CANCER AS A
METABOLIC DISEASE

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 [12].

Cancer images from cancer genome projects. Source: (a) Modified from Jones et al. [13]

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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 [13]. 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 [14]. 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.

Akt signaling

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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) [15], simple calorie restriction effectively targets angiogenesis in tumors [16, 17].

Tumor angiogenesis.

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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.

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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].
  • 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 .

(a) Breast cancer, (b) lung cancer, (c) colon cancer, (d) melanoma, (e) glioblastoma, and (f) liver cancer.

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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 [21]. 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).

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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.

Radiation. Source: Reprinted from Pope (p. 52).

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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.

Chemotherapy. Source: Reprinted from Pope (p. 47).

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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.

Chemotherapy injection. Source: Reprinted from Pope (p. 62).

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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].

Three men. Source: Reprinted from Pope (p. 89).

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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.

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

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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.

Erica. Source: Reprinted from Pope (p. 80).

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depicts a son’s artistic impression of the neurological devastation of glioblastoma in his father.

Fading away. Source: Reprinted from Gupta and Sarin [23].

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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”) [24] and Siddhartha Mukherjee (“The Emperor of All Maladies: A Biography of Cancer”) [25].

1.1.1 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 show that we are not winning the war on cancer, regardless of what the pundits say [8]. 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 [30]. 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 [31]. My goal is to provide scientific evidence supporting this view.

Cancer Statistics from 1990 to 2010

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References

1. Kiberstis P, Marshall E. Cancer crusade at 40. Celebrating an anniversary. Introduction. Science. 2011;331:1539.
2. Anand P, Kunnumakkara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, et al. Cancer is a preventable disease that requires major lifestyle changes. Pharm Res. 2008;25:2097–116.
3. Bailar JC, 3rd, Gornik HL. Cancer undefeated. N Engl J Med. 1997;336:1569–74.
4. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.
5. Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002. CA Cancer J Clin. 2002;52:23–47.
6. Gabor Miklos GL. The human cancer genome project–one more misstep in the war on cancer. Nat Biotechnol. 2005;23:535–37.
7. Jemal A, Center MM, Ward E, Thun MJ. Cancer occurrence. Methods Mol Biol. 2009;471:3–29.
8. Faguet G. The War on Cancer: an Anatomy of a Failure, a Blueprint for the Future. Dordrecht, The Netherlands: Springer; 2008.
9. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin. 2003;53:5–26.
10. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–49.
11. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007;57:43–66.
12. Salk JJ, Fox EJ, Loeb LA. Mutational heterogeneity in human cancers: origin and consequences. Annu Rev Pathol. 2010;5:51–75.
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.
26. Hambley TW, Hait WN. Is anticancer drug development heading in the right direction? Cancer Res. 2009;69:1259–62.
27. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
28. Gibbs JB. Mechanism-based target identification and drug discovery in cancer research. Science. 2000;287:1969–73.
29. Couzin-Frankel J. Immune therapy steps up the attack. Science. 2010;330:440–3.
30. Fishman J, Ten Have T, Casarett D. Cancer and the media: how does the news report on treatment and outcomes?. Arch Intern Med. 2010;170:515–8.
31. Seyfried TN, Shelton LM. Cancer as a metabolic disease. Nutr Metab. 2010;7:7.

Chapter 2

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 [14]. 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 [21]. 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.

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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 [22]. 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 [19]. 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 [24]. 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 [24]. 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 [29]. 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 [5]. This review was later expanded into a book on the Biology of Cancer [31]. These six alterations were described as the hallmarks of nearly all cancers and have guided research in the field for the last decade [32]. 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 [33]. 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 [5]. 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.

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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 [5]. See color insert.

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2.2.1 Genomic Instability

According to Hanahan and Weinberg, genome instability is considered to be the essential enabling characteristic for manifesting the six major hallmarks of cancer [5, 32]. Genome instability was assumed to elicit the large numbers of mutations found in tumor cells, supporting the idea that cancer is a type of genetic disease. However, the mutation rate for most genes is low, making it unlikely that the thousands and even millions of pathogenic mutations found in cancer cells would occur sporadically within a normal human lifespan [15, 26, 36]. Pathogenic mutations are those that disrupt normal cell physiology and differ from nonpathogenic mutations, which generally do not have any physiological effect on cell homeostasis. This then creates another paradox. If mutations are such rare events, then how is it possible that cancer cells can express so many different types and kinds of mutations during the development of a malignant tumor?

The loss of genomic “caretakers” or “guardians”, involved in sensing and repairing DNA damage, was proposed to explain the increased mutability of tumor cells [26, 37–39]. The loss of these caretaker systems would allow genomic instability, thus enabling premalignant cells to reach the six essential hallmarks of cancer [5, 32]. Attempts to classify cancer mutations as either “drivers” or “passengers” have done little to clarify the situation [13, 15, 22, 40]. It has been difficult to define with certainty the origin of premalignancy and the mechanisms by which the caretaker/guardian systems themselves are lost during the emergent malignant state [4, 6, 26]. If the genome guardians are so essential for maintaining genomic integrity, then why are these guardians prone to such high mutability? Indeed, the p53 genome guardian is one of the most commonly mutated genes found in tumors [38]. Most genes necessary for survival, for example, ubiquitin, histones etc., show little mutability across species. It is difficult for me to see how natural selection would select high mutability genes as “guardians of the genome.” This would be like bank owners hiring tellers who are highly prone to corruption!

It appears that the route taken by the driver genes and their passengers to explain cancer seems more circular than straight with neither the drivers nor the passengers knowing the final destination. This is further highlighted with suggestions that some cancer genes, such as the isocitrate dehydrogenase gene 1 (IDH1), can act as either a tumor-provoking oncogene or as a tumor-inhibiting suppressor gene (reference IDH1) [41]. The situation is even more confusing with suggestions that IDH1 is both an oncogene and a tumor-suppressor gene! The view of cancer as a genetic disease reminds me of a traffic jam in Calcutta, India, where passengers direct drivers onto sidewalks and into opposite lanes of traffic in order to arrive at their destination. The attempt to link the six hallmarks of cancer to genomic instability is like a Calcutta traffic jam, but without a clear destination.

2.2.2 The Warburg Theory

In addition to the six recognized hallmarks of cancer, aerobic fermentation or the Warburg effect is also a robust metabolic hallmark of most tumors whether they are solid or blood born [42–47]. Aerobic fermentation involves elevated glucose uptake with lactic acid production in the presence of oxygen. Elevated glucose uptake and lactic acid production is a defining characteristic of most tumors and is the basis for tumor imaging using labeled glucose analogs [48–50]. Labeled glucose analogs have become an important diagnostic tool for cancer detection and management using positron emission tomography (PET). The radiolabeled glucose collects in the tumor tissue because nearly all tumors depend heavily on glucose for survival. Consequently, it is easy to detect many tumor types based on their requirement for glucose as shown in .

Source.

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Any new features or tools which are added to the current website shall also be subject to the Terms of Use. You can review the most current version of the Terms of Use at any time on this page. We reserve the right to update, change or replace any part of these Terms of Use by posting updates and/or changes to our website. It is your responsibility to check this page periodically for changes. Your continued use of or access to the website following the posting of any changes constitutes acceptance of those changes.

 

SECTION 1 – ONLINE WEBSITE TERMS

By agreeing to these Terms of Use, you represent that you are at least the age of majority in your state, province, country or city of residence, or that you are the age of majority in your state, province, country or city of residence and you have given us your consent to allow any of your minor dependents to use this site.

You may not use any of our website for any illegal or unauthorized purpose nor may you, in the use of the Service, violate any laws in your jurisdiction (including but not limited to copyright laws).

You must not transmit any worms or viruses or any code of a destructive nature.

A breach or violation of any of the Terms will result in an immediate termination of your Services.

 

SECTION 2 – GENERAL CONDITIONS

We reserve the right to refuse service to anyone for any reason at any time.

You agree not to reproduce, duplicate, copy, sell, resell or exploit any portion of the Service, use of the Service, or access to the Service or any contact on the website through which the service is provided, without express written permission by us.

The headings used in this agreement are included for convenience only and will not limit or otherwise affect these Terms.

You understand and agree that this website is for information purposes only, and that by providing the information contained herein, we are not diagnosing, treating, curing, mitigating, or preventing any type of disease or medical condition. You understand and agree that before beginning any type of natural, integrative or conventional treatment regimen, it is advisable to seek the advice of a licensed healthcare professional.

You understand and agree that the information on the site is presented for the sole purpose of disseminating health information for general educational purposes only. You understand and agree that if you think you may have a medical emergency, you should call your doctor or 911. You understand and agree that the information on this site is not intended or implied to be medical advice, and you understand and agree that the information does not constitute the provision or practice of medical, nursing, or professional health care advice or services. You understand and agree that you will not use the information on this site as a substitute for professional medical advice, diagnosis, or treatment. You understand and agree that you should always seek the advice of your physician or other qualified health care provider prior to starting any treatment or with any questions you may have regarding a medical condition.

You understand and agree that nothing contained on this site is intended to be or will be used by you for medical diagnosis or treatment. You understand and agree that you should never disregard professional medical advice or delay in seeking treatment based on the information contained on this site. You understand and agree that the service and any content or information contained on the site is provided on an ‘as is’ basis. You understand and agree that while efforts have been made to assure the accuracy of the information on this site, there is no guarantee that such information is accurate or up-to-date. You understand and agree that, except for information, products, or services clearly identified as being supplied by the site, the site does not operate, control, or endorse any information, products, or services on the internet, in any way.

In addition, access to this site constitutes acceptance and understanding of the following,

By accessing this system, you hereby acknowledge, consent, and agree to all listed provisions and consent to monitoring.

You understand and agree that any copyright laws pertaining to the ownership and reproduction of all data fall exclusively under Panamanian legal jurisdiction for drfarrahcancercenter.com

If you are a copyright holder, or a director, officer, owner, employee, agent, supplier, licensor, contributor, service provider, website hosting company, trade partner, heir or assign of a copyright holder and feel that you or anyone you are engaged in any form of relationship whatsoever may have rights to data as part of this site or related sites, your agreement with the terms of use constitutes the following agreement, which is mandatory in order to access the data contained on this site.

I do hereby declare, understand, agree and warrant that I am a copyright owner, or an authorized representative of a copyright owner of film, print, slide, movie, video, artwork, digital image, negatives or any other material in any format whatsoever (hereafter referred to as “COPYRIGHTED DATA”) which I believe to be, known to be, or suspect to be contained on the drfarrahcancercenter.com website.

I hereby freely grant a non-exclusive license to drfarrahcancercenter.com and its agents to reproduce these COPYRIGHT DATA in perpetuity, and I represent and warrant that I have the legal right and authority to grant such a license. I may at my discretion ask to be credited for my contribution or the contributor I represent to the drfarrahcancercenter.com site as a contributor whether this occurred with or without my knowledge, but even if I or the contributor I represent remains uncredited, this agreement shall survive since participation in the free flowing of information for the public at large is a paramount responsibility we all should share. Therefore, in the best interest of free-flowing information for the public at large, I am freely undertaking this agreement, and clearly warrant that I have the authority to do so. I agree to indemnify and hold harmless drfarrahcancercenter.com and any of its directors, officers, owners, employees, agents, suppliers, licensors, contributors, service providers, website hosting companies, trade partners, heirs and assigns from any and all liability, damages, and expenses (including reasonable actual attorney’s fees) that may incur as a result of use and publication of said material, including any claims brought by any person claiming an interest in the COPYRIGHTED DATA or their subject matter. I agree and warrant that anyone containing any format of data from drfarrahcancercenter.com contained in any medium outside of the drfarrahcancercenter.com website itself, is bound by this agreement, since acceptance of this agreement is the only way to legally access such data. In addition, I understand and agree that accessing or storing any format of data contained in any medium outside of the drfarrahcancercenter.com website where it is hosted, constitutes a violation of the copyright laws of Panama against the offending party. I understand and agree that if I copy, contain, possess, or transmit any such data from the drfarrahcancercenter.com site in any format outside of the website itself, that my possession of such materials is a violation of Panamanian laws, and I agree to destroy such data forthwith.

 

SECTION 3 – ACCURACY, COMPLETENESS AND TIMELINESS OF INFORMATION

We are not responsible if information made available on this site is not accurate, complete or current. The material on this site is provided for general information only and should not be relied upon or used as the sole basis for making decisions without consulting primary, more accurate, more complete or more timely sources of information. Any reliance on the material on this site is at your own risk.

This site may contain certain historical information. Historical information, necessarily, is not current and is provided for your reference only. We reserve the right to modify the contents of this site at any time, but we have no obligation to update any information on our site. You agree that it is your responsibility to monitor changes to our site.

 

SECTION 4 – MODIFICATIONS TO THE SERVICE

We reserve the right at any time to modify or discontinue the Service (or any part or content thereof) without notice at any time.

We shall not be liable to you or to any third-party for any modification, change, suspension or discontinuance of the Service.

 

SECTION 5 – OPTIONAL TOOLS

Any use by you of optional tools offered through the site is entirely at your own risk and discretion and you should ensure that you are familiar with and approve of the terms on which tools are provided by the relevant third-party provider(s).

We may also, in the future, offer new services and/or features through the website (including, the release of new tools and resources). Such new features and/or services shall also be subject to these Terms of Use.

 

SECTION 6 – THIRD-PARTY LINKS

Certain content, products and services available via our Service may include materials from third-parties.

Third-party links on this site may direct you to third-party websites that are not affiliated with us. We are not responsible for examining or evaluating the content or accuracy and we do not warrant and will not have any liability or responsibility for any third-party materials or websites, or for any other materials, products, or services of third-parties.

We are not liable for any harm or damages related to the purchase or use of goods, services, resources, content, or any other transactions made in connection with any third-party websites. Please review carefully the third-party’s policies and practices and make sure you understand them before you engage in any transaction. Complaints, claims, concerns, or questions regarding third-party products should be directed to the third-party.

 

SECTION 7 – USER COMMENTS, FEEDBACK AND OTHER SUBMISSIONS

If, at our request, you send certain specific submissions (for example contest entries) or without a request from us you send creative ideas, suggestions, proposals, plans, or other materials, whether online, by email, by postal mail, or otherwise (collectively, ‘comments’), you agree that we may, at any time, without restriction, edit, copy, publish, distribute, translate and otherwise use in any medium any comments that you forward to us. We are and shall be under no obligation (1) to maintain any comments in confidence; (2) to pay compensation for any comments; or (3) to respond to any comments.

We may, but have no obligation to, monitor, edit or remove content that we determine in our sole discretion are unlawful, offensive, threatening, libelous, defamatory, pornographic, obscene or otherwise objectionable or violates any party’s intellectual property or these Terms of Use.

You agree that your comments will not violate any right of any third-party, including copyright, trademark, privacy, personality or other personal or proprietary right. You further agree that your comments will not contain libelous or otherwise unlawful, abusive or obscene material, or contain any computer virus or other malware that could in any way affect the operation of the Service or any related website. You may not use a false e-mail address, pretend to be someone other than yourself, or otherwise mislead us or third-parties as to the origin of any comments. You are solely responsible for any comments you make and their accuracy. We take no responsibility and assume no liability for any comments posted by you or any third-party.

 

SECTION 8 – ERRORS, INACCURACIES AND OMISSIONS

Occasionally there may be information on our site or in the Service that contains typographical errors, inaccuracies or omissions that may relate to product descriptions, pricing, promotions, offers, product shipping charges, transit times and availability. We reserve the right to correct any errors, inaccuracies or omissions, and to change or update information or cancel orders if any information in the Service or on any related website is inaccurate at any time without prior notice (including after you have submitted your order).

We undertake no obligation to update, amend or clarify information in the Service or on any related website, including without limitation, pricing information, except as required by law. No specified update or refresh date applied in the Service or on any related website, should be taken to indicate that all information in the Service or on any related website has been modified or updated.

 

SECTION 9 – PROHIBITED USES

In addition to other prohibitions as set forth in the Terms of Use, you are prohibited from using the site or its content: (a) for any unlawful purpose; (b) to solicit others to perform or participate in any unlawful acts; (c) to violate any international, federal, provincial or state regulations, rules, laws, or local ordinances; (d) to infringe upon or violate our intellectual property rights or the intellectual property rights of others; (e) to harass, abuse, insult, harm, defame, slander, disparage, intimidate, or discriminate based on gender, sexual orientation, religion, ethnicity, race, age, national origin, or disability; (f) to submit false or misleading information; (g) to upload or transmit viruses or any other type of malicious code that will or may be used in any way that will affect the functionality or operation of the Service or of any related website, other websites, or the Internet; (h) to collect or track the personal information of others; (i) to spam, phish, pharm, pretext, spider, crawl, or scrape; (j) for any obscene or immoral purpose; or (k) to interfere with or circumvent the security features of the Service or any related website, other websites, or the Internet. We reserve the right to terminate your use of the Service or any related website for violating any of the prohibited uses.

 

SECTION 10 – DISCLAIMER OF WARRANTIES; LIMITATION OF LIABILITY

We do not guarantee, represent or warrant that your use of our service will be uninterrupted, timely, secure or error-free.

We do not warrant that the results that may be obtained from the use of the service will be accurate or reliable.

You agree that from time to time we may remove the service for indefinite periods of time or cancel the service at any time, without notice to you.

You expressly agree that your use of, or inability to use, the service is at your sole risk. The service and all products and services delivered to you through the service are (except as expressly stated by us) provided ‘as is’ and ‘as available’ for your use, without any representation, warranties or conditions of any kind, either express or implied, including all implied warranties or conditions of merchantability, merchantable quality, fitness for a particular purpose, durability, title, and non-infringement.

In no case shall anyone affiliated with drfarrahcancercenter.com including our directors, officers, employees, affiliates, agents, contractors, interns, suppliers, service providers or licensors be liable for any injury, loss, claim, or any direct, indirect, incidental, punitive, special, or consequential damages of any kind, including, without limitation lost profits, lost revenue, lost savings, loss of data, replacement costs, or any similar damages, whether based in contract, tort (including negligence), strict liability or otherwise, arising from your use of any of the service or any products procured using the service, or for any other claim related in any way to your use of the service or any product, including, but not limited to, any errors or omissions in any content, or any loss or damage of any kind incurred as a result of the use of the service or any content (or product) posted, transmitted, or otherwise made available via the service, even if advised of their possibility. Because some states or jurisdictions do not allow the exclusion or the limitation of liability for consequential or incidental damages, in such states or jurisdictions, our liability shall be limited to the maximum extent permitted by law.

You understand and agree that no singular individual, group of individuals or entity in any form whatsoever is responsible or liable in any manner for any content generated on, for, or as a result of the existence of this site, since this is a community generated site. You understand and agree that as this is a community generated site, and as a result of this, there is no good way to control what users and contributors post on or through the sites and drfarrahcancercenter.com cannot be responsible for any offensive, inappropriate, obscene, unlawful, infringing or otherwise objectionable or even illegal user generated content you may encounter on the sites or, in connection with your use of the sites.

You understand and agree with the following statement made on behalf of drfarrahcancercenter.com, “We, on behalf of our directors, officers, employees, agents, suppliers, licensors, contributors and service providers, exclude and disclaim liability for any losses and expenses of whatever nature and howsoever arising including, without limitation, any direct, indirect, general, special, punitive, incidental or consequential damages; loss of use: loss of data; loss caused by a virus: loss of income or profit: loss of or damage to property: loss of life: claims of third parties: or other losses of any kind or character, or the inability to use, the site or the content even if we have been advised of the possibility of such damages or losses, arising out of or in connection with the use of this site or any web site with which it is linked.”

 

SECTION 11 – INDEMNIFICATION

You agree to indemnify, defend and hold harmless drfarrahcancercenter.com and our parent, subsidiaries, affiliates, partners, officers, directors, agents, contractors, licensors, service providers, subcontractors, suppliers, interns and employees, harmless from any claim or demand, including reasonable attorneys’ fees, made by any third-party due to or arising out of your breach of these Terms of Use or the documents they incorporate by reference, or your violation of any law or the rights of a third-party.

 

SECTION 12 – SEVERABILITY

In the event that any provision of these Terms of Use is determined to be unlawful, void or unenforceable, such provision shall nonetheless be enforceable to the fullest extent permitted by applicable law, and the unenforceable portion shall be deemed to be severed from these Terms of Use, such determination shall not affect the validity and enforceability of any other remaining provisions.

 

SECTION 13 – TERMINATION

The obligations and liabilities of the parties incurred prior to the termination date shall survive the termination of this agreement for all purposes.

These Terms of Use are effective unless and until terminated by us. You may terminate use of the drfarrahcancercenter.com site, but this Terms of Use shall survive in perpetuity.

If in our sole judgment you fail, or we suspect that you have failed, to comply with any term or provision of these Terms of Use, we also may terminate this agreement at any time without notice and you will remain liable for all amounts due up to and including the date of termination; and/or accordingly may deny you access to our Services (or any part thereof).

 

SECTION 14 – ENTIRE AGREEMENT

The failure of us to exercise or enforce any right or provision of these Terms of Use shall not constitute a waiver of such right or provision.

These Terms of Use and any policies or operating rules posted by us on this site or in respect to The Service constitutes the entire agreement and understanding between you and us and govern your use of the Service, superseding any prior or contemporaneous agreements, communications and proposals, whether oral or written, between you and us (including, but not limited to, any prior versions of the Terms of Use).

Any ambiguities in the interpretation of these Terms of Use shall not be construed against the drafting party.

 

SECTION 15 – GOVERNING LAW

These Terms of Use and any separate agreements whereby we provide you Services shall be governed by and construed in accordance with the laws of the Republic of Panama.

 

SECTION 16 – CHANGES TO TERMS OF USE

You can review the most current version of the Terms of Use at any time at this page.

We reserve the right, at our sole discretion, to update, change or replace any part of these Terms of Use by posting updates and changes to our website. It is your responsibility to check our website periodically for changes. Your continued use of or access to our website or the Service following the posting of any changes to these Terms of Use constitutes acceptance of those changes.

 

SECTION 17 – CONTACT INFORMATION

Questions about the Terms of Use should be sent to us at staff@drfarrahcancercenter.com

Upon agreeing to these terms and conditions, you gain access to the drfarrahcancercenter.com website and assume total responsibility for any and all actions undertaken by you as a result of your access to the drfarrahcancercenter.com website. You agree and understand that the terms of this agreement shall be binding upon you, your respective heirs, successors, assigns and legal representatives. You understand and agree that all provisions of this Terms of Use agreement that by their nature should survive termination shall survive termination, including, without limitation, ownership provisions, warranty disclaimers, indemnity, licensing in perpetuity and limitations of liability.