Cancer - A Pragmatic Switch to Combat Metabolic Syndrome?
John Claras
Independent Scientific Investigator
1262 Lawrence Station Road,
Sunnyvale CA 94089, USA
jclaras@onlinecables.com
ACKNOWLEDGEMENTS
I wish to thank Michael Klüppel, PhD, of MKPhD Scientific Consulting, for editing and proofreading, as well as helpful scientific discussions and advice during the preparation of this manuscript. Without his help the publication of the paper would not have been possible. Further wish to thank my Daughter, Kristina, BS BioEngineering, who contributed to this paper with her knowledge, wisdom, joyfulness of life and love.
Key words
cancer, metabolic syndrome, nutrition, switch,
The author declares no conflict of interest.
Let food be thy medicine and medicine be thy food. (Hippocrates)
When diet is wrong, medicine is of no use. When diet is correct, medicine is of no need. ~Ayurvedic proverb.
ABSTRACT
Both cancer and metabolic disease have become the prevalent health risks in modern societies worldwide. Cancer is a complex set of illnesses with many definitions. About 15% of cancers are caused by infections and 10% carry a hereditary burden. The remaining 70-75% cancers are associated with a variety of processes, often associated with metabolic syndrome and chronic inflammation. This review examines the role of metabolic dysfunction and chronic inflammation in cancer development. I propose a novel concept in which our intelligent body uses its sophisticated set of subsystems and sensors to pragmatically anticipate and combat metabolic dysfunction as its’ most direct and dire threat first, while temporarily accepting cancer as a state that in any other circumstances would be considered detrimental.
HYPOTHESIS
I hypothesize that our body is able to control the growth of some cancers in a pragmatic and bi-directional switch-like manner. Metabolic syndrome is the most immediate threat to the body’s short-term survival, and our body might induce, promote, or tolerate cancers as a mechanism to consume large amounts of blood glucose through the cancer’s Warburg effect in order to combat this metabolic threat. Conversely, this switch can be reversed to attempt to halt or reverse tumor growth after the metabolic pathology has been resolved. When utilizing this switch greatly depends on the nutritional status of a person: a constant high calorie and carbohydrate diet leads to chronic inflammation with the switch for cancer growth frozen in the on-state to consume as much glucose as possible to counteract the metabolic dysfunction. However, when metabolic dysfunction and chronic inflammation is resolved, for example through a modified diet, the switch for cancer growth is turned off and the body attempts to shut down cancer growth. Our body makes pragmatic and intelligent decisions that address immediate threats first and deals with potential long-term risks after the immediate threat has been eliminated. This review will ask several key questions: Why does a high-glucose diet suppress the immune system? Why does cancer almost always choses a highly inefficient energy metabolism? Why is cancer not contagious? Why does the body allow large blood supplies to the tumor? Why do large tumors suppress smaller tumors? Why to cancers take toxic glucose and turn it into nontoxic lactate without using toxic oxygen? Why cancers are so sensitive to a drop in glucose and normal cells are not? Why is there linear relationship between major cancers and calorie intake?
INTRODUCTION
Cancer is a major health concern in modern human society, with an estimated 600,000 deaths from cancer in 2020 [1]. Cancer progression utilizes several mechanisms, including oncogenic mutations to allow cancer cells to proliferate, expression of the CD-47 protein to defeat the immune system [2], initiate angiogenesis to ensure blood supply, and to enable cell mobility cells to escape the primary tumor site and metastasize to distant organs.
Cancer cells also make a curious metabolic choice: cancer frequently does not utilize oxidative phosphorylation of glucose for energy production, but instead show dramatically increased uptake of glucose, and glycolysis of glucose into lactate, even in the presence of abundant oxygen (Warburg effect [3]).
But perhaps there is also another story: that, under certain conditions, cancer has a purpose. Our body, in the face of an immediate existential threat like metabolic syndrome, has an explicit interest to promote cancer cells to survive in order to pragmatically use the specialized cancer metabolism to combat excessive and toxic glucose levels when the body becomes insulin resistant. The interactions of an organism and cancer cells are complex - but several characteristics of these interactions might suggest that cancer growth is promoted in situations of metabolic syndrome, for example by suppression of the immune system, allowing a large blood supply to the tumor, and impairment of the growth of secondary tumors. Furthermore, the body can reverse this process of promoting cancer growth as soon as the metabolic emergency has been resolved, as cancer cannot survive in a low glucose environment unlike normal cells. I propose that our body uses levels of chronic inflammation as a switch to pragmatically turn cancer growth on and off depending on the short-term survival needs for the organism.
Metabolic syndrome is one of the biggest medical problems in modern society [4]. Progression towards full blown metabolic syndrome is a decade-long process during which the body tries to keep metabolic dysfunction under control. However, with increasing insulin resistance blood sugar levels cannot be controlled anymore, and our body has reached a stage where this decade-long metabolic battle appears to have been lost [4]. In “A new link between diabetes and Cancer” [5] the authors state: ”Certain experimental cancers behave more aggressively when animals overeat, and less aggressively when animals are calorically restricted” and “Animals fed a calorie-restricted diet show a strong reduction in plasma glucose levels and prolonged survival. The direct effects of high glucose on tumor cells include increased proliferation and the wiring of the cancer associated signaling pathways.”. Another literature example is Wilhelm Brunigns’ contribution to the metabolic treatment of cancer utilizing hypoglycemia [6]: ”Ketogenic diets (KD) that are capable of slowing down tumor growth in many animal models. Blood Glucose curves between the cancer patients and normal subjects found elevated fasting glucose concentrations for the former, but also abnormal postprandial elevation after a very low carbohydrate meal. KD’s by themselves have been shown to impair glycolytic tumor metabolism in humans…in which tumor lactate levels dropped significantly after only a few days on the diet”.
This communication wants to propose a novel concept in which our body uses its sophisticated set of subsystems and sensors to intelligently and pragmatically anticipate and combat the most direct and dire threat first, while temporarily accepting a state that in any other circumstances would be considered detrimental. Our body is able to control cancer growth in a pragmatic and bi-directional switch-like manner to firstly induce and/or promote cancers as a mechanism to consume large amounts of blood glucose through the Cancer’s Warburg effect in order to combat the most immediate threat to the body’s short-term survival, and then reverse this switch to halt or reverse tumor growth after the metabolic pathology has been resolved.
Cancer metabolism is adapted to hypoxic conditions by utilizing glycolysis, and not oxidative phosphorylation, to produce energy [3]. Since glycolysis is a very inefficient energetic mechanism, large amounts of glucose are used by cancer cells to provide the energy needed [3] and thus represents a mechanism by which glucose is removed from circulation. This mechanism has the potential to contribute to counteracting the problem of an ever-increasing insulin resistance and systemic accumulation of glucose. Once glucose levels and metabolic syndrome are normalized with the help of the cancer’s glucose consumption, chronic inflammation is reduced, which in turn will reduce oncogenic signaling from the microenvironment to tumor cells and will slow down or prevent further tumor growth. In this model, our body makes a decision to fight the most immediate threat first by supporting cancer growth through chronic inflammation and associated signaling molecules to ensure survival. Interestingly, new research suggests that dietary restrictions, including fasting and low carbohydrate diets, indeed appear to slow down tumor growth and reduce the size of tumors, suggesting that these life-style choices can be utilized to reduce chronic inflammation and the associated oncogenic signaling from microenvironment to cancer [7]. Since in this scenario survival is not threatened by metabolic syndrome and high blood glucose levels anymore, our body has no further need to support a tumor and thus starves it of the oncogenic signals it requires for growth. Our body appears to have the ability to both induce and restrict cancer growth, depending on the needs to best ensure short-term survival. The potent mechanism utilized for this regulation of cancer growth include inflammation and associated signaling pathways [8]. This novel model presented here proposes that our body makes intelligent and pragmatic choices that, for any given circumstance, represent the best chance for short-term survival, even at the cost of promoting potentially changes that, if not reversed, might be detrimental in the long-term.
Observations supporting the proposed model
1. Cancer provides a short-term survival benefit by metabolizing large amounts of glucose.
Most cells in our body utilize oxidative phosphorylation of glucose in mitochondria to produce energy. However, cancer cells feature an altered metabolism with dramatically increased uptake of glucose and glycolysis of glucose into lactate, even in the presence of abundant oxygen (Warburg effect) [3]. Energy production through glycolysis is not efficient and requires far greater amounts of glucose to produce equivalent amounts of the energy produced by oxidative phosphorylation. Indeed, it has been estimated that tumor cells can consume 10-100 times more glucose than normal cells [3]. It is not clear why cancer cells would prefer this inefficient metabolic pathway, even when oxygen for the much more efficient oxidative phosphorylation pathway is abundant. This curious preference of cancer cells could however be advantageous when the most imminent threat to the body’s survival is severe insulin resistance, with an ever-increasing accumulation of glucose threatening the very functioning of vital organs. In this instance, any means to reduce systemic glucose levels would be critical to ensure survival. Promoting cancer growth in such a dire emergency would be a pragmatic and intelligent choice for our body to reduce toxic systemic glucose levels and ensure short term survival.
2. Glucose concentrations correlate with clinical cancer outcomes.
Systemic glucose levels are closely correlated with cancer growth. High glucose levels have been shown to accelerate cancer cell proliferation in vitro, while glucose deprivation has led to cancer cell apoptosis [7, 9]. All tumors utilize glucose, and the vast majority of the tumors proliferate optimally on excess glucose [10]. Patients with type I and type II diabetes have higher cancer rates [4, 11], and exposure of cancer cells to hyperglycemic conditions leads to the activation of oncogenic pathways [8]. Clinical evidence has shown that lower blood glucose levels in late-stage cancer patients is correlated with better outcomes [7]. Dietary restrictions, including fasting and low carbohydrate diets, have been suggested to slow down tumor growth and reduce the size of tumors [7, 9, 12]. Thus, blood glucose levels and tumor growth appear to be closely correlated. This theory might also explain why exercise reduces the risk of cancer. Regular exercise promotes insulin sensitivity and normal blood glucose levels [13], thus making cancer as a mechanism to reduce toxic levels of glucose unnecessary. Proof-of-principle that hypoglycemia itself can induce tumor regression was provided in 1962 by Koroljow who reported the achievement of a one-year complete remission in two metastasized cancer patients who were put into an insulin coma (lowest blood glucose reading 22mg/dl) [14]. In 1941 and 1942, Brunings published two reports and findings that carbohydrate metabolism is a general factor necessary for cancer development [6].
In contrast to normal cells, cancer cells cannot tolerate a low-calorie environment. In a mouse model of human metastatic cancer, after 34 days of five 48-hour fasting cycles, tumor size was less than half of that in normally fed mice [9]. Indeed, fasting alone was effective in retardation of the growth of many cancer types, and in some cases was similar to the effect of chemotherapy drugs [9]. Moreover, while fasting was as effective as chemotherapy alone, adding fasting to chemotherapy showed synergistic effectiveness. These studies concluded that the use of fasting is a potential tool to increase the effectiveness of chemotherapy while lowering side effects [9]. Similar results have been obtained for a number of different types of cancers [12], suggesting that normal cell have a defense against the environmental stress of low-calorie intake, but cancer cells do not. Fasting also affects hormones such as thyroid hormone, testosterone, insulin, cholesterol, and C-reactive protein [15-17], and many cancers are linked to high levels of these proteins and hormones [16, 17]. These observations support the hypothesis presented here that as soon as glucose levels and calorie intake are not problematic anymore, inflammation is reduced, and cancer growth can be slowed or halted, as this function of the tumor is no longer needed. In contrast, 80% of cholesterol is produced by our body, and only 20% are taken up through our diet. Moreover, autoregulatory mechanisms appear to balance endogenous production when dietary cholesterol intake is increased ( Sollman, 2018 [35]). Thus, it appears that hyperglycemia is more of a modifiable risk factor when compared to hypercholesterolemia. Despite this, it was not my intention to indicate that other metabolic changes associated with obesity are not important in cancer progression as well.
3. Cancers can evade the human immune system.
Cancer cells utilize sophisticated masking mechanisms to evade the immune system. Expression of CD47 protein has been found to be common in many cancers [18]. CD47 is normally used as a date code by the body’s own cells in order to prevent young cells from being attacked by the immune system. Aging cells lose CD47 expression and are targeted for elimination by the immune system [18]. Cancer cells utilize this system and express cell surface CD47 to evade attacks by immune cells. Weissman calls CD47 molecule the “Don’t Eat Me” molecule which blinds the immune system to the cancer cell [18]. The model proposed here argues that natural selection would have eliminated this problem unless there are circumstances under which it is beneficial for the body to tolerate and even support growth of a tumor. Late-stage metabolic syndrome would be an example of such a circumstance under which a tumor would be tolerated to contribute to the fight against the immediate metabolic threat.
4. Tumors can promote angiogenesis to ensure sufficient blood supply.
Cancers can promote angiogenesis to initiate and maintain vascularization and therefore ensure sufficient blood supply to tumor tissue [19]. This observation is consistent with a functional importance of a tumor to participate in the removal of glucose from circulation - indeed, in order to significantly change systemic glucose levels, it is critical that a good vascularization of the tumor is maintained. The model presented here argues that the body tolerating a large tumor that requires significant resources and blood supply and might indicate that there are circumstances when this tumor represents a temporary benefit to the organism.
The Reverse Warburg Effect describes the ability of epithelial cancer cells to manipulate surrounding normal stroma to undergo myofibroblastic differentiation and become tumor-associated stroma, thus creating a cancer-supportive tumor microenvironment (TME) that facilitates further tumor growth and tumor angiogenesis (Pavlides et al., 2009) [28]. It has been postulated that this is achieved through secretion of hydrogen peroxide by cancer cells, leading to oxidative stress in surrounding stromal cells and causing their metabolic change to aerobic glycolysis and production and release of high energy metabolites, which subsequently can be utilized by cancer cells to accelerate tumor growth (Liang et al., 2022). This Reverse Warburg Effect has been described as inflammation of the tumor microenvironment, and thus would accelerate the chronic inflammation already present in obese patients. The Reverse Warburg Effect would thus decrease of excessive blood glucose levels even further by utilizing metabolic changes to aerobic glycolysis in both cancer cells as well as the surrounding TME (Liang et al., 2022 [29]; Pavlides et al, 2010 [30]). Mechanistically, it has been proposed that Caveolin-1 (Cav-1) is a key regulator of the Reverse Warburg Effect and TME phenotype, suggesting that pharmacological targeting of Cav-1 might be a promising avenue for targeted anti-cancer therapies (Pavlides et al., 2010).
5. Tumors secret inhibitors that suppress secondary tumors and metastases.
One of the most mysterious aspects of cancer biology is the ability of primary tumors to inhibit growth of secondary tumors and metastases [20]. Surgical removal of the primary tumor may stimulate growth of its metastatic secondary tumors [20]. It is not clear why this would be an advantage for the cancer. However, looking at this from the perspective of an organism trying to get the immediate threat of toxic glucose levels under control, this observation could make sense. The primary tumor is supported by the body to help reduce glucose levels, but the organism also wants to make sure that its survival is not compromised by out-of-control metastases formation. This scenario might suggest that our body chooses an intelligent compromise between temporarily tolerating one, but not many tumors, in order to fight metabolic dysfunction, even though multiple tumors would consume more glucose. A single tumor mass that assists in the re-establishment of normal glucose levels is easier to control when the immediate threat of metabolic syndrome has been resolved. In this case, reduced chronic inflammation would reduce pro-tumorigenic signaling from the microenvironment to the tumor and halt or even revert tumor growth, without ill effect on the organism’s survival.
6. Early tumor cell dissemination and metastasis formation.
Literature has provided “striking evidence that tumor cells start to disseminate during the initial steps of tumor development that late appearing metastases arise from these early disseminated tumor cells” [21]. However, in the above paragraph it was argued that the primary tumor can inhibit growth of metastasis. This discrepancy can be reconciled by a scenario in which the body wants to support a primary tumor for its metabolic activity and its ability to remove glucose from circulation, but does not want to create a situation in which a significant metastasis burden threatens survival of the organism. Early tumor dissemination and formation of microscopic metastases, the further growth of which is subsequently controlled by the primary tumor, allows a tight control of cancer cell activity to reduce glucose levels without the life-threatening consequences of a large metastasis burden. Importantly, these micro-metastases could function as a backup system in case the primary tumor cannot fulfil its presumed function anymore, for example after surgical removal of the tumor. In this case, the back-up system is activated to allow the micro-metastases to grow and continue to reduce systemic glucose levels.
7. High amounts of glucose inhibit the immune system.
If our body wants to promote a cancer to grow and assist in the reduction of toxic glucose levels, then it would be beneficial if the immune system would be suppressed in situations of metabolic syndrome and excess consumption of sugars and fat. Indeed, the immune system is suppressed with the body ingests larger quantities of both. In the article “Fast Food Fever” the authors state: “In vitro evidence suggest processed, simple sugars also reduce white blood cell phagocytosis and possibly increase inflammatory cytokine markers in the blood.” [22]. Of note, the authors attribute their findings to “glycemic load” of meals rather than sugars themselves. This statement describes a scenario in which sugars decrease immune function, which allows a tumor to grow or survive and, in the model proposed here, would allow the tumor to participate in the reduction of the chronic glycemic load.
8. The control of cancer cells by microenvironmental cues and inflammation status.
While it is widely accepted that DNA damage and mutation in specific genes can drive tumor progression, it also has been shown that microenvironmental cues can promote or inhibit tumor growth. For example, studies showed that transplantation of cancer cells into an embryonic tissue environment cause cancer cells to adopt non-cancerous phenotypes, and normal control of proliferation was re-established [23, 24]. Thus microenvironmental signals can override the phenotypic effects of oncogenic mutations and normalize cell behavior [25]. Vice versa, chronic inflammation and tumor stromal cells have been shown to secrete pro-tumorigenic signaling molecules that can drive tumor progression [8, 26]. These well-documented observations show that our body can utilize signaling mechanism from the cellular microenvironment to control tumor growth bi-directionally, i.e. cancer growth can be induced and accelerated, but also inhibited. These data might also suggest that there could be a benefit for an organism to be able to control cancer growth in this bi-directional manner. This manuscript argues that metabolic syndrome with high systemic glucose levels is such an instance - tumor growth is induced and accelerated through microenvironmental inflammatory signals in order to activate an additional mechanism that can contribute to the reduction in glucose levels. Once glucose is brought under control, chronic inflammation is reduced, which leads to a reduction of pro-tumorigenic signaling and a stop of tumor growth. This proposed mechanism would utilize inflammation and associated signaling events as the principal switch to allow the bi-directional control of cancer cells, even in the presence of oncogenic mutations, to enable an organism to better resolve chronic physiological and metabolic challenges.
9. Metformin Reduces risk of cancer in diabetic Patients.
Metformin is a drug that lower blood sugars and prescribed for type 2 diabetes.
usefulness of Metformin in cancer treatment has been controversial; evidence from two clinical trials showed no significant improvements (Morales and Morris, 2015 [31]), while a recent phase II clinical trial of Metformin as a cancer stem cell-targeting agent in ovarian cancer suggested that Metformin-treated tumors showed a decrease in ovarian cancer stem cells and increased sensitivity to cisplatin treatment, as well as improved survival (Brown et al., 2020 [32]). Laboratory and observational studies have demonstrated a beneficial effect of Metformin in cancer prevention and treatment. For example, metformin improved prognosis and survival rates of diabetic patients with breast, liver, ovarian/endometrial, colorectal and pancreatic cancers (Morales and Morris, 2015). Metformin has also been evaluated in non-diabetic cancer trials. In breast cancer patients, Metformin lead to a significant reduction in Ki67, BRCA1, and cell cycle genes in cancer cells, and also caused a significant increase of breast cancer cells undergoing apoptosis. Further studies seem to indicate that this effect of Metformin is greater in Insulin-resistant patients (Morales and Morris, 2015), again supporting the hypothesis of this review that functional mechanisms to reduce blood glucose are critical to interfere with cancer growth. Thus, the current limited evidence seems to support the value for further evaluation of Metformin in phase III clinical studies. These studies might well identify specific patient subpopulations with certain cancers and/or oncogenic mutations that might benefit from Metformin treatment. Mechanistically, it is plausible that metformin interferes with cancer growth due to its upregulation of AMP kinase (AMPK), which leads to a block of mTOR and impairment of angiogenesis as well as cell growth and proliferation, key components of cancer progression (Morales and Morris, 2015
10. Cancer Cachexia helped by Insulin treatments
Cancer cachexia is a wasting syndrome characterize by weight loss anorexia, asthenia and anemia. The pathogenicity of this syndrome is a multifactorial interaction of the tumor and the bodily functions. Inflammatory stimulation activates pathways associated with muscle protein breakdown. This condition is associated with Cancers of: Pancreas, esophagus, stomach, lung live and bowel and is found in late stage cancers. The newer treatments include: anti-inflammatory agents such as fish oils and low dosage of insulin “which is anabolic to skeletal muscle and inhibits lipolysis is an attractive candidate for treatment of cachexia” Lundholm [33]. These treatments are consistent with the switch theory of cancer even on a late stage Cachexia.
11. What about people who suffered starvation?
Holocaust survivors and Anorexia Neurosis sufferers have higher rates of cancer along with persons who suffered the Norwegian famine in 1944. The Holocaust was a horrific ordeal for its victims. Many we deprived of basic nutrition, experimented upon, and subject to constant threat of violence and uncertainty. This type of stress will trigger strong Cortisol response. PTSD will cause high Cortisol for years and depredation of nutrition will cause metabolic slowing with weight loss. After the stressors are removed the body tends to gain weight as a response to the loss of nutrition with all the inflammatory side effects such as cancer and heart disease. Several studies have demonstrated a protective effect of moderate calorie restriction on cancer incidence. In contrast, extreme and severe calorie and nutrient restrictions, as experienced during famines and during the holocaust, have been shown to significantly increase cancer rates (Boker, 2018 [34]). All of these factors are likely to have significant effects of metabolic dysregulation, immune function, and (subsequently) cancer rates, and thus are not likely to give relevant insight in the isolated role of moderate calorie and glucose restriction on cancer development.
SUMMARY
This concept paper proposes a novel hypothesis that envisions cancer as a tool that can be controlled intelligently and pragmatically by an organism in a switch-like bi-directional manner depending on physiological or pathological needs. In the context of metabolic syndrome, severe insulin resistance, and toxic systemic glucose levels, our body will attempt to activate every mechanism possible to ensure short-term survival. One of these mechanisms might be the induction of tumor growth, in order to capitalize on the metabolic specificity of cancer cells to utilize large amounts of glucose for their energy need and thus assist in the body’s attempts to remove glucose from circulation. When the immediate metabolic emergency has been resolved and the tumor is no longer needed, the body can again engage this bi-directional switch to try halt or reverse tumor growth to avoid long-term detrimental effects. I propose that this unique bi-directional switch is the pragmatic initiation and reduction of inflammation and associated signaling pathways. Of note, cancer might not be the only bi-directional tool activated to reduce glucose level, and subsequently needs to be reversed and inactivated again. For example, the covalent attachment of glucose to many different proteins to form Advanced Glycation End products (AGEs) might also be an emergency mechanism to increase cellular uptake of glucose to remove glucose from circulation and thus ensure short-term survival during metabolic syndrome. Like cancer, AGEs are detrimental to an organism’s long-term survival, have been shown to accumulate in conditions of chronic inflammation, and also promote tumor growth [27]. One could view AGEs as synergistic activators of tumor growth in the context of type II diabetes and metabolic syndrome. AGE molecules will be eliminated through the normal protein elimination pathways, including proteasome and autophagy pathways. Provided that the metabolic emergency has been resolved and systemic glucose levels have returned to normal, new proteins will not be glycated and thus can fulfil their normal function without the negative long-term effects of AGEs. I believe that the evidence presented here supports my hypothesis that our body might be able to pragmatically use and control temporary pathological states like cancer and AGEs to its advantage to resolve short-term threats, including metabolic syndrome, and ensure survival of the organism. It is my hope that this hypothesis might help open novel avenues for intellectual and experimental exploration in order to exploit the pragmatic control of pathological states for better health outcomes.
THE AUTHOR
John Claras is independent researcher, and the CEO/ founder of Applied Interconnect Inc. and is a 30 year veteran of aerospace engineering. He views the body as a sophisticated set of subsystems and sensors trying to anticipate its’ threats and fuel needs in a complex environment.
REFERENCES
1. Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2020. CA Cancer J Clin, 2020. 70(1): p. 7-30.
2. Bissell, M.J. and W.C. Hines, Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med, 2011. 17(3): p. 320-9.
3. Pascale, R.M., et al., The Warburg Effect 97 Years after Its Discovery. Cancers (Basel), 2020. 12(10).
4. Harding, J.L., et al., Cancer risk among people with type 1 and type 2 diabetes: disentangling true associations, detection bias, and reverse causation. Diabetes Care 2015;38:264-270. Diabetes Care, 2015. 38(4): p. 734-5.
5. García-Jiménez, C., et al., A new link between diabetes and cancer: enhanced WNT/β-catenin signaling by high glucose. J Mol Endocrinol, 2014. 52(1): p. R51-66.
6. Klement, R.J., Wilhelm Brünings’ forgotten contribution to the metabolic treatment of cancer utilizing hypoglycemia and a very low carbohydrate (ketogenic) diet. J Tradit Complement Med, 2019. 9(3): p. 192-200.
7. Luo, J., Y.J. Chen, and L.J. Chang, Fasting blood glucose level and prognosis in non-small cell lung cancer (NSCLC) patients. Lung Cancer, 2012. 76(2): p. 242-7.
8. Coussens, L.M. and Z. Werb, Inflammation and cancer. Nature, 2002. 420(6917): p. 860-7.
9. Naveed, S., M. Aslam, and A. Ahmad, Starvation based differential chemotherapy: a novel approach for cancer treatment. Oman Med J, 2014. 29(6): p. 391-8.
10. Kanarek, N., B. Petrova, and D.M. Sabatini, Dietary modifications for enhanced cancer therapy. Nature, 2020. 579(7800): p. 507-517.
11. Ryu, T.Y., J. Park, and P.E. Scherer, Hyperglycemia as a risk factor for cancer progression. Diabetes Metab J, 2014. 38(5): p. 330-6.
12. Lee, C., et al., Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci Transl Med, 2012. 4(124): p. 124ra27.
13. Roberts, C.K., A.L. Hevener, and R.J. Barnard, Metabolic syndrome and insulin resistance: underlying causes and modification by exercise training. Compr Physiol, 2013. 3(1): p. 1-58.
14. KOROLJOW, S., Two cases of malignant tumors with metastases apparently treated successfully with hypoglycemic coma. Psychiatr Q, 1962. 36: p. 261-70.
15. Tantamango-Bartley, Y., et al., Vegetarian diets and the incidence of cancer in a low-risk population. Cancer Epidemiol Biomarkers Prev, 2013. 22(2): p. 286-94.
16. Akhmedkhanov, A., A. Zeleniuch-Jacquotte, and P. Toniolo, Role of exogenous and endogenous hormones in endometrial cancer: review of the evidence and research perspectives. Ann N Y Acad Sci, 2001. 943: p. 296-315.
17. Lee, C.H., et al., Obesity, adipokines and cancer: an update. Clin Endocrinol (Oxf), 2015. 83(2): p. 147-56.
18. Weiskopf, K., Cancer immunotherapy targeting the CD47/SIRPα axis. Eur J Cancer, 2017. 76: p. 100-109.
19. Folkman, J., Tumor angiogenesis: therapeutic implications. N Engl J Med, 1971. 285(21): p. 1182-6.
20. Janssen, L.M.E., et al., The immune system in cancer metastasis: friend or foe? J Immunother Cancer, 2017. 5(1): p. 79.
21. Klein, C.A., Cancer progression and the invisible phase of metastatic colonization. Nat Rev Cancer, 2020. 20(11): p. 681-694.
22. Myles, I.A., Fast food fever: reviewing the impacts of the Western diet on immunity. Nutr J, 2014. 13: p. 61.
23. Kulesa, P.M., et al., Reprogramming metastatic melanoma cells to assume a neural crest cell-like phenotype in an embryonic microenvironment. Proc Natl Acad Sci U S A, 2006. 103(10): p. 3752-7.
24. Kasemeier-Kulesa, J.C., et al., Reprogramming multipotent tumor cells with the embryonic neural crest microenvironment. Dev Dyn, 2008. 237(10): p. 2657-66.
25. Costa, F.F., et al., Epigenetically reprogramming metastatic tumor cells with an embryonic microenvironment. Epigenomics, 2009. 1(2): p. 387-98.
26. Iyengar, N.M., et al., Obesity and Cancer Mechanisms: Tumor Microenvironment and Inflammation. J Clin Oncol, 2016. 34(35): p. 4270-4276.
27. Garay-Sevilla, M.E., et al., Contribution of RAGE axis activation to the association between metabolic syndrome and cancer. Mol Cell Biochem, 2021. -
28 Pavlides, S et al., The Reverse Warburg Effect, Cell Cycle Landes Bioscience, 2009 8:23, p 3984-4001
29 Liang 2022
30 Pavlides, S et al, Loss of stromal caveloin-1 leads to oxidative stress, mimics hypoxia and drives inflammation in the tumor microenvironment, conferring the “reverse Warburg effect” Landes Bioscience, Cell Cycle Landes Bioscience, 9-11 P 2201-2219
31 Morales, D et al Metformin in Cancer Treatment and Prevention,
The annual Review of Medicine, 66: 17-29
32 Brown, JR et al, Phase II clinical trial of Metformin as a cancer stem cell-
targeting agent in ovarian cancer,JCI insight 5(11) P 1-12
33 Lundholm, K et al, Insulin Treatment in Cancer Cachexia,: Effects on Survival, Metabolisum, and physical Functioning. Cancer Therapy: Clinical Res 2007:13(9) p2699-2706
34 Boker et al, Increased cancer indidence in Holocaust survivors and implications for survivors of other extreme events, Expert Review of Anticancer therapy 2018, Vol, 18 no 11 1059-1062
35 Soliman, GA, Dietary Cholesterol and the Lack of Evidence in Cardiovascular Disease, Nutrients 2018, 10, 780
Copyrighted 2016, 2020, 2021, 2022 John Claras.
Does Cancer have a benefit? –– Your immune system might think so.
Abstract:
Cancer has been present in species for over 240 million years. Most modern-day species get cancer. Perhaps there are benefits to cancer that your immune system has identified that we have overlooked. If cancer had no benefit, wouldn’t it have been deselected from the genome by now? In our industrial society, where calories are abundant cancers are more closely linked to metabolic syndrome and chronic inflammation. Perhaps cancer is an ancient “Pragmatic Switch to Combat Metabolic Syndrome”? Cancer might exist to convert large amounts of glucose to lactate and protect the organs from excess glucose while limiting exposure to toxic oxygen- Warburg Effect.
Introduction:
In humans, cancer is a complex set of illnesses with many manifestations. About 10% of cancers are hereditary and about 15% are a result of infections. Cancers in the wild appear to be associated with infection. An example is the Tasmanian devil which is plagued by: devil facial tumors which are spread by biting. The remaining 75% are largely unknown in origin but are associated with metabolic syndrome and chronic inflammation, which is common in our calorie-abundant industrial society with both humans and captive animals.
Discussion:
In a high-glucose environment, the immune system is less aggressive and becomes less active. This is curious because the immune system requires energy to operate, and this seems counterintuitive. This could explain the old saying “Starve a cold and feed a fever”. It also could explain why people with diabetes are at high risk of Covid and cancer. [1]
The immune system does another curious thing. In most cases, it ignores the cancer cell and its vast circulatory network. The immune system is very good at identifying damaged or mutant cells or cells that have been compromised by a virus and targeting them for apoptosis. Not so with cancer cells. The cancer cell uses the body’s own CD47 marker to evade the immune system. [2] This is more curious because researchers have found malignant cancers such as osteosarcoma in turtle bones dating back 240 million years. Dinosaurs such as T-Rex had non-Hodgkin lymphoma. These cancers imply that these ancient creatures also suffered soft tissue cancers which were not preserved in the fossil record. [3]
One would think cancer would have been deselected within the genome by now. Let’s go one step further, the immune system can learn in real-time about virtually any virus and create an antibody. The immune system can target infected and mutant cells for apoptosis using the killer T cells. The immune system can differentiate between good and bad bacteria with regard to their location in the intestine. Yet with all these capabilities why does the immune system largely ignore cancer cells even though cancer is visually and structurally different?
These two curiosities can be linked with one hypothesis: cancer is an ancient method of the body dealing with metabolic syndrome. This was proposed in the article “Cancer—A Pragmatic Switch to Combat Metabolic Syndrome? 2023 By the Author.
Let’s examine some interesting facts about cancer and ask, “If it’s been around for at least 240 million years could cancer have some benefits?”
Possible Benefits of Cancer:
Almost always, cancers do not utilize oxidative phosphorylation of glucose for energy production but demonstrate a dramatically increased uptake of glucose and glycolysis of glucose into lactate, even in the presence of abundant oxygen (Warburg effect). Cancer can consume 10 to 100 times more glucose than a normal cell. Cancer’s by-product is lactate which can be consumed by every cell in the body and is non-toxic to organs. A good measure of the extent of cancer in the body is to measure the level of lactate. Let us not forget that the body has chosen two toxic and powerful components, the element oxygen and the compound glucose, to create power or ATP. Cancer converts glucose into lactate without the need for oxygen. So, the problem solved is lower toxic glucose which prevents the damage to internal organs, and less oxygen, which can damage all cells through oxidation, with the by-product of lactate which can be stored as fat.
Now you say cancer is a deadly condition. That is true. But let’s think about the cycle of life. In the spring and summer, there are abundant calories. The number of calories available in the fall drops. Then comes the very lean winter where many animals need to live off their fat stores of summer. Cancer has another interesting property; it cannot survive in a low-calorie, low-glucose environment, it will apoptosis or turn back to normal. In a calorie-limited low glucose environment, the normal cell can go into starvation mode. It is interesting that people who try to lose weight through starvation frequently gain more weight as the body adjusts to the low-calorie environment. As for cancer, it cannot tolerate a low-calorie environment and will apoptosis. [4,5] So perhaps cancer existed in the ancient genome to solve the problem that if the animal found a large number of calories, instead of passing them out during the fat months or damaging organs and starving during the winter months, the animal could convert the surplus glucose to lactate with high conversion cells called cancer. Then, when the lean months occurred and a low-calorie (Glucose) environment, these special cells could revert back to normal or simply die off. We all have taste buds for sweets (glucose/fructose), fats, and salt. All of these are scarce in the wild, long before industrialization created a year-round high-calorie environment. Another interesting fact is people on a high-fat diet suffer higher rates of leukemia. Acute myeloid leukemia (AML). In both human and animal models, increased consumption of a high-saturated-fat diet has been linked to vascular dysfunction and cognitive impairments.[6] When a person has leukemia, the plaques are reduced. Is cancer trying to prevent this problem?
Let’s talk about the immune system again. Let’s say for cancer to operate, the body would need a high-glucose environment. That then triggers the need for the immune system to be degraded and which allows angiogenesis and visually different cells to flourish to consume large amounts of glucose. Those cells are called cancer cells. If you look at a cancer tumor, this is a very large vascular network. Why again would the body tolerate this for 240 million years, unless perhaps there was a benefit?
Cancer does another curious thing. In the case of the large main tumor, it actually secretes inhibitors that suppress secondary tumors. If cancer was some random occurrence, this would not happen. But if the body is trying to maintain control of this dangerous group of cells, it makes sense. There seems to be too much logic for a random cell that is just growing wildly, out of control. Further examples are the microenvironment signals that can override the phenotypic effects on oncogenic mutations and normalize cell behavior. An example is a transplanted cancer cell into an embryonic tissue environment that causes cancer cells to adapt to non-cancerous phenotypes and normal control of proliferation. [7]
Conclusion:
For 240 million years, a cell that is visually and functionally different from other cells, which can initiate angiogenesis and hide from the immune systems, has existed in many creatures; why is that? Now consider all of the above stated; the distribution of the causes of cancers in humans are: 15% caused by infections, 10% hereditary, but the remaining 70-75% of cancers are of unknown origin but are strongly linked to metabolic syndrome and inflammation. Perhaps cancer is a “Pragmatic Switch to Control Metabolic Syndrome”. Further, perhaps the viral and hereditary causes of cancer are simply changing the switch’s sensitivity causing cancer to engage more easily. Perhaps the treatment to run away (malignant) cancer is a low glucose environment as proposed by Wilhelm Brünings.[4] Maybe the popular Mediterranean diet and exercise does help prevent this switch from being turned on because of its lower glycemic load. Further research is needed to confirm these linkages.
“Our food should be our medicine and our medicine should be our food. If we could give every individual the right amount of nourishment and exercise, not too little and not too much, we would have found the safest way to health”- Hippocrates.
Further reading:
Claras, J Cancer—A Pragmatic Switch to Combat Metabolic Syndrome? Oncol Rev., 15 February 2023 doi.org/10.3389/or.2023.10573
Harding, JL, Shaw, JE, Peeters, A, Cartensen, B, and Magliano, DJ. Cancer Risk Among People with Type 1 and Type 2 Diabetes: Disentangling True Associations, Detection Bias, and Reverse Causation. Diabetes Care 2015;38:264-270. Cancer Risk Among People Type 1 Type 2 Diabetes: Disentangling True Associations, Detection Bias, Reverse Causation Diabetes Carediabetes Care (2015) 3838(4):264734–2705. doi:10.2337/dc15-er04a
2 Irving Weissman et all CD47 Is an Adverse Prognostic Factor and Therapeutic Antibody Target on Human Acute Myeloid Leukemia Stem Cells VOLUME 138, ISSUE 2, P286-299, JULY 23, 2009 DOI:https://doi.org/10.1016/j.cell.2009.05.045
3
Yara
Haridy, MS,
1 Florian
Witzmann, PhD,1 Patrick
Asbach, MD,2 Rainer
R. Schoch, PhD,3 Nadia
Fröbisch, PhD,1 and Bruce
M. Rothschild, MD4 Triassic Cancer—Osteosarcoma in a
240-Million-Year-Old Stem-Turtle Published online 2019 Feb 7. doi: 10.1001/JAMA
Oncol.2018.6766 JAMA
Oncol. 2019 Mar; 5(3): 425–426.
Klement, RJ. Wilhelm Brünings’ Forgotten Contribution to the Metabolic Treatment of Cancer Utilizing Hypoglycemia and a Very Low Carbohydrate (Ketogenic) Diet. J Traditional Complement Med (2019) 9(3):192–200. doi:10.1016/j.jtcme.2018.06.002
5 Naveed, S, Aslam, M, and Ahmad, A. Starvation Based Differential Chemotherapy: a Novel Approach for Cancer Treatment. Oman Med J (2014) 29(6):391–8. doi:10.5001/omj.2014.107
6 Francois Hermetet, High-fat diet intensifies MLL-AF9-induced acute myeloid leukemia through activation of the FLT3 signaling in mouse primitive hematopoietic cells Scientific Reports Volume 10, Article number: 16187 2020 doi.org/10.1038/s41598-020-73020-4
7 Kasemeier-Kulesa, JC, Teddy, JM, Postovit, LM, Seftor, EA, Seftor, RE, Hendrix, MJ, et al. Reprogramming Multipotent Tumor Cells with the Embryonic Neural Crest Microenvironment. Dev Dyn (2008) 237(10):2657–66. doi:10.1002/dvdy.21613