Holistic cancer causes—the story continues.
My previous post focused on
Mitochondria
What is the meaning of life? Not from a spiritual perspective. Not from a psychological perspective, but rather, from a biochemistry perspective? Life is about energy—the energy to heal, energy to repair, energy to fight infection, and the energy to grow. The capacity to produce energy is at the core of whether life exists or not. A body that can make energy efficiently can do all the things that are required to survive and thrive. A body that can not produce energy does not thrive and does not survive. That same applies to the cell. After all, the body is estimated to contain 3.72 × 10(13) number of cells [i]. That is 3,720,000,000,000,000 or 3.72 quadrillion. But who is counting? More, a cell that cannot make energy, cannot survive, cannot thrive and is targeted for destruction and recycling through the normal biochemical processes of apoptosis and autophagy.
Mitochondria are at the core of this biochemical life perspective. Mitochondria are the energy powerhouses of the cell. Mitochondria exist within every cell because every cell requires energy production to perform the day to day tasks necessary to survive. They must co-exist. Without mitochondria, there is no sustainable capacity for a cell to make energy. The energy production pathways of glycolysis, the Krebs cycle, and the electron transport chain are the energy production pathway forward within every mitochondrion for the benefit for cell survival.
The question is, which came first, the chicken or the egg? Does mitochondrial dysfunction initiate cancer, or does the process of cancer initiate mitochondrial dysfunction? As in most cases, the answer is yes. Yes, mitochondrial dysfunction is involved in the genesis of cancer, and yes, cancer is involved in the genesis of mitochondrial dysfunction. Both are proven true [ii]. They are not independently true, but they are simultaneously true. The process of the biochemistry of cancer can no longer be viewed through a linear, one-dimensional sequence of events. That thinking is compartmentalization. That thinking is the modus operandi of conventional medicine. That thinking is not holistic.
The scientific literature leaves little evidence for any other conclusion, but that cancer is the result of poor adaptation to metabolic stress in an attempt to survive. I want you to look at cancer in a different light. Cancer is the body’s very attempt to adapt, though this is a very poor attempt to adapt to an inhospitable environment for survival. In the short-term, this adaptation equals survival. It is good. It equals life. In the long-term, this adaptation equals unregulated survival. It is bad. It can lead to cancer. Energy production is at the core of the survival of the healthy cell or the cancer cell. It is the mitochondrial defects so often found in cancer that are more often the result of massive metabolic dysfunction that, again, is the result of the cell’s attempt to survive.
Metabolic dysfunction
“Complexity is the prodigy of the world. Simplicity is the sensation of the universe. Behind complexity, there is always simplicity to be revealed. Inside simplicity, there is always complexity to be discovered.”
Gang Yu
Cancer is a complex metabolic disease. As simple as this statement is to write, it does nothing to reveal the complexity that is cancer metabolism. Numerous research and medical journal publications have been published on this very topic. Even the top researcher on the subject, Dr. Thomas Seyfried entitled his 2010 paper and his 2012 book, Cancer as a Metabolic Disease [iii]. As prominent as these recent publications are, it all began with Dr. Otto
Warburg and his description of the aerobic glycolysis metabolism of cancer in the article, On the Origins of Cancer [iv], in 1956. His identification and description of this aerobic glycolysis effect justly bears his name— “Warburg effect.”
Dr. Warburg first described the complexity of the metabolic changes in cancer in the simple as aerobic glycolysis. To better understand aerobic glycolysis, let’s take a stroll down the biochemistry memory lane. All cells must make energy to survive. The currency of energy in the body is Adenosine Triphosphate (ATP). That is the simple inside the complex.
The complex is the cell’s complete pathway for energy production, which includes three seperate yet connected pathways: glycolysis, the Krebs cycle, and the electron transport chain. Energy production can begin with glucose, amino acids, or fats, but glucose is the most readily available and preferred source. The glycolysis pathway uses glucose as its sole source for energy production. In contrast, the Krebs cycle and the electron transport chain can use amino acids and fats, in addition to glucose, as additional sources for energy production. It is this diversity of energy substrate (glucose, amino acids, and fats) that gives cells the flexibility to adapt to energy source supply deficiencies. Cancers lack this flexibility, which should be a target for therapy.
Aerobic glycolysis is the cancer cell’s use of glucose in the energy pathway of glycolysis under aerobic conditions. The energy yield from glucose in glycolysis is lower (8 molecules of ATP under aerobic conditions and only 2 under anaerobic conditions) than if through the entire pathway (38 molecules of ATP). In perspective, glycolysis is a more inefficient process versus the more efficient combination of glycolysis-Krebs cycle-electron transport chain. The problem is that this takes more time and creates more oxidative stress. The use of glycolysis by cancer cells in the mismatched aerobic environment on face value is somewhat of a paradox. Glycolysis should dominate in the presence of a low oxygen (anaerobic) environment, instead of the oxygen-rich (aerobic) environment. Though anaerobic conditions favor glycolysis, glycolysis can operate under both conditions. It is this paradox that is called aerobic glycolysis.
An oxygen-rich environment favors the more efficient energy pathway of oxidative phosphorylation (Krebs cycle and the electron transport chain). In cancer, the low oxygen state of hypoxia favors the inefficient yet faster energy production time. In a way, cancer sacrifices efficiency for the speed of energy production to meet the high energy demand of the rapidly growing cancer.
The paradoxical state of cancer cell metabolism, aerobic glycolysis, has been the debated dogma of cancer cell metabolism since its first description by Dr. Otto Warburg. This debate is the simple truth that lies behind the more complex statement that cancer loves sugar. As in so many things, the story does not end there—it is too simple. Some cancer types (breast cancer, Hodgkin’s lymphoma, B-cell Lymphoma, Leukemias) don’t utilize the Warburg effect, but instead, use oxidative phosphorylation [v]. Then there is Cancer Stem Cells (CSC). Cancer Stem Cells can use the building blocks of protein, amino acids, to drive energy production via the efficient oxidative phosphorylation metabolism pathway of energy production [vi]. This amino acid driven oxidative phosphorylation is the predominant cell metabolism in leukemia, brain, breast, and pancreatic cancer CSCs. Some cancer, i.e., triple-negative breast cancer, types just prefer oxidative phosphorylation rather than Otto Warburg’s described anaerobic glycolysis [vii]. I’ll take it one step further; cancer can even alter fat metabolism to support survival and spread [viii]. The simple of cancer cell metabolism is that it is complicated.
Voltage
The body is energy. Don’t doubt me; just look at the evidence. Some of the more common tests that are found in medicine measure energy output. Take the electrocardiogram (EKG), for example. The inference is in the name—electro. The EKG measures the energy pattern output from the heart to look for damage to the heart in those individuals with a suspected or known heart attack. The electroencephalogram (EEG) measures the energy output from the brain to look for damage to the brain in those individuals with seizures. Even the basal body temperature (BBT) measures the heat output to determine thyroid function. Heat is the byproduct of energy production. Thus, it is the BBT that measures the energy output by the thyroid through heat. This begs the question, how can anyone question energy medicine? Medicine is the study and application of energy.
The cell is essentially a battery with stored energy potential. The energy potential is used for the cells to process its day to day activities that are required to heal, survive, and thrive. A cell without energy potential is a cell that will not heal and will die. This battery power potential of the cell is stored in the polarization of the cell membrane. It is important to remember that mitochondria are the energy powerhouses of the cell. The mitochondrial membrane polarization maintains and supports the outer cell membrane polarization. The loss of either will result in the loss of polarization, loss of stored energy potential, and as a result, the loss of healing potential.
How about a little more specifics on the matter of voltage? It is postulated by Dr. Jerry Tennant in his book Healing is Voltage that inflamed, damaged cells have an approximate voltage of -20 mV. This voltage is a state of low energy potential for healing. This state compares to an optimal voltage of -50 to -70 mV, which is a high stored energy potential for healing. What about cancer? As one might expect, cancer is just the opposite. The typical voltage of cancer is + 20 mV and higher. This voltage is a state of little to no stored energy potential. Simply stated, the battery has no juice. The result is the altered energy production so often evident in cancer. No energy equals no healing.
Vitamin C is the perfect example of the simple (vitamin C) in the treatment of the complex (energy metabolism of cancer). Just look at the effect of vitamin C on the membrane potential of immune cells as the perfect example. Critically sick individuals, including cancer (particularly advanced cancer) and infections, i.e., pneumonia and sepsis, are low vitamin C statues in the body [ix] [x] [xi] [xii] [xiii]. In actuality, cancer and infections deplete the body of vitamin C. This has a significant negative impact on the cells (leukocytes, monocytes…) of the immune system. Research in sepsis has repeatedly shown low vitamin C status in patients with sepsis [xiv]. It is not a stretch to say that vitamin C depletion appears to play a role in immune cell paralysis and death through mitochondrial and cell membrane depolarization [xv] [xvi]. Vitamin C helps to maintain the mitochondrial membrane polarization, which maintains cell membrane polarization, which maintains immune cell function [xvii]. Vitamin C restoration is key to an optimal functioning immune system [xviii] [xix] [xx]. Vitamin C depletion results in immune cell death, suppression of the function of the immune cells, the immune system as a whole, and immune system paralysis—the perfect set up for cancer, sepsis, and pneumonia. If you want an optimally functioning immune system, vitamin C should be the first addition to any treatment program to help restore optimal immune function. That is the evidence.
Acid/Base balance
Most have heard that there is a link between an acid environment and cancer. The concept is true, but this is an overgeneralization and is not accurate. The entire body cannot be acidic; an acidic body cannot co-exist with life. The concept of an acidic environment and cancer does apply to microenvironment around the growing tumor, called the Tumor Microenvironment (TME). Why is this possible, and why is this important? The cause, interestingly enough, is the altered metabolism so often described and found in cancer—aerobic glycolysis, which was first described by Dr. Otto Warburg in 1957 and reviewed above.
The acid environment is localized to the Tumor Microenvironment because it is the result of the altered of hypoxia and cellular metabolism of cancer. The result is an epigenetic modification to increase HIF-1alpha, which increases lactate dehydrogenase activity through the up-regulation of the pyruvate dehydrogenase kinase enzymes [xxi] [xxii] [xxiii]. The result is an increase in the production of lactic acid by the cancer cells. Oversimplified, but the basics are correct. It is important to remember that cancer is the epigenetic response to an inhospitable toxic environment. The simple is that anaerobic glycolysis increases lactic acid production by the cancer cells of the tumor. Cancer cells then pump the lactic acid outside the cell into the surrounding tumor environment, which creates an acidic environment in the TME. This acidic TME establishes a buffer zone that protects the growing tumor and its local environment from the immune system. Cancer is a series of effects that ripple through the body metabolically.
Not all cancer survives and thrives on the Warburg effect alone. In addition to the reliance on glucose via aerobic glycolysis, cancer can use amino acids. The most abundant amino acid in the body, glutamine stimulates cancer growth and spread [xxiv] [xxv] [xxvi]. In fact, it can be said that cancer cannot exist without a source of glutamine as much as it cannot exist without glucose. The well known and often over-supplemented, branched-chain amino acids (valine, leucine, iso-leucine), stimulate cancer growth and spread [xxvii] [xxviii] [xxix]. Even what appears to be the holy grail of nutrition intervention for cancer, fats or lipids, can support the altered energy pathways of cancer . Research links fats as a way to meet the high energy demand of cancer cell replication and contribute to the growth of liver cancer [xxx]. It can no longer be said that cancer relies only on glucose. Certainly, the high protein and high fat dietary crazes of today do not help to eliminate cancer’s ability to survive, but, in fact, may unintentionally support the growth and survival of cancer through altered energy pathways.
Then there are the back-ups that nobody wants any part of—cancer stem cells. Research points to cancer stem cells’ unique ability to use amino acids and proteins via oxidative phosphorylation and not the aerobic glycolysis described by the Warburg effect. This difference highlights the metabolism uniqueness of cancer cells without stem activity and cancer cells with stem activity. There is even the “reverse Warburg effect”, but there is so little time.
Alkalinity is important in the fight against cancer. However, the alkalinity of the TME is the target, not the body as a whole. One cannot alkalinize the entire body. Like acidity, this is unsustainable. The body works to buffer the extremes to maintain homeostasis. It is in the TME that this debate applies and rages.
[i] Bianconi E, Piovesan A, Facchin F, et al. An estimation of the number of cells in the human body [published correction appears in Ann Hum Biol. 2013 Nov-Dec;40(6):471]. Ann Hum Biol. 2013;40(6):463-471. doi:10.3109/03014460.2013.807878
[ii] Senyilmaz D, Teleman AA. Chicken or the egg: Warburg effect and mitochondrial dysfunction. F1000Prime Rep. 2015;7:41. Published 2015 Apr 2. doi:10.12703/P7-41
[iii] Seyfried, T.N., Shelton, L.M. Cancer as a metabolic disease. Nutr Metab (Lond) 7, 7 (2010). https://doi.org/10.1186/1743-7075-7-7
[iv] Warburg O. On the Origins of Cancer Cells. Science. Feb 1956;123(3191):309-314.
[v] Ashton TM, McKenna WG, Kunz-Schughart LA, Higgins GS. Oxidative Phosphorylation as an Emerging Target in Cancer Therapy. Clin Cancer Res. 2018;24(11):2482-2490. doi:10.1158/1078-0432.CCR-17-3070
[vi] Jones CL, Stevens BM, D’Alessandro A, et al. Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells [published correction appears in Cancer Cell. 2019 Feb 11;35(2):333-335]. Cancer Cell. 2018;34(5):724‐740.e4. doi:10.1016/j.ccell.2018.10.005
[vii] Lee KM, Giltnane JM, Balko JM, et al. MYC and MCL1 Cooperatively Promote Chemotherapy-Resistant Breast Cancer Stem Cells via Regulation of Mitochondrial Oxidative Phosphorylation. Cell Metab. 2017;26(4):633‐647.e7. doi:10.1016/j.cmet.2017.09.009
[viii] Munir, R., Lisec, J., Swinnen, J.V. et al. Lipid metabolism in cancer cells under metabolic stress. Br J Cancer 120, 1090–1098 (2019). https://doi.org/10.1038/s41416-019-0451-4
[ix] Maryland C, Bennett MI, Allan K. Vitamin C deficiency in cancer patients. Palliative Medicine. Feb 2005;19(1):17-20.
[x] Kuhn SO, Meissner K, Mayes LM, Bartels K. Vitamin C in sepsis. Curr Opin Anaesthesiol. 2018;31(1):55-60. doi:10.1097/ACO.0000000000000549
[xi] Hemilä H. Vitamin C and Infections. Nutrients. 2017;9(4):339. Published 2017 Mar 29. doi:10.3390/nu9040339
[xii] Vitamin C and Infection, Nutrition Reviews, Volume 1, Issue 7, May 1943, Pages 202–203, https://doi.org/10.1111/j.1753-4887.1943.tb08049.x
[xiii] Anthony H.M. and Schorah C.J. (1982) Severe hypovitaminosis C in lung-cancer patients: the utilization of vitamin C in surgical repair and lymphocyte-related host resistance. Br. J. Cancer 46, 354–367 10.1038/bjc.1982.211
[xiv] Fowler AA, Syed AA, Knowlson S, Sculthorpe R, Farthing D, DeWilde C, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014;12:32.
[xv] KC S, Cárcamo JM, Golde DW. Vitamin C enters mitochondria via facilitative glucose transporter 1 (Glut1) and confers mitochondrial protection against oxidative injury. FASEB J. 2005;19(12):1657-1667. doi:10.1096/fj.05-4107com
[xvi] Witenberg B, Kletter Y, Kalir HH, et al. Ascorbic acid inhibits apoptosis induced by X irradiation in HL60 myeloid leukemia cells. Radiat Res. 1999;152(5):468-478.
[xvii] KC S, Cárcamo JM, Golde DW. Vitamin C enters mitochondria via facilitative glucose transporter 1 (Glut1) and confers mitochondrial protection against oxidative injury. FASEB J. 2005;19(12):1657-1667. doi:10.1096/fj.05-4107com
[xviii] Ang A, Pullar JM, Currie MJ, Vissers MCM. Vitamin C and immune cell function in inflammation and cancer. Biochem Soc Trans. 2018;46(5):1147-1159. doi:10.1042/BST20180169
[xix] Carr AC, Maggini S. Vitamin C and Immune Function. Nutrients. 2017;9(11).
[xx] Mousavi S, Bereswill S, Heimesaat MM. Immunomodulatory and Antimicrobial Effects of Vitamin C. Eur J Microbiol Immunol (Bp). 2019;9(3):73-79. Published 2019 Aug 16. doi:10.1556/1886.2019.00016
[xxi] Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006;3(3):177-185. doi:10.1016/j.cmet.2006.02.002
[xxii] Miao P, Sheng S, Sun X, Liu J, Huang G. Lactate dehydrogenase A in cancer: a promising target for diagnosis and therapy. IUBMB Life. 2013;65(11):904-910. doi:10.1002/iub.1216
[xxiii] Jeoung NH. Pyruvate Dehydrogenase Kinases: Therapeutic Targets for Diabetes and Cancers. Diabetes Metab J. 2015;39(3):188-197. doi:10.4093/dmj.2015.39.3.188
[xxiv] Hensley CT, Wasti AT, DeBerardinis RJ. Glutamine and cancer: cell biology, physiology, and clinical opportunities. J Clin Invest. 2013;123(9):3678-3684. doi:10.1172/JCI69600
[xxv] Rajagopalan KN, DeBerardinis RJ. Role of glutamine in cancer: therapeutic and imaging implications. J Nucl Med. 2011;52(7):1005-1008. doi:10.2967/jnumed.110.084244
[xxvi] Long JP, Li XN, Zhang F. Targeting metabolism in breast cancer: How far we can go?. World J Clin Oncol. 2016;7(1):122-130. doi:10.5306/wjco.v7.i1.122
[xxvii] Ananieva EA, Wilkinson AC. Branched-chain amino acid metabolism in cancer. Curr Opin Clin Nutr Metab Care. 2018;21(1):64-70. doi:10.1097/MCO.0000000000000430
[xxviii] Lee, J.H., Cho, Y., Kim, J.H. et al. Branched-chain amino acids sustain pancreatic cancer growth by regulating lipid metabolism. Exp Mol Med 51, 1–11 (2019). https://doi.org/10.1038/s12276-019-0350-z
[xxix] Russell E. Ericksen et al. Loss of BCAA Catabolism during Carcinogenesis Enhances mTORC1 Activity and Promotes Tumor Development and Progression, Cell Metabolism (2019). DOI: 10.1016/j.cmet.2018.12.020
[xxx] Guri Y, Colombi M, Dazert E, et al. mTORC2 Promotes Tumorigenesis via Lipid Synthesis. Cancer Cell. 2017;32(6):807-823.e12. doi:10.1016/j.ccell.2017.11.011
