Progression 322 Implications of
Dietary Energy Reduction for Anticancer Therapeutics 324 Targeting Glucose
325 Metformin 326 Synergistic Interaction of the Restricted Ketogenic Diet
(KD-R) and 2-Deoxyglucose (2-DG) 327 Can Synergy Occur with the KD-R and
Hyperbaric Oxygen Therapy? 331 Targeting Glutamine 333 Glutamine Targeting
Inhibits Systemic Metastasis 334 Targeting Phagocytosis 339 Targeting the
Microenvironment 340 Dietary Energy Reduction as a Mitochondrial
Enhancement Therapy (MET) 341 Summary 341 References 341 18. Patient
Implementation of Metabolic Therapies for Cancer Management 355
Introduction 355 Guidelines for Implementing the Restricted Ketogenic Diet
as a Treatment Strategy for Cancer 356 Complicating Issues for Implementing
the KD-R as a Treatment Strategy for Cancer 366 Radiation and Chemotherapy
is a Standard Treatment for Many Malignant Cancers 366 Compliance 367
Cancer as a Genetic Disease 367 Mechanism of Action? 368 Cachexia 368
Summary 369 References 370 19. Cancer Prevention 375 Cell Phones and Cancer
376 Alzheimer's Disease and Cancer Risk 377 Ketone Metabolism Reduces
Cancer Risk 378 Mitochondrial Enhancement Therapy 379 Therapeutic Fasting
and Cancer Prevention 379 Autophagy and Autolytic Cannibalism: A
Thermodynamic Approach to Cancer Prevention 381 Cancer Prevention by
Following Restricted Ketogenic Diet 382 References 384 20. Case Studies and
Personal Experiences in Using the Ketogenic Diet for Cancer Management 387
Effects of a Ketogenic Diet on Tumor Metabolism and Nutritional Status in
Pediatric Oncology Patients: Comments from Dr. Linda Nebeling 387 Raffi's
Story: Comments from Miriam Kalamian 389 Biological Plausibility that
Cancer is a Metabolic Disease Dependent for Growth on Glucose and
Glutamine: Comments from Dr. Bomar Herrin 395 Using the Restricted
Ketogenic Diet for Brain Cancer Management: Comments from Neuro-Oncologist,
Dr. Kraig Moore 397 The Ketogenic Diet for Brain Cancer Management:
Comments from Beth Zupec-Kania 400 Summary 402 References 403 21.
Conclusions 405 Major Conclusions 407 References 408 Index 409
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 Phenotypes 200 Enhanced Differentiation and
Suppressed Tumorigenicity in the Liver Microenvironment 202 Summary of
Nuclear-Cytoplasmic Transfer Experiments 203 References 204 12.
Abnormalities in Growth Control, Telomerase Activity, Apoptosis, and
Angiogenesis Linked to Mitochondrial Dysfunction 207 Growth Signaling
Abnormalities and Limitless Replicative Potential 208 Linking Telomerase
Activity to Cellular Energy and Cancer 209 Evasion of Programmed Cell Death
(Apoptosis) 209 Sustained Vascularity (Angiogenesis) 210 References 211 13.
Metastasis 215 Metastasis Overview 215 Cellular Origin of Metastasis 217
Macrophages and Metastasis 221 Carcinoma of Unknown Primary Origin 232 Many
Metastatic Cancers Express Multiple Macrophage Properties 233 Linking
Metastasis to Mitochondrial Dysfunction 233 Revisiting the "Seed and Soil"
Hypothesis of Metastasis 235 Revisiting the Mesenchymal Epithelial
Transition (MET) 236 Genetic Heterogeneity in Cancer Metastases 237
Transmissible Metastatic Cancers 240 The Absence of Metastases in
Crown-Gall Plant Tumors 240 Chapter Summary 241 References 241 14.
Mitochondrial Respiratory Dysfunction and the Extrachromosomal Origin of
Cancer 253 Connecting the Links 254 Addressing the Oncogenic Paradox 255 Is
Cancer Many Diseases or a Singular Disease of Energy Metabolism? 258
References 258 15. Nothing in Cancer Biology Makes Sense Except in the
Light of Evolution 261 Revisiting Growth Advantage of Tumor Cells,
Mutations, and Evolution 262 Tumor Cell Fitness in Light of the
Evolutionary Theory of Rick Potts 269 Cancer Development and Lamarckian
Inheritance 271 Can Teleology Explain Cancer? 272 References 272 16. Cancer
Treatment Strategies 277 Current Status of Cancer Treatment 277 The
"Standard of Care" for Glioblastoma Management 280 References 285 17.
Metabolic Management of Cancer 291 Is it Dietary Content or Dietary
Composition that Primarily Reduces Tumor Growth? 292 Dietary Energy
Reduction and Therapeutic Fasting in Rodents and Humans 294 Ketogenic Diets
295 Glucagon and Insulin 297 Basal Metabolic Rate 298 Ketones and Glucose
298 Metabolic Management of Brain Cancer Using the KD 299 Glucose
Accelerates Tumor Growth! 301 Glucose Regulates Blood Levels of Insulin and
Insulin-Like Growth Factor 1 302 Dietary Energy Reduction is Antiangiogenic
302 Dietary Energy Reduction Targets Abnormal Tumor Vessels 307 Dietary
Energy Reduction is Proapoptotic 309 Dietary Energy Reduction is
Anti-Inflammatory 310 Targeting Energy Metabolism in Advanced Cancer 314
Differential Response of Normal Cells and Tumor Cells to Energy Stress 316
Dietary Energy Reduction is Anti-Invasive in Experimental Glioblastoma 318
Influence of Growth Site and Host on Tumor Progression 322 Implications of
Dietary Energy Reduction for Anticancer Therapeutics 324 Targeting Glucose
325 Metformin 326 Synergistic Interaction of the Restricted Ketogenic Diet
(KD-R) and 2-Deoxyglucose (2-DG) 327 Can Synergy Occur with the KD-R and
Hyperbaric Oxygen Therapy? 331 Targeting Glutamine 333 Glutamine Targeting
Inhibits Systemic Metastasis 334 Targeting Phagocytosis 339 Targeting the
Microenvironment 340 Dietary Energy Reduction as a Mitochondrial
Enhancement Therapy (MET) 341 Summary 341 References 341 18. Patient
Implementation of Metabolic Therapies for Cancer Management 355
Introduction 355 Guidelines for Implementing the Restricted Ketogenic Diet
as a Treatment Strategy for Cancer 356 Complicating Issues for Implementing
the KD-R as a Treatment Strategy for Cancer 366 Radiation and Chemotherapy
is a Standard Treatment for Many Malignant Cancers 366 Compliance 367
Cancer as a Genetic Disease 367 Mechanism of Action? 368 Cachexia 368
Summary 369 References 370 19. Cancer Prevention 375 Cell Phones and Cancer
376 Alzheimer's Disease and Cancer Risk 377 Ketone Metabolism Reduces
Cancer Risk 378 Mitochondrial Enhancement Therapy 379 Therapeutic Fasting
and Cancer Prevention 379 Autophagy and Autolytic Cannibalism: A
Thermodynamic Approach to Cancer Prevention 381 Cancer Prevention by
Following Restricted Ketogenic Diet 382 References 384 20. Case Studies and
Personal Experiences in Using the Ketogenic Diet for Cancer Management 387
Effects of a Ketogenic Diet on Tumor Metabolism and Nutritional Status in
Pediatric Oncology Patients: Comments from Dr. Linda Nebeling 387 Raffi's
Story: Comments from Miriam Kalamian 389 Biological Plausibility that
Cancer is a Metabolic Disease Dependent for Growth on Glucose and
Glutamine: Comments from Dr. Bomar Herrin 395 Using the Restricted
Ketogenic Diet for Brain Cancer Management: Comments from Neuro-Oncologist,
Dr. Kraig Moore 397 The Ketogenic Diet for Brain Cancer Management:
Comments from Beth Zupec-Kania 400 Summary 402 References 403 21.
Conclusions 405 Major Conclusions 407 References 408 Index 409