CANCER VS. KETO DIET
James Sloane
October 8, 2020
I was asked by a cancer patient to review some claims from a couple of cancer videos. Got through this one
Prof. Thomas Seyfried - 'Cancer as a Metabolic Disease: Implications for Novel Therapies'
https://youtube.com/watch?v=06e-PwhmSq8My response:
In the first video he is getting several things confused. First of all cancers are in fact genetic as they involve changes in the genes. This is not the same as being hereditary, which is a passing of genes.
He also refers to lactate and lactic acid several times throughout the video even though they are different things. Lactate is the non-acidic salt of lactic acid and is what is secreted by cancer cells, not lactic acid. In fact, lactic acid only survives a microsecond in the body before being converted in to lactate.
Cancer cells secrete non-acidic lactate, not lactic acid:
Tumor metabolism of lactate: the influence and therapeutic potential for MCT and CD147 regulation. Future Oncol 2010 Jan;6(1):127-48
Enzymes involved in L-lactate metabolism in humans. Mitochondrion 2013 Sep 9. pii: S1567-7249(13)00244-4
Tumor metabolism: cancer cells give and take lactate. J Clin Invest 2008 Dec;118(12):3835-7
Mitochondrial fission induces glycolytic reprogramming in cancer-associated myofibroblasts, driving stromal lactate production, and early tumor growth. Oncotarget 2012 Aug;3(8 ):798-810
He also brought up that asbestos does not cause mutations, which is somewhat true. It can lead to irritation and inflammation though and he later states that inflammation can lead to cancer. Although this still alone is not the cause of cancer. Virtually all cancers have been linked to viral infections. These viruses insert their genes in to our genes altering the way our genes function by turning off tumor suppressor genes, inhibiting apoptosis, increasing growth hormones, etc. Mesothelioma is often blamed on asbestos but studies have shown that mesothelioma is actually the result of the simian vacuole virus type 40 (SV40) with the asbestos being a co-factor.
It is interesting that in his one graph he shows viruses and a cause as well as the RAS oncogene, which again the cancer causing RAS oncogene is a viral oncogene. Yet he never really comes out and mentions the fact that virtually all cancers have been linked to viruses.
Then he gets in to Warburg but fails to mention the fact that some of Warburg’s hypotheses such as the hypothesis that cancer cells rely almost entirely on fermentation were disproven. In his graph he shows cancer cells using only 5% oxidative phosphorylation (OxPhos) for energy production. Actually studies have shown that around 50% of the cancer cells energy production comes from OxPhos, not 5%. And if glycolysis was the cause of cancer as he is implying then all cells would be cancerous as healthy cells like cancer cells use glycolysis followed by OxPhos for energy production.
Reliance of cancer cells on oxygen:
Oxygen Consumption Can Regulate the Growth of Tumors, a New Perspective on the Warburg Effect. PLoS One 2009 Sep 15;4(9):e7033
Choosing between glycolysis and oxidative phosphorylation: a tumor's dilemma? Biochim Biophys Acta 2011 Jun;1807(6):552-61
Comparison of Metabolic Pathways between Cancer Cells and Stromal Cells in Colorectal Carcinomas: a Metabolic Survival Role for Tumor-Associated Stroma. Cancer Res January 15, 2006 66;632
Akt Stimulates Aerobic Glycolysis in Cancer Cells. Cancer Res June 1, 2004 64; 3892
Cancer growth is inhibited by low oxygen levels an die in the absence of oxygen:
Oxygen consumption can regulate the growth of tumors, a new perspective on the Warburg effect. PLoS One 2009 Sep 15;4(9):e7033
Anoxia is necessary for tumor cell toxicity caused by a low-oxygen environment. Cancer Res 2005 Apr 15;65(8 ):3171-8
Relationship between oxygen and glucose consumption by transplanted tumors in vivo. Cancer Res 1967 Jun;27(6):1041-52
Death of cancer cells by lack of oxygen and angiogenesis stimulation to increase the growth rate of tumors by increasing oxygen levels to the tumor:
Computational models of VEGF-associated angiogenic processes in cancer. Math Med Biol 2012 Mar;29(1):85-94
Blood Flow, Oxygen Consumption, and Tissue Oxygenation of Human Breast Cancer Xenografts in **** Rats. Cancer Res 47, 3496-3503, July 1,1987
A Mathematical Model for the Diffusion of Tumour Angiogenesis Factor into the Surrounding Host. Tissue Math Med Biol (1991) 8 (3): 191-220
The History of Tumour Angiogenesis as a Therapeutic Target. University of Toronto Medical Journal Vol 87, No 1 (2009)
The higher affinity for oxygen by cancer cells than healthy cells:
Utilization of Oxygen by Transplanted Tumors in Vivo. Cancer Res 1967;27:1020-103
Growth-related changes of oxygen consumption rates of tumor cells grown in vitro and in vivo. J Cell Physiol 1989 Jan;138(1):183-91
The reason cancer cells have such a high affinity for oxygen and grow faster with higher oxygen levels is due to their high reliance of OxPhos for energy production, which is oxygen dependent. If cancer cells relied mainly on glycolysis then low oxygen levels would not inhibit growth of cancer cells.
He also claims carcinogens cause cancer, which is not quite true. Most carcinogens have been shown to activate cancer viruses that cause the cancer. For example, estrogen and progesterone are classified as carcinogens. Yet everyone has these hormones and not everyone has cancer. What these hormones do is to activate cancer viruses. Progesterone for example has been shown to activate cancer causing human papilloma viruses. And sunlight, which produces anti-cancer vitamin D has been shown in studies to activate cancer causing human papilloma viruses in the skin.
Then he makes reference to “inherited mutations”. First of all if these mutations were really inherited then that would again make these cancers genetic, not metabolic. Secondly, the mutations he mentions such as the BRCA mutations are not hereditary. These mutations are viral. Again viruses inserting their genes in to our genes altering the way our genes function. In this case inhibiting the tumor suppressor effects of the BRCA genes.
Then I see some contradictions in his claims about reactive oxygen species (ROS) being the byproduct of the mitochondrial damage. Numerous studies have shown that ROS is a cause of mitochondrial damage, not the byproduct. Regardless he is saying the ROS is not the cause of the cancer and that ROS also damages OxPhos, which is much higher in cancer cells than he claims. He is also overlooking the fact that ROS also kills cancer cells. This is the basis for radiation therapy and many chemotherapy drugs, which I addressed in a previous post, and is also the mechanism by which the body destroys cancer cells in the body when they can be detected.
He makes mention of cellular proliferation several times in the video. What he is overlooking is the fact that proliferation is not the same as cancer. Many cells can undergo excess proliferation such as benign tumors and psoriasis. Yet these are not cancer. And as with cancer cells these other cells are also highly reliant on sufficient oxygen for survival and growth. In fact, this is the main reason for angiogenesis, which is stimulated by the death of cancer cells from a lack of oxygen to begin with. The angiogenesis increases oxygen supply to the tumor allowing it to survive and grow faster.
He also claims apoptosis is controlled by the mitochondria, which I disagree with. Apoptosis is controlled by specific genes regulated by the BRCA genes, which get turned off by certain viruses.
I also disagree with much of what he says about metastases. The one part he got right is that cancer cells can metastasize by traveling through the bloodstream to other areas of the body. Although he is overlooking a lot. Metastases can also occur from things like biopsies or surgeries knocking cancer cells loose and spreading them around. This is common with surgery for example where cancer cells can get on the surgeon’s gloves or on surgical equipment then transferred elsewhere as the contaminated gloves and surgical equipment get moved around. So the doctor is like the Johnny Apple Seed of cancer cells. The cancer cells can also travel through the lymphatic system. And metastases also occurs in part from the acidic microenvironment that occurs immediately around the outside of malignant tumors during their later stages of growth when the export of acidic protons outside the cancer cells so that they can maintain their internal alkalinity to survive and to drive glycolysis exceeds the removal rate. This localized acidity activates proteolytic enzymes such as hyaluronidase breaking down hyaluronic acid that “cements” our cells together allowing the cancer cells to invade tissues.
I disagree with his macrophage hypothesis of metastases for a major reason. Cancer cells are in essence embryonic cells and as embryonic cells have developed means to avoid immune detection just like the fetus. One mechanism is through coatings of human chorionic gonadotropin (HCG), which also coats fetuses so they are not detected by the mother’s immune system and destroyed. This is why a single cancer cell in the body, which is an abnormal cell can multiply to form massive tumors without every being detected and destroyed by the immune system. So how are these macrophages (immune cells) supposedly finding these cancer cells when the cancer cells are generally shielded from the immune system? Furthermore, if this hypothesis was correct then we would see a clear difference between the original cancer cells and the “fused” metastasized cells. I have never seen any evidence of differences to support this hypothesis.
In addition, he keeps referring to the fuels, which he claims are glucose and glutamine. Again not quite true. It has been shown in various studies that cancer cells can use glucose, fructose, ketones, lactate, fatty acids various amino acids for fuel sources. This not only blows his fermentation hypothesis out of the water but also his recommendation of increasing ketones, which being acidic also promote metastases.:
KETONES AND LACTATE “FUEL” TUMOR GROWTH AND METASTASIS
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3047616/"Ketones are a “super-fuel” for mitochondria, producing more energy than lactate and simultaneously decreasing oxygen consumption.15–17"
"So, just as ketones are a “super-fuel” under conditions of ischemia in the heart and in the brain, they could fulfill a similar function during tumorigenesis, as the hypoxic tumor exceeds its blood supply. Stromal ketone production could obviate the need for tumor angiogenesis. Once ketones are produced and released from stromal cells, they could then be re-utilized by epithelial cancer cells, where they could directly enter the TCA cycle, just like lactate. In this sense, ketones are a more powerful mitochondrial fuel, as compared with lactate."
"Similarly, acute fasting in rodent animal models is also sufficient to dramatically increase tumor growth.22Both of these experimental conditions (diabetes and fasting/starvation) are known to be highly ketogenic and, thus, are consistent with our current hypothesis that ketone production fuels tumor growth. Finally, given our current findings that ketones increase tumor growth, cancer patients and their dieticians may want to re-consider the use of a “ketogenic diet” as a form of anti-cancer therapy."
KETONE BODY UTILIZATION DRIVES TUMOR GROWTH AND METASTASIS
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507492/"Thus, the tumor stroma may serve as a reservoir for ketone body production, while cancer cells upregulate the enzymes required for ketone body re-utilization, driving oxidative mitochondrial metabolism (OXPHOS) in epithelial cancer cells (Fig. 9).
To prevent this form of “two-compartment tumor metabolism,” ketone inhibitors should be designed to halt ketone body production in cancer-associated fibroblasts and ketone body re-utilization in epithelial cancer cells. This simple strategy could effectively starve cancer cells to death by “cutting off their fuel supply.”
Finally, it is worth noting that ketogenic fibroblasts were more prone to a loss of stromal Cav-1 expression. In breast cancer patients, a loss of stromal Cav-1 expression is associated with increased tumor recurrence, metastasis, drug resistance and overall poor clinical outcome.10-13Thus, stromal Cav-1 could be used as a biomarker to select patients that would be more likely to benefit from therapy with ketone inhibitors, allowing biomarker-based treatment stratification and personalized cancer therapy."
KETONE BODIES AND TWO-COMPARTMENT TUMOR METABOLISM
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507491/"We have previously suggested that ketone body metabolism is critical for tumor progression and metastasis. Here, using a co-culture system employing human breast cancer cells (MCF7) and hTERT-immortalized fibroblasts, we provide new evidence to directly support this hypothesis. More specifically, we show that the enzymes required for ketone body production are highly upregulated within cancer-associated fibroblasts. This appears to be mechanistically controlled by the stromal expression of caveolin-1 (Cav-1) and/or serum starvation. In addition, treatment with ketone bodies (such as 3-hydroxy-butyrate, and/or butanediol) is sufficient to drive mitochondrial biogenesis in human breast cancer cells. This observation was also validated by unbiased proteomic analysis. Interestingly, an MCT1 inhibitor was sufficient to block the onset of mitochondrial biogenesis in human breast cancer cells, suggesting a possible avenue for anticancer therapy. Finally, using human breast cancer tumor samples, we directly confirmed that the enzymes associated with ketone body production (HMGCS2, HMGCL and BDH1) were preferentially expressed in the tumor stroma. Conversely, enzymes associated with ketone re-utilization (ACAT1) and mitochondrial biogenesis (HSP60) were selectively associated with the epithelial tumor cell compartment. Our current findings are consistent with the "two-compartment tumor metabolism" model. Furthermore, they suggest that we should target ketone body metabolism as a new area for drug discovery, for the prevention and treatment of human cancers."
He presents some studies that he claims proves that ketones help with cancer. I am not going to take the time to research each and every one. One did peak my interest though as it was the one he focused most on and implied the therapy he is promoting cured the patient, although he did also mention the patient had chemo and radiation therapy. So I looked up the study. Turns out that Seyfried left out the fact that the patient underwent surgery to remove the tumor after the chemo and radiation therapy and was given a variety of various other therapies including hyperbaric oxygen therapy, high dose vitamin D, EGCG, chloroquine, etc. In my opinion this entirely discredits this guy. Any real researcher would know that you cannot take a patient give them a dozen different treatments then just decide what you wish helped is what actually worked. Especially when the tumor was surgically removed after being treated with chemo and radiation therapy, which is a common practice to first reduce the tumor size before surgical removal. Here is a link to this full study:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884883/Again one study with multiple therapies does not support Seyfried’s claims that the ketogenic diet was responsible for a favorable response in this study. And they even state in the study that his favorable outcome could have been due to genetics when they wrote “We cannot, however, rule out the possibility that our patient’s tumor contained certain genes (IDH1 mutation, ATRX and 1p/19q deletion) that might have also contributed to his favorable response.”
So Seyfried is already being highly misleading, which makes me also question his claim that the patient died from necrosis 6 months after this report was written. If the radiation had been given before the tumor was surgically removed then the surgical removal of the remaining tumor would mean no further need for radiation therapy. This is where things get really confusing in this study and with his claim the patient died as a result of the radiation. So the study states that among other therapies. Including chemo and surgery, that the patient underwent 30 radiation treatments “without significant side effects or noticeable neurological deficits”. So no mention of the radiation necrosis that Seyfried claims the patient died from. Furthermore, the patient completed all of his radiation therapy after 20 months and the report was a follow up at 24 months and Seyfried claims the patient died at 30 months. So at best Seyfried is saying this patient died of radiation necrosis of the brain 10 months after his therapy ended and which they reported no significant side effects. I find this claim very fishy. If there was really radiation necrosis present it should have occurred at the time of the radiation therapy, which ended 10 months earlier and the necrosis would have led to severe edema of the brain with very visible side effects and likely death at that time, not 10 months down the line.
In addition, they first say in the study “The patient remains in good health with no noticeable clinical or neurological deficits (Karnofsky Score, 100%)”, which again would show a lack of radiation necrosis of the brain. And they mention his good health again in the study stating “The patient is now 40 years old and remains in excellent health with no noticeable neurological issues (Karnofsky Score, 100%) after 24 months of treatment.”. Although they also state “We suggest that the targeting of glucose and glutamine in a press-pulse therapeutic strategy together with a modified SOC could have contributed to the favorable outcome in this GBM patient despite evidence of postoperative residual tumor.”
Bottom line is what I see is a whole lot of guessing, just as much misrepresentation by Seyfried, no real proof of what the patient really died from with what appears to be a very bogus claim of the cause of death and despite the various therapies used including surgical removal of most of the tumor the patient apparently still had the tumor at the time of this study after 24 months of treatment. So which of the various treatments led to improvement? How much did genetics play a role?
And if the ketogenic diet really helps how come the tumor was still present even when the tumor was drastically reduced in size first with chemo, radiation and surgery? In my opinion the ketogenic diet appears to be a complete failure in this study as the study shows no regression that can be attributed to the diet and that with what little of the tumor was remaining to begin with after all the other therapies.
Management of Glioblastoma Multiforme in a Patient Treated With Ketogenic Metabolic Therapy and Modified Standard of Care: A 24-Month Follow-Up
NCBI.NLM.NIH.GOV
Management of Glioblastoma Multiforme in a Patient Treated With Ketogenic Metabolic Therapy and Modified Standard of Care: A 24-Month Follow-Up