CANCER AS A
1.1 How Cancer Is Viewed
The image of cancer depends on your perspective. It depends on whether you are a cancer 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 of cancer can be framed from these various perspectives.
a shows the number of genetic alterations detected through sequencing and copy number analyses in each of the 24 different pancreatic cancers. According to the figure, point mutations are more common in pancreatic cancer than are larger deletions or amplifications. The authors of this study, and of many similar studies, believe that the cataloguing of mutations found in various tumors will be important for disease identification and management. While cataloguing cancer genetic defects is interesting, it is important to recognize that the defects often vary from one neoplastic cell to another within the same tumor .
Cancer images from cancer genome projects. Source: (a) Modified from Jones et al. 
b shows the percentage of genetic alterations found in brain tumors (glioblastoma multiforme). Similar kinds of alterations are found in pancreatic and ovarian cancers. Primary sequence alterations and significant copy number changes for components of the RTK/RAS/PI(3)K (A), p53 (B), and RB (C) signaling pathways are shown. The different shades of gray are indicative of different degrees of genetic alteration . For each altered component of a particular pathway, the nature of the alteration and the percentage of tumors affected are indicated. Boxes contain the final percentages of glioblastomas containing alterations in at least one known component gene of the designated pathway. It is also interesting to note that no alterations in any of the pathways occur in about 15% of glioblastomas despite similarity in histological presentation. It remains unclear how these genomic alterations relate to the origin or progression of the disease.
Akt (v-Akt murine thymoma viral oncogene) or PKB (protein kinase-B) is a serine/threonine kinase that is involved in mediating various biological responses, such as inhibition of programmed cell death (apoptosis), stimulation of cell proliferation, and enhancement of tumor energy metabolism (). Akt expression is generally greater in cancer cells than in normal cells. Although targeting of Akt-related pathways is part of cancer drug development, the simple restriction of calorie intake will reduce Akt expression in tumors . This image is synthesized from information on the molecular biology of cancer. I refer to these types of cancer images as balloons on strings. They convey an ordered arrangement of pathways for a disease that is biologically chaotic. SABiosciences is a QIAGEN company specializing in molecular array technologies that can help analyze gene expression changes, epigenomic patterns, microRNA expressions, and so on.
Angiogenesis involves the production of new blood vessels from existing blood vessels and involves interactions among numerous signaling molecules (). Cancer therapies that target angiogenesis are thought to help manage the disease. Besides expensive antiangiogenic cancer drugs such as bevacizumab (Avastin) , simple calorie restriction effectively targets angiogenesis in tumors [16, 17].
Depicts the cancer images of cellular pathology.
(a) Histological image of breast cancer. Source: Reprinted with permission from the NCI. (b) Histological images of glioblastoma multiforme.
The following is a list of the mortality rate of different cancers:
- Breast cancer killed about 40,170 women in 2010 .
- Lung and bronchus cancer killed about 159,390 persons in 2010 .
- Colon/rectum cancer killed about 49,920 persons in 2010 .
- Skin cancer killed about 11,590 persons in 2010 .
- Brain and nervous system cancer killed about 12,920 persons in 2010 .
- Liver and bile duct cancer killed about 18,910 people .
Cancer images of organ pathology are shown in .
(a) Breast cancer, (b) lung cancer, (c) colon cancer, (d) melanoma, (e) glioblastoma, and (f) liver cancer.
I think the artwork of Robert Pope, who died from the adverse effects of chemotherapy and radiation, is especially powerful in conveying the image of cancer from the perspective of the patient, the family, and the physician [19, 20]. I also think the Commentary by Donald Cohodes on the experience of chemotherapy should be read as a supplement to Pope’s book . I have included below a few of Pope’s many paintings and drawings.
In the painting in , Pope depicts the subtleties of communication among cancer doctors. The doctors talk among themselves about cancer differently than they do to the patient or to the patient’s family so as not to alarm the sensitivity of 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 the long-term well-being of cancer patients.
The Conference. Source: Reprinted from Pope (p. 113).
The image in is an acrylic on canvas depicting a man lying underneath a radiation machine. Radiation therapy is given to many cancer patients. Radiation will kill both cancer cells and normal cells. Some normal cells that are not killed outright can be metabolically transformed into tumor cells. Moreover, those tumor cells that survive the radiation treatment will sometimes grow back as more aggressive and less manageable cancers in the future.
is also an acrylic on canvas that conveys the psychological impact of cancer drugs. The chemical in the syringe is Adriamycin (doxorubicin), which Pope received along with other drugs during his battle with cancer. In this painting, Pope depicts an older woman with lymphatic cancer who is getting chemotherapy. The woman 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 within the syringe elicits thoughts of either life or alarm. According to Pope, the painting shows the human encounter with poisonous drug therapy, an all-too-familiar scene for the cancer patient.
The ink on paper image in depicts the suffering of a woman receiving her scheduled chemotherapy. Pope recalled that the injection days were the worst days of his life. The woman pictured winces in pain as the poisonous drug is administered. In contrast to the treated patient, the mask and gloves protect the nurse from the toxic effects of the chemotherapy.
is also an ink on paper image that conveys Pope’s memories of his sickness from chemotherapy treatment and the responses of his father (driving) and brother (in back seat) to Pope’s suffering. Many cancer patients and their family members continue to experience these emotions. Indeed, these sufferings have become even worse with some of the newer drugs available [15, 22].
Another ink on paper image in conveys a woman’s emotional trauma associated with mastectomy, which involves the surgical removal of a breast to prevent the spread of cancer.
is a charcoal on paper image that conveys the suffering of a young girl from the ravages of chemotherapy. She gently touches the instrument of her suffering, while her doll in the background and the metal pan in foreground are reminders of the comfort and pain in her life.
depicts a son’s artistic impression of the neurological devastation of glioblastoma in his father.
In addition to these pictorial images of cancer, we can also obtain a literary image of cancer from a paraphrase of Herman Melville’s “Moby-Dick,” when captain Ahab (played by the actor Gregory Peck) utters these words:
Look ye, Starbuck, all visible objects are but as pasteboard masks. Some inscrutable yet 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; the malignant thing that has plagued mankind since time began; the thing that maws and mutilates our race, not killing us outright but letting us live on, with half a heart and half a lung.
More personal accounts of cancer images can be found in the 2010 HBO movie, Wit, starring Emma Thompson, and in the popular books by physicians David Servan-Schreiber (“Anticancer: A New Way of Life”)  and Siddhartha Mukherjee (“The Emperor of All Maladies: A Biography of Cancer”) .
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 show that we are not winning the war on cancer, regardless of what the pundits say . The promises of new drugs based on improved understanding of cancer genetics and biology have not materialized [26–28]. As each new “miracle” cancer drug is discontinued due to no efficacy or unacceptable toxicity, a new “miracle” drug with similar disappointing effects quickly takes its place [15, 29]. The media feeds into this process, providing false hope and misinformation . When will this continuum end? It will end, in my opinion, only after we come to recognize cancer as a metabolic disease that can be effectively managed with nontoxic metabolic therapies . My goal is to provide scientific evidence supporting this view.
Cancer Statistics from 1990 to 2010
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13. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801–6.
14. Marsh J, Mukherjee P, Seyfried TN. Akt-dependent proapoptotic effects of dietary restriction on late-stage management of a phosphatase and tensin homologue/tuberous sclerosis complex 2-deficient mouse astrocytoma. Clin Cancer Res. 2008;14:7751–62.
15. Fojo T, Parkinson DR. Biologically targeted cancer therapy and marginal benefits: are we making too much of too little or are we achieving too little by giving too much? Clin Cancer Res. 2010;16:5972–80.
16. Mukherjee P, Zhau JR, Sotnikov AV, Clinton SK. Dietary and Nutritional Modulation of Tumor Angiogenesis. In: Teicher BA, editor. Antiangiogenic Agents in Cancer Therapy. Totowa (NJ): Humana Press; 1999. p.237–61.
17. Mukherjee P, Abate LE, Seyfried TN. Antiangiogenic and proapoptotic effects of dietary restriction on experimental mouse and human brain tumors. Clin Cancer Res. 2004;10:5622–9.
18. Zuccoli G, Marcello N, Pisanello A, Servadei F, Vaccaro S, Mukherjee P, et al. Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: case report. Nutr Metab. 2010;7:33.
19. Carlson T. Turning sickness into art: Robert Pope and his battle with cancer. CMAJ. 1992;147:229–32.
20. Pope R. Illness & Healing: Images of Cancer. Hantsport (NS): Lancelot Press; 1991.
21. Cohodes DR. Through the looking glass: decision making and chemotherapy. Health Aff (Millwood). 1995;14:203–8.
22. Uhm JH, Ballman KV, Wu W, Giannini C, Krauss JC, Buckner JC, et al. Phase II evaluation of gefitinib in patients with newly diagnosed grade 4 astrocytoma: Mayo/North central cancer treatment group study N0074. Int J Radiat Oncol Biol Phys. 2010;80:347–53.
23. Gupta T, Sarin R. Poor-prognosis high-grade gliomas: evolving an evidence-based standard of care. Lancet Oncol. 2002;3:557–64.
24. Servan-Schreiber D. Anticancer: A New Way of Life. New York: Viking; 2009.
25. Mukherjee S. The Emperor of all Maladies: A Biography of Cancer. New York: Scribner; 2010.
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31. Seyfried TN, Shelton LM. Cancer as a metabolic disease. Nutr Metab. 2010;7:7.
Confusion Surrounds the Origin of Cancer
A major impediment in the effort to defeat cancer has been due, in large part, to the confusion surrounding the origin of the disease. “Make no mistake about it, the origin of cancer is far from settled.” Contradictions and paradoxes continue to plague the field [1–5]. Much of the confusion surrounding the origin of cancer arises from the absence of a unifying theory that can integrate the diverse observations on the nature of the disease. Without a clear idea on cancer origins, it becomes difficult to formulate a clear strategy for effective management and prevention. The failure to clearly define the origin of cancer is responsible in large part for the failure to significantly reduce the death rate from the disease.
Currently, most researchers consider cancer as a type of genetic disease where damage to a cell’s DNA underlies the transformation of a normal cell into a potentially lethal cancer cell. The finding of hundreds and thousands of gene changes in different cancers has led to the idea that cancer is not a single disease, but is a collection of many different diseases. Consideration of cancer as a “disease complex” rather than as a single disease has contributed to the notion that management of various forms of the disease will require individual or “personalized” drug therapies [6–8]. This therapeutic strategy would certainly be logical if, in fact, most cancers were of genetic origin. What if most cancers are not of genetic origin? What if most of the gene changes identified in tumor tissue arise as secondary downstream epiphenomena of tumor progression? What if cancer were a disease of respiratory insufficiency?
The somatic mutation theory, which has guided cancer research and drug development for over half a century, is now under attack. Carlos Sonnenschein and Anna Soto along with others have identified major inconsistencies in the evidence supporting the genetic origin of cancer [2–4, 9–12]. Despite these concerns, the cancer field slogs forward with massive genome-based projects to identify all gene defects that occur in various tumor types [13–16]. Gabor Miklos provided a compelling argument for the unlikelihood that data generated from cancer genome projects will provide effective cures for the disease . A recent commentary in Science supports Miklos’ argument in mentioning that little new information was uncovered from a comprehensive analysis of the ovarian cancer genome (Jocelyn Kaiser, 333:397, 2011). Is anyone listening to these arguments? Do people comprehend these messages? We have a financial crisis in the federal government and yet we are wasting enormous resources on genome projects that provide little useful information for cancer patients.
While the cancer genome projects are commendable for their technical achievement and have advanced the field of molecular biology, they have done little to defeat cancer [17–19]. At the 2011 meeting of the American Association of Cancer Research, Dr. Linda Chin mentioned in her plenary lecture that improved genomic sequencing speed was a major beneficiary of the cancer genome projects. Another benefit has been the increased number of jobs created in the biotechnology sector as a result of the genome projects. How many dying cancer patients would be comforted by knowing this? While enhanced sequencing speed and creation of new jobs are certainly important and noteworthy, these achievements are not connected to curing cancer.
The information collected from the large cancer genome projects has done more to confuse than to clarify the nature of the cancer [13, 15, 20]. To make matters worse, there are now suggestions for an international effort to identify all abnormal proteins in tumors, that is, a cancer proteome project . If the ratio of “information in to useful information out” was so low for the cancer genome projects (), what is the justification that the ratio would be better for a cancer proteome project? If technology improvement and new jobs creation is the justification, then this should be clearly stated, as a cure for cancer will not likely be the ultimate outcome.
Too much in, nothing out. According to Serge Koscielny, the gene microarray bioinformatics literature is polluted with many gene expression signatures that have inadequate validation or no validation at all. Even if the expression signatures were adequately validated, the information would have little impact on the daily cancer death rate.
In my opinion, it is wishful thinking that the vast information generated from the cancer genome atlas will someday serve as a foundation for the development of new and more effective cancer therapies despite recent arguments to the contrary . While gene-based targeted therapies could be effective against those few cancers that are inherited and where all cells within the tumor have a common genetic defect, most cancers are not inherited through the germ line and few cancer cells have gene defects that are expressed in all cells of the tumor [1, 8, 11, 14, 16, 17, 20]. Although almost 700 targeted therapies have been developed from the cancer genome projects, no patients with solid tumor have been cured from this strategy . How many times must we beat the dead horse before we realize that it will not get up and walk?
Most mutations found in tumors arise sporadically, as do most cancers. The types of mutations found in one tumor cell will differ from those found in another tumor cell within the same tumor [7, 15, 23]. Genetic heterogeneity and randomness is the norm rather than the exception for mutations found in most sporadic cancers. We have recently shown how the majority of cancer gene defects could arise as downstream epiphenomena of tumor progression rather than as cancer causes . In light of these findings, it is not likely that gene-based targeting strategies will be useful for managing most advanced cancers. Recent evidence bears this out [7, 19, 25].
It is my opinion that most genetic changes in tumors are largely irrelevant to the origin or treatment of cancer. They are but epiphenomena of biological chaos. While genomic changes might participate in disease progression, they do not cause the disease. If my prognosis is accurate, then where should one look for real solutions to the cancer problem?
Emerging evidence suggests that cancer is primarily a metabolic disease rather than a genetic disease . I will present evidence showing how cancer is a disease of defective cellular energy metabolism and that most of the genomic defects found in cancer cells arise as secondary downstream effects of defective energy metabolism. Most genetic defects found in tumors are “red herrings” that have diverted attention away from mitochondrial respiratory insufficiency, the central feature of the disease. I trained in classical genetics with Herman Brockman at Illinois State University and in biochemical genetics with William Daniel at the University of Illinois. I was, like many people, swept up in the hype surrounding the gene theory of cancer. Unfortunately, much of my original enthusiasm for the genetic origin of cancer has given way to skepticism and frank disbelief. This will become clear to all who read this treatise.
Regardless of cell type or tissue origin, the vast majority of cancer cells share a singular problem involving abnormal energy metabolism. While many in the cancer field consider gene defects as being responsible for the metabolic abnormalities in cancer cells, I do not share this view. In fact, I will present evidence showing how the gene defects in cancer cells can arise following damage to respiration. I predict that targeting the defective energy metabolism of tumors will eventually become the most cost-effective, nontoxic approach to cancer prevention and management. Moreover, the therapeutic efficacy of molecularly “targeted” therapies could be enhanced if combined with therapies that target energy metabolism. I will review substantial evidence supporting my views.
2.1 The Oncogenic Paradox
Although very specific processes underlie malignant transformation, a large number of unspecific influences can initiate the disease including radiation, chemicals, viruses, and inflammation. Indeed, it appears that prolonged exposure to almost any provocative agent in the environment can potentially cause cancer [26, 27]. That a very specific process could be initiated in very unspecific ways was considered “the oncogenic paradox” by Albert Szent-Gyorgyi, a leading cancer researcher of his day [27, 28]. Oncogenesis is the term used to describe the biological process leading to tumor formation. John Cairns also struggled with this paradox in his essay on The Origins of Human Cancers . The oncogenic paradox persists today as an unresolved issue in cancer research [26, 30]. I will show how respiratory insufficiency is the origin of the oncogenic paradox.
2.2 Hallmarks of Cancer
In a landmark review on cancer, Drs. Hanahan and Weinberg suggested that six essential alterations in cell physiology were largely responsible for malignant cell growth . This review was later expanded into a book on the Biology of Cancer . These six alterations were described as the hallmarks of nearly all cancers and have guided research in the field for the last decade . The six hallmarks () include the following:
1. Self-Sufficiency in Growth Signals This process involves the uncontrolled proliferation of cells owing to self-induced expression of molecular growth factors. In other words, dysregulated growth would arise through abnormal expression of genes that encode growth factors. The released growth factors would then bind to receptors on the surface of the same cell (autocrine stimulation) or bind to receptors on other nearby tumor cells (paracrine stimulation), thereby locking-in signaling circuits that perpetuate continuous replication. Complicated cybernetic-type diagrams are often presented to illustrate these phenomena (). Cybernetics is generally viewed as the study of goal-directed control and communication systems . The abnormal circuitry in tumor cells is assumed to result in large part from the dominant expression of cancer-causing oncogenes.
2. Insensitivity to Growth-Inhibitory (Antigrowth) Signals In order to carry out specific functions in mature differentiated tissues, most cells must remain quiescent or nonproliferative. A complex signaling circuitry involving the action of tumor-suppressor genes is necessary to maintain the quiescent state. In addition to these internal signals, interactions with other cells (cell–cell) and the external environment (cell–matrix) also act to maintain quiescence. Damage to suppressor genes or the microenvironment is assumed to dampen growth inhibition and provoke proliferation, as the cell no longer responds appropriately to the growth-inhibitory actions of these genes or molecules. Tumor cells are known to express multiple defects in tumor-suppressor genes and in cell–cell or cell–matrix interactions.
3. Evasion of Programmed Cell Death (Apoptosis) Programmed cell death is an effective means of eliminating damaged or dysfunctional cells. Elimination of damaged cells is necessary in order to maintain tissue homeostasis and health. Cell damage can initiate the release of mitochondrial cytochrome c, a protein of the mitochondrial electron transport chain, which is a potent inducer of apoptosis in normal cells. In contrast to normal cells, however, tumor cells lose their sensitivity to apoptotic death signals. Consequently, tumor cells continue to live and proliferate despite damage to their nuclear DNA and respiration. Loss of tumor-suppressor genes, which sense cell damage and initiate cell death, is responsible in part for resistance of tumor cells to programmed cell death. The acquired resistance to apoptosis is a recognized hallmark of most cancers [5, 32].
4. Limitless Replicative Potential All cells of a given species possess a finite number of divisions before they reach mortality. This is a cell-autonomous program that induces senescence and prevents immortality . Tumor cells, however, lose responsiveness to this program and continue to divide. The phenomenon of limitless replicative potential is closely connected to the first three acquired capabilities.
5. Sustained Vascularity (Angiogenesis) Angiogenesis involves neovascularization or the formation of new blood capillaries from existing blood vessels and is associated with the processes of tissue inflammation and wound healing. Many solid tumors have difficulty growing unless enervated with blood vessels, which can deliver nutrients while removing metabolic waste products (Fig. ). The dissemination of tumor cells throughout the body is assumed to depend in part on the degree of tumor vascularization. The more blood vessels in tumors, the greater will be the potential to invade and metastasize. Tumor cells release growth factors that stimulate nearby host stromal cells (vascular endothelial cells and macrophages) to proliferate, thus providing the tumor with a vasculature and the means for more rapid growth. The endothelial cells form the vessel walls, while the local macrophages and other stromal cells degrade the microenvironment facilitating neovascularization. A switch from low vascularization to high vascularization is considered to be an essential acquired capability for tumor progression [5, 32, 34].
6. Tissue Invasion and Metastasis Invasion of tumor cells into local tissue and their spread to distant organs underlies the phenomenon of metastasis. Metastasis or complications of metastasis is associated with about 90% of all cancer deaths [32, 35]. The prevention of metastasis remains the single most important challenge for cancer management.
The six hallmarks of cancer from Hanahan and Weinberg. An updated version of this figure recently appeared in Ref. 32.
The emergent integrated circuit of the cell. Progress in dissecting signaling pathways has begun to lay out a circuitry that will likely mimic electronic integrated circuits in complexity and finesse, where transistors are replaced by proteins (e.g., kinases and phosphatases) and the electrons by phosphates and lipids, among others. In addition to the prototypical growth signaling circuit centered around Ras and coupled to a spectrum of extracellular cues, other component circuits transmit antigrowth and differentiation signals or mediate commands to live or die by apoptosis. As for the genetic reprogramming of this integrated circuit in cancer cells, some of the genes known to be functionally altered are given in gray. An updated version of this figure has appeared in Ref. 32. Source: Reprinted with permission from of Hanahan and Weinberg . See color insert.