Read this in: Nederlands🖨️ Print post
The theory of cancer has been shifting in recent years. According to the conventional theory, referred to as the “somatic mutation theory,” cancer results from DNA damage. After a sequence of mutations, the cells develop “oncogenes” (genetic material that carries the ability to induce cancer), which then lead to the typical behavior of cancer. This theory has gone largely unquestioned in mainstream circles for many years.
In 2006, the U.S. launched The Cancer Genome Atlas (TCGA) as part of the sixteen-nation International Cancer Genome Consortium.1 Funded to the tune of three hundred and seventy-five million dollars in the U.S., the endeavor mapped out all the genes in thousands of cancer cells to determine which mutations were connected to which cancers. The final goal was to develop targeted therapies to address specific mutations.
There was tremendous enthusiasm at the start of TCGA that it would finally lead to “the answer” to cancer treatment. Unfortunately, the results primarily created more confusion. As summarized in 2015 in the journal Nature, “most mutations formed a bewildering hodgepodge of genetic oddities, with little commonality between tumours.”1 Moreover, the Nature reporter observed, “cancers are often quick to become resistant, typically by activating different genes to bypass whatever cellular process is blocked by the treatment.”1 In other words, not only were there no consistent mutations connected to different types of cancer, but even when specific “targets” were found and drugs developed to block them, the cancer cells would often just bypass that process. This has led to the failure of many of the very expensive biologic or targeted therapies that have been developed.
With the genome project results having left the conventional somatic mutation theory in disarray, some people have concluded that cancer is “just too complicated” to figure out. Others, however, have been quietly elaborating other compelling theories of cancer, which offer hope of dispelling the confusion and leading to meaningful therapeutic alternatives.
THE WARBURG EFFECT
Otto Warburg’s work has been the focus of revived interest for some time. Starting in the 1930s, Warburg discovered one quality of cancer cells that seemed to be consistent across every cancer cell type that he examined. Detailed by Warburg in a 1956 paper published in Science2 and paraphrased more recently by Thomas Seyfried (author of Cancer as a Metabolic Disease3), the Warburg theory of cancer has four basic tenets: “Cancer arises from damage to cellular respiration; energy through fermentation gradually compensates for insufficient respiration; cancer cells continue to ferment lactate in the presence of oxygen; [and] enhanced fermentation is the signature metabolic malady of all cancer cells.”4 Although the conventional oncology world came to accept this property of cancer (now known as the “Warburg Effect”), it mainly saw it as an interesting quirk of most cancers—just something that cancer cells do as a result of the mutations. Warburg differed in making the radical statement that “damaged cellular respiration” and “energy through fermentation” defined cancer cells and how they originate.
Modern support for Warburg’s theory came out of some laboratory studies done at a couple of American universities in the late 1980s, which looked at cancer from a different, but related, perspective.5,6 Improved technologies allowed experiments to be carried out that Warburg could not do in his time. One experiment involved taking the nucleus from a cancer cell (containing the presumed cancer mutations) and transferring it to the cytoplasm of a healthy cell. This generally resulted in extinguishing the “tumorigenic phenotype,” meaning that the new cell behaved as a non-cancerous cell.7 The researchers then carried out the reverse, transferring the nucleus of a normal cell (with no mutations) to the cytoplasm of a cancer cell. This usually resulted in the cell behaving as a cancer cell. Thus, it seemed that whatever was going on in the cell nucleus had little bearing on the malignancy of the cell. So what was the deciding factor?
Further work done with the help of electron microscopy made it possible to look at the internal structures of cells. Researchers found that cancer cells had fewer mitochondria, and the mitochondria had abnormal internal architecture. 8,9,10 This observation structurally supported Warburg’s theory. Because the mitochondria are the location of the primary metabolic (energy-producing) activity of a cell, the impaired and malfunctioning mitochondria reflected the damaged cellular respiration on a biochemical level that Warburg had discovered years before.
MITOCHONDRIAL DAMAGE AND CANCER
How does mitochondrial damage lead to cancer? A paper published in 2005 in the journal Medical Hypotheses (before the cancer genome project had even begun) concluded that signaling pathways from dysfunctional mitochondria to the nucleus could affect cellular metabolism, proliferation, tumor progression, metastasis and resistance to apoptosis (programmed cell death).11 Thomas Seyfried, PhD, contributed much to dissecting and understanding these mechanisms. In a 2010 paper in the journal Nutrition and Metabolism, Seyfried and his coauthor concluded: “Emerging evidence indicates that impaired cellular energy metabolism is the defining characteristic of nearly all cancers regardless of cellular or tissue origin.”12 The general hypothesis that Seyfried put forth in the paper was that “genomic instability and essentially all hallmarks of cancer, including aerobic glycolysis (Warburg effect), can be linked to impaired mitochondrial function and energy metabolism.”12
As far back as 1986, The New England Journal of Medicine published a paper that described another piece of the cancer puzzle. Titled “Tumors: wounds that do not heal,”13 the paper argued that cancer behaves much like a healing wound, activating many of the same cellular mechanisms such as inflammation, growth factors, enzymes and angiogenic (formation of new blood vessels) factors. In contrast to a normal wound, however, cancer “healing” is never completed, and the process just continues autonomously.
If we try to assemble all this information into one picture, we can see a process of initial damage to mitochondria, which can result from any of the known cancer risk factors such as oxidative stress, hypoxia, radiation and certain infectious agents. The mitochondria then give out signals to the nucleus to activate genes in an attempt to repair the damage. (This process of mitochondrial signaling, known as “retrograde regulation,” is broadly defined as “cellular responses to alterations in [the] functional state of mitochondria.”11)
Next, a concurrent shift in metabolism takes place—where the normal oxidative phosphorylation (the process in which ATP [energy] is formed) occurring in the mitochondria is primarily replaced by glycolysis (generation of energy from glucose) in the cytoplasm—accomplishing at least two goals. The first is to have an alternative energy source to replace the damaged metabolism. However, glycolysis is a much less efficient method of energy production than oxidative phosphorylation; only a fraction of the ATP that is normally generated by the mitochondria per molecule of glucose is produced from glycolysis. Thus, a much larger supply of glucose is needed to meet the energy requirements. Secondly, this enhanced glycolysis provides material for production of nucleic acids needed for increased cell division (through something called the “pentose phosphate shunt”).
Mitochondria are, in addition, responsible for regulating apoptosis. When a cell is sufficiently damaged, signals from the mitochondria will normally direct them to self-destruct. With further damage, however, the mitochondria will eventually lose or skip this role, in effect creating “immortal” cells—another defining quality of cancer.
In the end, in an attempt to save itself, the cell turns on emergency responses to reestablish healthy functioning. Ordinarily, the emergency response should only be temporary, but the cancer cell becomes autonomous and, instead of contributing to the well-being of the body, is only concerned with its own survival at the body’s expense.
Another developing theory of cancer is the cancer stem cell (CSC) theory. This theory states that in cancer, some cells are unable to initiate new tumors, while other cells (CSCs) are capable of initiating, promoting and spreading neoplastic growth. The latter are hard to kill, are generally not eliminated by conventional cytotoxic therapies and are responsible for cancer relapses. Cancer stem cells also tend to be more poorly differentiated, or primitive, in their functioning, which includes relying on the more primitive form of metabolism (glycolysis).14 So we may just be looking at another view of the results of disruption of the normal, more developed mitochondrial respiration and regression
How can these theories lead to new approaches in managing cancer? Because we have a consistent difference between the functions of healthy and cancer cells in this metabolic shift, there is the possibility of targeting this quality—what has been called cancer’s Achilles heel.
One direction is through diet. Given that cancer is dependent on a large supply of glucose, it is logical to try to reduce the supply. What has become popularly known as the “ketogenic diet for cancer” is an attempt to do just that, with encouraging initial results. The ketogenic diet is a diet low in carbohydrates and high in fats with moderate proteins. With the significant reduction in carbohydrates, the body will break down fats into ketones as a replacement energy source. However, because ketones are metabolized in the mitochondria, cancer cells—with their defective mitochondria—are not able to make use of this option to a significant degree. It also appears that increased ketones, in and of themselves and even without reduced glucose levels, have some inhibitory effect on cancer growth.
In laboratory and preclinical animal studies as well as case reports and small clinical trials, we are seeing improved outcomes, mainly when the ketogenic diet is used in combination with standard therapies. There are benefits in terms of reduced toxicity to healthy tissues from cytotoxic treatments and also in terms of improved tumor responses. This approach has been promising enough to warrant a number of clinical trials that combine the ketogenic diet with conventional treatments.
In addition to dietary modification, it is possible to target the amplified glycolysis pathways in cancer cells. A number of substances have been found to inhibit various enzymes in cancer metabolism and weaken or even kill cancer cells. A few have progressed through basic research, animal studies and small clinical trials. One of these substances is dichloroacetate (DCA), which is actually an old drug used for treating a rare metabolic disease in children. A review paper published in 2014 summarized the research, suggesting that DCA may induce “two fundamental changes in tumor metabolism.”15 First, the review noted an “anti-proliferative” effect whereby DCA “reverses” the Warburg effect by “redirect[ing] glucose metabolism from glycolysis to oxidation.” Second, the review described a “pro-apoptotic” effect, with DCA reestablishing apoptotic function of the mitochondria. Citing preclinical and small clinical trials, the authors suggest that DCA has “additive or synergistic effects when used in combination with standard agents.”15
The enzyme hexokinase-2 (HK2) is a key enzyme in glycolysis and is significantly overexpressed in cancer cells exhibiting the Warburg effect. Another substance recently attracting attention—3-bromopyruvate (3BP)—is a powerful blocker of this enzyme (and some others).16 Very positive initial results have been seen in animal studies and a couple of case reports.17 The main challenge at this point is how to most effectively get 3BP into the cancer cells. (The other challenge is getting the research funding to develop this treatment further.)
Methylglyoxal is an interesting molecule that has been looked at a number of times in the past half century or more. It is naturally produced in cells as a byproduct of metabolism. It also appears to be the main ingredient responsible for antibacterial effects in the popular Manuka honey. With regard to cancer, a review paper in 2008 indicated that methylglyoxal was an inhibitor, in cancer cells, of glyceraldehyde-3-phosphate dehydrogenase (a key enzyme in glycolysis) and mitochondrial complex I (one of the four complexes needed for mitochondrial energy production).18 Interestingly, methylglyoxal did not seem to inhibit mitochondrial complex I in healthy cells—another indicator of the altered function in cancer metabolism. Further, a three-phase study with eighty-six cancer patients showed benefits to most patients, including many complete remissions, and there was symptomatic improvement (“palliation”) even in the non-responders with progressive disease.18 Although some prior in vitro studies showed possible glycation-type toxicity, the 2008 paper reported an absence of harmful side effects in animal and human studies.18
Melatonin has shown many anticancer mechanisms in the past, with positive effects in a number of clinical trials.19 In addition to the mechanisms already identified, a recent paper described the use of melatonin in preclinical research for leiomyosarcoma (LMS), a highly malignant, soft tissue sarcoma.20 Summarizing their findings, the researchers stated, “These results demonstrate that nocturnal melatonin directly inhibited tumour growth and invasion of human LMS via suppression of the Warburg effect, LA [lactic acid] uptake and other related signalling mechanisms.”20 It may turn out that many other natural substances shown to be helpful in cancer management are, like melatonin, at least partly operating on the metabolism of the cancer cells.
An interesting clinical trial published in 2014 specifically addressed cancer metabolism.21 In prior work, the research team assessed a library of twenty-seven compounds known to affect glucose metabolism. Following in vitro testing, they narrowed the list down to seven combinations and tested the pairs to find the most effective combination, which they determined to be alpha-lipoic acid (α-LA) and hydroxycitrate (also known as garcinia).22
At this point, the researchers started a clinical trial with forty advanced cancer patients with a life expectancy of two to six months.21 A combination of the two identified compounds (α-LA and hydroxycitrate) were given along with low-dose naltrexone. One group received only the metabolic therapy and a second group additionally received chemotherapy. The one-year survival was approximately the same (68 to 70 percent) in both groups. This study supported the potential of metabolic therapy, which hopefully can be further enhanced by combinations with other promising substances.
Even though I think that a metabolic approach is improving quality of life and even length of life in many cancer patients (including some long-term survivors in complete remission), life is never that simple. We are still not close to where we want to be in terms of dealing with this disease, particularly for the majority of more advanced cancers. In addition, dietary carbohydrates are not the only way for cancer cells to get energy. The amino acid glutamine can be an alternate source through the analogous pathway of glutaminolysis. Glucose can also be produced through gluconeogenesis in the liver, a process “encouraged” by many cancers. So the challenge continues to find ways to cut off the methods that cancer cells can employ to bypass our interventions. This will likely require multipronged use of synergistic combinations while preempting anticipated escape pathways.
Of course, cancer prevention is the ideal. At this level, we need to rely on the well-established dietary principles of nutrient-dense and “clean” foods with low toxicity. The basics of dealing with oxidative stress, inflammation and immune balance can go a long way in protecting our precious mitochondria and preventing the consequences of neglecting them, including cancers. If the damage is already done, then we still need to employ the same basic dietary precautions. In addition, we can use metabolic-targeted approaches to assist in damage control, support elimination of irreparably dysfunctional cells and even, in certain circumstances, rehabilitate these wayward cells.
The Fall 2017 issue of Wise Traditions includes more articles and book reviews focusing on cancer (westonaprice.org/journal-fall-2017-cancer-issue/), including book reviews of Thomas Seyfried’s Cancer as a Metabolic Disease3 and The Metabolic Approach to Cancer: Integrating Deep Nutrition, the Ketogenic Diet, and Nontoxic Bio-Individualized Therapies by Nasha Winters and Jess Higgins Kelley.23
1. Ledford H. End of cancer-genome project prompts rethink. Nature 2015 Jan. 8;517:128-129.
2. Warburg O. On the origin of cancer cells. Science 1956;123(3191):309-314.
3. Seyfried TN. Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer. Hoboken, NJ: Wiley; 2012.
4. Seyfried TN. “Cancer: a metabolic disease with metabolic solutions” (slide #7). Boston College, n.d. http://dose-response.org/wp-content/uploads/2015/05/Seyfried.pdf.
5. Israel BA, Schaeffer WI. Cytoplasmic suppression of malignancy. In Vitro Cell Dev Biol 1987;23(9):627-632.
6. Israel BA, Schaeffer WI. Cytoplasmic mediation of malignancy. In Vitro Cell Dev Biol 1988;24(5):487-490.
7. Shay JW, Werbin H. Cytoplasmic suppression of tumorigenicity in reconstructed mouse cells. Cancer Res 1988;48(4):830-833.
8. Pedersen PL. Tumor mitochondria and the bioenergetics of cancer cells. Prog Exp Tumor Res 1978;22:190-274.
9. Mathupala SP, Ko YH, Pedersen PL. The pivotal roles of mitochondria in cancer: Warburg and beyond and encouraging prospects for effective therapies. Biochim Biophys Acta 2010;1797(6-7):1225-1230.
10. Ma Y, Bai RK, Trieu R, Wong LJ. Mitochondrial dysfunction in human breast cancer cells and their transmitochondrial cybrids. Biochim Biophys Acta 2010;1797(1):29-37.
11. Erol A. Retrograde regulation due to mitochondrial dysfunction may be an important mechanism for carcinogenesis. Med Hypotheses 2005;65(3)525-529.
12. Seyfried TN, Shelton LM. Cancer as a metabolic disease. Nutr Metab (Lond) 2010;7:7.
13. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986;315(26):1650-1659.
14. Chae YC, Kim JH. Cancer stem cell metabolism: target for cancer therapy. BMB Rep 2018;51(7):319-326.
15. Kankotia S, Stacpoole PW. Dichloroacetate and cancer: new home for an orphan drug? Biochim Biophys Acta 2014;1846(2):617-629.
16. Pedersen PL. 3-Bromopyruvate (3BP) a fast acting, promising, powerful, specific, and effective “small molecule” anti-cancer agent taken from labside to bedside: introduction to a special issue. J Bioenerg Biomembr 2012;44(1):1-6.
17. Ko YH, Verhoeven HA, Lee MJ, Corbin DJ, Vogl TJ, Pedersen PL. A translational study “case report” on the small molecule “energy blocker” 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside. J Bioenerg Biomembr 2012;44(1):163-170.
18. Talukdar D, Ray S, Ray M, Das S. A brief critical overview of the biological effects of methylglyoxal and further evaluation of a methylglyoxal-based anticancer formulation in treating cancer patients. Drug Metabol Drug Interact 2008;23(1-2):175-210.
19. Wang YM, Jin BZ, Ai F, et al. The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials. Cancer Chemother Pharmacol 2012;69(5):1213-1220.
20. Mao L, Dauchy RT, Blask DE, et al. Melatonin suppression of aerobic glycolysis (Warburg effect), survival signaling and metastasis in human leiomyosarcoma. J Pineal Res 2016;60(2):167-177.
21. Schwartz L, Buhler L, Icard P, Lincet H, Summa MG, Steyaert JM. Metabolic cancer treatment: intermediate results of a clinical study. Cancer Therapy 2014;10:13-19.
22. Schwartz L, Buhler L, Icard P, Lincet H, Steyaert JM. Metabolic treatment of cancer: intermediate results of a prospective case series. Anticancer Res 2014;34(2):973-980.
23. Winters N, Kelley JH. The Metabolic Approach to Cancer: Integrating Deep Nutrition, the Ketogenic Diet, and Nontoxic Bio-Individualized Therapies. White River Junction, VT: Chelsea Green Publishing; 2017.
This article appeared in Wise Traditions in Food, Farming and the Healing Arts, the quarterly journal of the Weston A. Price Foundation, Winter 2018🖨️ Print post
Read this in: Nederlands