cancer as a metabolic · 2013. 7. 23. · references 27 3. cancer models 31 problems with some...

Cancer as a MetabolicDisease

Cancer as a MetabolicDiseaseOn the Origin, Managementand Prevention of Cancer

Thomas N. Seyfried

A John Wiley & Sons, Inc., Publication

Copyright © 2012 by John Wiley & Sons, Inc. All rights reserved

Published by John Wiley & Sons, Inc., Hoboken, New JerseyPublished simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data:

Seyfried, Thomas N., 1946–Cancer as a metabolic disease : on the origin, management, and prevention

of cancer / by Thomas N. Seyfried.p. ; cm.

Includes bibliographical references and index.ISBN 978-0-470-58492-7 (cloth)I. Title.[DNLM: 1. Neoplasms–diet therapy. 2. Neoplasms–metabolism. 3. Energy

Metabolism. 4. Ketogenic Diet. 5. Mitochondria–metabolism. QZ 200]

616.99′40654–dc232011049798

Printed in the United States of America

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This book is dedicated to the millions of people who have sufferedand died from toxic cancer therapies

Contents

Forword xiiiPreface xv

1. Images of Cancer 1

How Cancer is Viewed 2References 13

2. Confusion Surrounds the Origin of Cancer 15

The Oncogenic Paradox 18Hallmarks of Cancer 18Reassessment 26References 27

3. Cancer Models 31

Problems with Some Cancer Models 31Animal Charges as a Major Impediment to Cancer Research 38Problems with Tumor Histological Classification 39Personal Perspective on Cancer 44References 45

4. Energetics of Normal Cells and Cancer Cells 47

Metabolic 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 68

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viii Contents

5. Respiratory Dysfunction in Cancer Cells 73

Normal 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 101

6. The Warburg Dispute 107

Sidney 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 116

7. Is Respiration Normal in Cancer Cells? 119

Pseudo-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 129

8. Is Mitochondrial Glutamine Fermentation a Missing Link in theMetabolic Theory of Cancer? 133

Amino Acid Fermentation can Maintain Cellular Energy Homeostasis DuringAnoxia 133

Evidence Suggesting that Metastatic Mouse Cells Derive Energy fromGlutamine Fermentation 134

Fermentation Energy Pathways can Drive Cancer Cell Viability UnderHypoxia 138

Competing Explanations for the Metabolic Origin of Cancer 141Chapter Summary 143References 143

Contents ix

9. Genes, Respiration, Viruses, and Cancer 145

Does 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 168

10. Respiratory Insufficiency, the Retrograde Response, and the Originof Cancer 177

The Retrograde (RTG) Response: An Epigenetic System Responsible forNuclear Genomic Stability 177

Inflammation 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 189

11. Mitochondria: The Ultimate Tumor Suppressor 195

Mitochondrial 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 204

12. Abnormalities in Growth Control, Telomerase Activity, Apoptosis,and Angiogenesis Linked to Mitochondrial Dysfunction 207

Growth Signaling Abnormalities and Limitless Replicative Potential 208Linking Telomerase Activity to Cellular Energy and Cancer 209Evasion of Programmed Cell Death (Apoptosis) 209Sustained Vascularity (Angiogenesis) 210References 211

x Contents

13. Metastasis 215

Metastasis 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 241

14. Mitochondrial Respiratory Dysfunction and the ExtrachromosomalOrigin of Cancer 253

Connecting the Links 254Addressing the Oncogenic Paradox 255Is Cancer Many Diseases or a Singular Disease of Energy

Metabolism? 258References 258

15. Nothing in Cancer Biology Makes Sense Except in the Light ofEvolution 261

Revisiting Growth Advantage of Tumor Cells, Mutations, andEvolution 262

Tumor Cell Fitness in Light of the Evolutionary Theory of Rick Potts 269Cancer Development and Lamarckian Inheritance 271Can Teleology Explain Cancer? 272References 272

16. Cancer Treatment Strategies 277

Current Status of Cancer Treatment 277The “Standard of Care” for Glioblastoma Management 280References 285

17. Metabolic Management of Cancer 291

Is it Dietary Content or Dietary Composition that Primarily Reduces TumorGrowth? 292

Dietary Energy Reduction and Therapeutic Fasting in Rodents andHumans 294

Contents xi

Ketogenic 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 341

18. Patient Implementation of Metabolic Therapies for CancerManagement 355

Introduction 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 367

xii Contents

Cancer as a Genetic Disease 367Mechanism of Action? 368Cachexia 368Summary 369References 370

19. Cancer Prevention 375

Cell 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 384

20. Case Studies and Personal Experiences in Using the Ketogenic Dietfor Cancer Management 387

Effects of a Ketogenic Diet on Tumor Metabolism and Nutritional Status inPediatric Oncology Patients: Comments from Dr. LindaNebeling 387

Raffi’s Story: Comments from Miriam Kalamian 389Biological Plausibility that Cancer is a Metabolic Disease Dependent for

Growth on Glucose and Glutamine: Comments from Dr. BomarHerrin 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 BethZupec-Kania 400

Summary 402References 403

21. Conclusions 405

Major Conclusions 407References 408

Index 409

Foreword

Cancer persists as a major disease of mortality and is afflicting more people todaythan ever before. Few families remain untouched by this insidious and viciousdisease. In fact, cancer is predicted to overtake heart disease as the prime cause ofdeath in industrialized societies during this century. I have worked in the cancermetabolism field since the late 1960s and have extensively published works onthe metabolic basis and properties of cancer. While I do not know Dr. Seyfriedpersonally, I am very impressed with the excellent job he has done in highlightingabnormal energy metabolism as the central issue of the cancer problem. I recognizedlong ago the pivotal role of mitochondria and of aerobic glycolysis in sustainingand promoting cancer growth. The Nobel laureate, Otto Warburg, was the first toprovide evidence during the early part of the last century for the involvement ofdisturbed respiration with compensatory fermentation (glycolysis) as a commonproperty of cancer, thus perceived to be related to its uncontrolled growth andprogression. Few subjects have been as controversial in the cancer field as OttoWarburg and his theory of cancer. It is nice to see how Seyfried shows that Warburgwas largely correct in defining the nature of the disease as involving insufficientrespiration with compensatory fermentation. I knew personally many of the keyfigures and their research mentioned in Seyfried’s book, including Dean Burk, PeterMitchell, Sidney Weinhouse, and my former Department Chair, Albert Lehninger,among others. Nevertheless, there were times in my early career when I felt almostalone in considering energy metabolism as important to the cancer problem. Ieven remember one of my colleagues, an expert in DNA technology, dumpingLehninger’s “Warburg Flasks” in the trash as relics of a bygone era in cancerresearch. Fortunately for him, Lehninger was no longer the Department Chair, andfortunately for me, I salvaged many of these flasks and am now glad I did. Afterreading Seyfried’s book, I think these flasks will become valuable as collectoritems.

The cancer field went seriously off course during the mid-1970s when manyinvestigators began considering cancer as primarily a genetic disease rather thanas a metabolic disease. The metabolic defects in cancer cells were thought to ariseas secondary consequences of genomic instability. Seyfried provides substantialevidence documenting the inconsistencies of the gene “only” theory. He criticallyreevaluates the evidence linking cancer progression to a Darwinian process andraises the intriguing possibility that cancer progression is an example of Lamarckianevolution. When viewed collectively, the documented inconsistencies of the gene

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“only” theory make it clear why little progress has been made in the cancer warand in the development of effective nontoxic therapies. A key point made bySeyfried is that most of the genomic instability seen in cancer likely arises asa consequence rather than as the cause of the disease. When viewed more asa metabolic disease, many cost effective therapeutic strategies become recognizedfor cancer management. I know this first hand from our studies of 3-bromopyruvate(3BP), discovered in my laboratory by Dr. Young Ko, as a potent anticancer agent.This is a low cost drug with powerful and quick antitumor effects against multiplecancers in animal models and in cancer patients. 3BP works primarily by targetingtumor cell energy metabolism, thus depleting the energy-rich compound “ATP”essential for growth. At the effective doses used, it does this without toxicity tonormal cells. Seyfried’s book provides substantial evidence showing how cancercan be managed using various other drugs and diets that target energy metabolism.In addition, the restriction of glucose and glutamine, which drive cancer energymetabolism, cripples the ability of cancer cells to replicate and disseminate. Thegene theory has deceived us into thinking that cancer is more than a single disease.Certainly, tumors do not all grow at the same rate. Nevertheless, cancer is a singulardisease involving aberrant energy metabolism as Warburg originally showed andas I, and more recently many others, have documented in biochemical studies.Seyfried drives home this message throughout his book.

Seyfried’s treatise refocuses attention on the central issue of cancer as ametabolic disease according to Warburg’s original theory. The book is unique inlinking nearly all aspects of the disease to respiratory insufficiency with com-pensatory fermentation. Cancer has remained incurable for many due largely toa general misunderstanding of its origin, biology, and metabolism. Hopefully,Seyfried’s thoughtful analysis of the “cancer problem” will change our under-standing of the disease and move the field in the right direction toward solutionsand therapies, such as 3BP, that act much faster and more effectively than thosecurrently available.

Dr. Peter PedersenProfessor of Biological Chemistry

Johns Hopkins University School of MedicineBaltimore, MD

Preface

Cancer persists as a plague in modern society. The lack of progress in eithermanaging or preventing cancer motivated me to write this treatise. I am a bio-chemical geneticist and have worked on the lipid biochemistry of cancer since theearly 1980s. I have developed numerous mouse models for brain tumors and forsystemic metastatic cancer. Several major findings planted the seed for this treatise.First, it became clear to me that the therapeutic action of some anticancer drugsoperated largely through reduced caloric intake. Second, that reduced caloric intakecould target the majority of cancer hallmarks. Third, that ketone bodies can serveas an alternative fuel to glucose in most cells with normal respiratory function.Fourth, that metastatic cancer arises from cells along macrophage lineage. Fifth,that all cancer cells regardless of tissue origin express a general defect in mito-chondrial energy metabolism. Finally, that cancer can be effectively managed andprevented once it becomes recognized as a metabolic disease.

In recognizing cancer as a metabolic disease, it gradually became clear to mewhy so many people die from the disease. Many of the current cancer treatmentsexacerbate tumor cell energy metabolism, thus allowing the disease to progress andeventually become unmanageable. Most cancer patients do not battle their diseasebut are offered toxic concoctions that can eventually undermine their physiologicalstrength and their will to resist. Cancer treatments are often feared as much asthe disease itself. The view of cancer as a genetic disease has confounded theproblem and is largely responsible for the failure to develop effective therapies.The view of cancer as a genetic disease is based on the flawed notion that somaticmutations cause cancer. Substantial evidence indicates that genomic instability islinked to protracted respiratory insufficiency. Once cancer becomes recognized asa metabolic disease with metabolic solutions, more humane and effective treatmentstrategies will emerge. My treatise highlights cancer as a metabolic disease andidentifies the inconsistencies of the gene theory of cancer. Moreover, my treatiseaddresses most of the so-called provocative questions raised by the National CancerInstitute regarding outstanding issues in cancer research. This treatise lays thefoundation for the eventual resolution of the disease.

I would like to thank my many students and colleagues for helping me inproducing the data and in developing the concepts for this treatise. I thank myformer graduate students Mary Louise Roy (MS, 1987), Michelle Cottericho (MS,1992), Mohga El-Abbadi (PhD, 1995), Hong Wei Bai (PhD, 1996), John Brigande(BS, 1989; MS, 1992; PhD, 1997), Jeffrey Ecsedy (PhD, 1998), Mark Manfredi

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xvi Preface

(PhD, 1999), Michaela Ranes (BS, 1998; MS, 2000), Dia Banerjee (MS, 2001),Michael Drage (MS, 2006), Christine Denny (BS, 2005; MS, 2006), Weihua Zhou(MS, 2006), Laura Abate (PhD, 2006), Michael Kiebish (PhD, 2008), Leanne Huy-sentruyt (PhD, 2008), John Mantis (PhD, 2010), and Laura Shelton (PhD, 2010). Iwould also like to acknowledge my current students Linh Ta and Zeynep Akgoc fortheir continued productivity. I would also like to thank the following undergraduatestudents for their input and help, including Katherine Holthause, Jeremy Marsh,Jeffery Ling, Will Markis, Tiernan Mulrooney, Todd Sanderson, Todd Theman,Lisa Mahoney, Michelle Levine, Emily Coggins, Erin Wolfe, Ivan Urits, TarynLeRoy, and Emily Gaudiano. I would like to thank those students from my BI503class on Current Topics in Cancer Research for their input.

I would like to thank faculty colleagues in the Boston College Biology Depart-ment, including Drs. Thomas Chiles, Fr. Richard McGowan SJ, and Jeffery Chuang.I would like to thank Dr. Robert K. Yu, Dr. James Fox and my son Dr. Nicholas T.Seyfried for technical assistance. I would like to thank Avtar Roopa for provocativediscussion. I would like to thank the late Drs. Sanford Palay, Harry Zimmerman,and Allan Yates for their encouragement and assistance. I would also like to givespecial acknowledgement to Dr. Purna Mukherjee and Roberto Flores. Purna wasthe first to make me aware of the powerful therapeutic action of calorie restric-tion. She is superbly trained in the areas of angiogenesis and inflammation and herwork provided seminal information on the mechanisms by which dietary energyreduction can both treat and prevent cancer. Roberto Flores is exceptional in hisdedication to finding the truth underlying the metabolic origin of cancer and inquestioning the metabolic origin of cancer. Finally, I would like to thank my insti-tution, Boston College, for providing animal care support over the first 23 yearsof my employment there (1985–2008). The data collected supporting my treatisewould not have been possible without this invaluable institutional support. Thissupport was consistent with the Ignatian philosophy of service to others.

Chapter 1

Images of Cancer

Cancer is a devastating disease both physically and emotionally and is projected toovertake heart disease as the leading killer of people in industrialized societies. Can-cer is complex. The disease involves multiple time- and space-dependent changesin the health status of cells, which ultimately lead to malignant tumors. Abnormalcell growth (neoplasia) is the biological endpoint of the disease. Tumor cell inva-sion of surrounding tissues and spread to distant organs is the primary cause ofmorbidity and mortality in most cancer patients. This phenomenon is referred toas metastasis . The biological process by which normal cells are transformed intomalignant cancer cells has been the subject of an enormous research effort in thebiomedical sciences for more than a century. Despite this effort, cures or long-termmanagement strategies for metastatic cancers are as challenging today as they were40 years ago when President Richard M. Nixon declared a war on cancer with theNational Cancer Act (1–3). According to the American Cancer Society, 569,490people died in the United States from cancer in 2010 (4). This comes to about1500 people each day! Remarkably, the number of deaths in 2002 was 555,500providing quantitative evidence of no real progress in management over a 8-yearperiod (5). All one needs to do is read the obituary pages from any local newspaperto know that the “cancer war” is not going well.

How is it possible that we are not winning the cancer war when this diseaseis under constant investigation in many major pharmaceutical companies and inmost leading medical centers throughout the world? One would think that effectivenontoxic therapies would be readily available from all this attention. We constantlyhear in the media of new breakthroughs in the fight against cancer, yet high profilecelebrities and politicians continue to die from the disease. If the breakthroughs arereal or meaningful, shouldnt the wealthy and powerful have access to any potentiallife-saving therapy? That these folks are just as vulnerable as the rest of us tothe ravages of the disease clearly indicates that the war is not won. The road tothe cancer front is littered with major breakthroughs that never materialized intoeffective solutions. A plateau in overall death rates for some cancers has been duemore to better awareness and avoidance of risk factors, for example, smoking for

Cancer as a Metabolic Disease: On the Origin, Management and Prevention of Cancer, First Edition.Thomas Seyfried.© 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.

1

2 Chapter 1 Images of Cancer

lung cancer, than to any real advances in the management of systemic metastasis,the most deadly feature of the disease (6, 7). Clearly, we are not wining the waron cancer, as Guy Faguet has emphasized (8).

HOW CANCER IS VIEWED

The image of cancer depends on your perspective. It depends on whether you are acancer patient, a friend or family member of a patient, an oncologist, a pathologist,a statistician, or a person who does basic research on the disease. The image ofcancer can be framed from these various perspectives.

Figure 1.1a shows the number of genetic alterations detected through sequenc-ing and copy number analyses in each of the 24 different pancreatic cancers.According to the figure, point mutations are more common in pancreatic cancerthan are larger deletions or amplifications. The authors of this study, and of manysimilar studies, believe that the cataloguing of mutations found in various tumorswill be important for disease identification and management. While cataloguingcancer genetic defects is interesting, it is important to recognize that the defectsoften vary from one neoplastic cell to another within the same tumor (12).

Figure 1.1b shows the percentage of genetic alterations found in brain tumors(glioblastoma multiforme). Similar kinds of alterations are found in pancreaticand ovarian cancers. Primary sequence alterations and significant copy numberchanges for components of the RTK/RAS/PI(3)K (A), p53 (B), and RB (C) sig-naling pathways are shown. The different shades of gray are indicative of differentdegrees of genetic alteration (13). For each altered component of a particularpathway, the nature of the alteration and the percentage of tumors affected areindicated. Boxes contain the final percentages of glioblastomas containing alter-ations in at least one known component gene of the designated pathway. It isalso interesting to note that no alterations in any of the pathways occur in about15% of glioblastomas despite similarity in histological presentation. It remainsunclear how these genomic alterations relate to the origin or progression of thedisease.

Akt (v-Akt murine thymoma viral oncogene) or PKB (protein kinase-B) is aserine/threonine kinase that is involved in mediating various biological responses,such as inhibition of programmed cell death (apoptosis), stimulation of cell prolif-eration, and enhancement of tumor energy metabolism (Fig. 1.2). Akt expressionis generally greater in cancer cells than in normal cells. Although targeting ofAkt-related pathways is part of cancer drug development, the simple restrictionof calorie intake will reduce Akt expression in tumors (14). This image is syn-thesized from information on the molecular biology of cancer. I refer to thesetypes of cancer images as balloons on strings . They convey an ordered arrange-ment of pathways for a disease that is biologically chaotic. SABiosciences isa QIAGEN company specializing in molecular array technologies that can helpanalyze gene expression changes, epigenomic patterns, microRNA expressions,and so on.

How Cancer Is Viewed 3

Individual pancreatic tumors

AmplificationsDeletions

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Amplification in 7%

Amplificationin 18%

Amplificationin 2%

Amplificationin 1%

Amplification in 2%

Mutation in 1%FOXO

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Activated oncogenes

(C)

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p53signalingalteredin 87%

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TP53

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Mutation, homozygousdeletion in 35%

Mutation, homozygousdeletion in 36%

Mutation, amplificationin 45%

Amplificationin 13%

Amplificationin 4%

Mutationin 8%

Mutation,homozygous

deletion in 18%

Homozygous deletion,mutation in 49%



Homozygousdeletion in 47%

Homozygousdeletion in 2%

Figure 1.1 Cancer images from cancer genome projects. Source: (a) Modified from Jones et al.(13); (b) Reprinted from Jones et al (13). To see this figure in color please go toftp://ftp.wiley.com/public/sci_tech_med/cancer_metabolic_disease.


p53 DegradationNo

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Respiratorybrust

Apoptosisinhibition

Insulinstimulated

mitogenesis

NF-κBpathway

Glucoseuptake

Elevation ofglucose import

Neuroprotection

Figure 1.2 Akt signaling. Source: Reprinted with permission from SABiosciences. See color insert.

Angiogenesis involves the production of new blood vessels from existing bloodvessels and involves interactions among numerous signaling molecules (Fig. 1.3).Cancer therapies that target angiogenesis are thought to help manage the disease.Besides expensive antiangiogenic cancer drugs such as bevacizumab (Avastin) (15),simple calorie restriction effectively targets angiogenesis in tumors (16, 17).

Figure 1.4 depicts the cancer images of cellular pathology.The following is a list of the mortality rate of different cancers:

• Breast cancer killed about 40,170 women in 2010 (4).

• Lung and bronchus cancer killed about 159,390 persons in 2010 (4).


Tumer

Small avascular tumor

Bloodvessels

Grouthfactors

Large, highlyvascularized tumor

Figure 1.3 Tumor angiogenesis. Source: Reprinted with permission from BioOncology. To see thisfigure in color please go to ftp://ftp.wiley.com/public/sci_tech_med/cancer_metabolic_disease.

• Colon/rectum cancer killed about 49,920 persons in 2010 (4).

• Skin cancer killed about 11,590 persons in 2010 (4).

• Brain and nervous system cancer killed about 12,920 persons in 2010 (3).

• Liver and bile duct cancer killed about 18,910 people (4).

Cancer images of organ pathology are shown in Figure 1.5.I think the artwork of Robert Pope, who died from the adverse effects of

chemotherapy and radiation, is especially powerful in conveying the image ofcancer from the perspective of the patient, the family, and the physician (19, 20). Ialso think the Commentary by Donald Cohodes on the experience of chemotherapyshould be read as a supplement to Pope’s book (21). I have included below a fewof Pope’s many paintings and drawings.

In the painting in Figure 1.6, Pope depicts the subtleties of communicationamong cancer doctors. The doctors talk among themselves about cancer differentlythan they do to the patient or to the patient’s family so as not to alarm the sensitivityof the layperson. In the hallway, the communication is considered scientific, blunt,and factual, while in the room it is considered more nurturing and emotional.Although many patients view cancer doctors as secular priests in today’s society,the toxic therapies doctors use to treat cancer are often counterproductive to thelong-term well-being of cancer patients.

The image in Figure 1.7 is an acrylic on canvas depicting a man lying under-neath a radiation machine. Radiation therapy is given to many cancer patients.Radiation will kill both cancer cells and normal cells. Some normal cells that arenot killed outright can be metabolically transformed into tumor cells. Moreover,


(a)

(b)

Figure 1.4 (a) Histological image of breast cancer. Source: Reprinted with permission from theNCI. (b) Histological images of glioblastoma multiforme. Source: Reprinted with permission fromReference 18. To see this figure in color please go to ftp://ftp.wiley.com/public/sci_tech_med/cancer_metabolic_disease.

those tumor cells that survive the radiation treatment will sometimes grow back asmore aggressive and less manageable cancers in the future.

Figure 1.8 is also an acrylic on canvas that conveys the psychological impact ofcancer drugs. The chemical in the syringe is Adriamycin (doxorubicin), which Popereceived along with other drugs during his battle with cancer. In this painting, Popedepicts an older woman with lymphatic cancer who is getting chemotherapy. Thewoman is wearing a turban to hide her baldness caused from the drug treatments.Pope attempts to convey the patient’s thoughts about the drug. The drug withinthe syringe elicits thoughts of either life or alarm. According to Pope, the paintingshows the human encounter with poisonous drug therapy, an all-too-familiar scenefor the cancer patient.


(a) (b)

(c) (d)

(e) (f)

Figure 1.5 (a) Breast cancer, (b) lung cancer, (c) colon cancer, (d) melanoma, (e) glioblastoma,and (f) liver cancer. See color insert for (a, d). To see figures (b, c, e, f) in color please go toftp://ftp.wiley.com/public/sci_tech_med/cancer_metabolic_disease.

Figure 1.6 The Conference. Source: Reprinted from Pope (p. 113) with permission. See colorinsert.


Figure 1.7 Radiation.Source: Reprinted from Pope(p. 52) with permission Seecolor insert.

Figure 1.8 Chemotherapy.Source: Reprinted from Pope(p. 47) with permission. Seecolor insert.

The ink on paper image in Figure 1.9 depicts the suffering of a woman receiv-ing her scheduled chemotherapy. Pope recalled that the injection days were theworst days of his life. The woman pictured winces in pain as the poisonous drugis administered. In contrast to the treated patient, the mask and gloves protect thenurse from the toxic effects of the chemotherapy.

Figure 1.10 is also an ink on paper image that conveys Pope’s memories ofhis sickness from chemotherapy treatment and the responses of his father (driving)and brother (in back seat) to Pope’s suffering. Many cancer patients and theirfamily members continue to experience these emotions. Indeed, these sufferingshave become even worse with some of the newer drugs available (15, 22).


Figure 1.9 Chemotherapy injection. Source: Reprinted from Pope (p. 62) with permission.

Figure 1.10 Three men. Source: Reprinted from Pope (p. 89) with permission.


Figure 1.11 Mastectomy. Source: Reprinted from Pope (p. 101) with permission.

Another ink on paper image in Figure 1.11 conveys a woman’s emotionaltrauma associated with mastectomy, which involves the surgical removal of a breastto prevent the spread of cancer.

Figure 1.12 is a charcoal on paper image that conveys the suffering of a younggirl from the ravages of chemotherapy. She gently touches the instrument of hersuffering, while her doll in the background and the metal pan in foreground arereminders of the comfort and pain in her life.

Figure 1.13 depicts a son’s artistic impression of the neurological devastationof glioblastoma in his father.

In addition to these pictorial images of cancer, we can also obtain a literaryimage of cancer from a paraphrase of Herman Melville’s “Moby-Dick,” whencaptain Ahab (played by the actor Gregory Peck) utters these words:

Look ye, Starbuck, all visible objects are but as pasteboard masks. Some inscrutableyet reasoning thing puts forth the molding of their features. The white whale tasks me;he heaps me. Yet he is but a mask. ′Tis the thing behind the mask I chiefly hate; themalignant thing that has plagued mankind since time began; the thing that maws andmutilates our race, not killing us outright but letting us live on, with half a heart andhalf a lung.

More personal accounts of cancer images can be found in the 2010 HBOmovie, Wit , starring Emma Thompson, and in the popular books by physicians


Figure 1.12 Erica.Source: Reprinted from Pope(p. 80) with permission.

Figure 1.13 Fading away.Source: Reprinted withpermission from Gupta andSarin (23). See color insert.


David Servan-Schreiber (“Anticancer: A New Way of Life”) (24) and SiddharthaMukherjee (“The Emperor of All Maladies: A Biography of Cancer”) (25).

Synopsis

The images of cancer have changed little for more than a hundred years. If anything,they have become worse in this new century. The data in Table 1.1 show that weare not winning the war on cancer, regardless of what the pundits say (8). Thepromises of new drugs based on improved understanding of cancer genetics andbiology have not materialized (26–28). As each new “miracle” cancer drug isdiscontinued due to no efficacy or unacceptable toxicity, a new “miracle” drugwith similar disappointing effects quickly takes its place (15, 29). The media feedsinto this process, providing false hope and misinformation (30). When will thiscontinuum end? It will end, in my opinion, only after we come to recognize canceras a metabolic disease that can be effectively managed with nontoxic metabolictherapies (31). My goal is to provide scientific evidence supporting this view.

Table 1.1 Cancer Statistics from 1990 to 2010

Year Number of new cases Number of deaths per year Number of deaths per day

1990a 1,040,000 510,000 13971996b 1,359,150 554,740 15202002c 1,284,900 555,500 15222003c 1,334,100 556,500 15252004c 1,368,030 563,700 15442005c 1,372,910 570,280 15622006c 1,399,790 564,830 15472007c 1,444,920 559,650 15332008c 1,437,180 565,650 15492009c 1,479,350 562,340 15412010c 1,529,560 569,490 1560

The data show that the number of new cancer cases and deaths per year is increasing, while thenumber of deaths per day has remained fairly constant from 1996 until 2010. The numbers clearlyindicate that the war on cancer is not going well. Indeed, the number of new cases, deaths per year,and deaths per day for cancer in 2010 was greater than the number of total casualties (1,076,245), totaldeaths (405,399), and deaths per day (416) suffered by all US military forces during the Second WorldWar (1941–1945; data from http://en.wikipedia.org/wiki/United_States_military_casualties_of_war).What does this say about the leadership of those who are directing the war on cancer? The persistenthigh number of cancer deaths per year is especially disheartening considering that the budget for theNational Cancer Institute (NCI) increased from $4.12 billion in 2002 to $5.10 billion in 2010. The24% increase in the NCI budget is comparable to the 19% increase in new cancer cases.a Data from Silverberg et al., http://caonline.amcancersoc.org/cgi/reprint/40/1/9.b Data from Parker et al., http://caonline.amcancersoc.org/cgi/reprint/46/1/5.cData from Jamal et al. (4, 5, 7, 9–11).

cancer as a metabolic · 2013. 7. 23. · references 27 3. cancer models 31 problems with some...

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