Positive Health Online

“The concept that cancer might in some way be related to stress or other emotional factors is probably as old as the history of recorded medicine itself” by Professor Doctor Paul J. Rosch, 1979.[1]

Abstract

In the present paper is discussed the recent evolution in the understanding of the role of lactate formation in promoting cancer. On it is postulated the hypothesis that chronic stress is the major risk factor and inductor of the increased lactate production which might lead to the carcinogenic process. It also explains how stress develops lactate formation, which was discovered in 1925.

The current hypothesis supports ketogenic diets for prevention and therapy for cancer. This follows the reasoning that while fats do not have appreciable effects on the sympathetic nervous system (SNS) or in lactate formation, high carbohydrate diets have significantly effects on both SNS and lactate formation.

At the end of the paper is a short explanation and link to a parallel article where is discussed cardiac glycosides as the fundamental drugs for prevention and treatment of cancer.

Introduction

The Recent Evolution of the Role of Lactate in Promoting Cancer

A paper by Thomas N Seyfried and Laura M Shelton has presented in 2010 a hypothesis that genomic instability and essentially all hallmarks of cancer, including aerobic glycolysis (Warburg effect), can be linked to impaired mitochondrial function and energy metabolism. This paper raised the point that emerging evidence questions the genetic origin of cancer and suggests that cancer is primarily a metabolic disease.[2]

This study from Seyfried and Shelton also stirred a great and new interest about the concept of Otto Warburg, developed in the early twenties of the past century. Warburg observed that cancer cells were characterized by accelerated glycolysis and excessive lactate formation even under fully oxygenated conditions. According to Warburg, many tumours depend heavily on glucose for their metabolic demands and ferment it to lactate. His concept was later called the Warburg effect

Advocating that energy restricted diets combined with drugs targeting glucose and glutamine can provide a rational strategy for the longer-term management and prevention of most cancers, these authors say that fats and especially ketone bodies can replace glucose as a primary metabolic fuel under calorie restriction. [2]

Mercedes Garcia-Alvarez and colleagues, in a study from 2013[3] expressed their point of view that “In almost all severe disease-related physiological stress, a raised blood lactate concentration is an independent predictor of mortality. However, the source, biochemistry, pathophysiology, and metabolic function of lactate remain unclear. Whether such stress hyperlactataemia represents a maladaptive or protective response is also unknown”.

Fortunately, Iñigo San-Millán and George A. Brooks, through a study published in 2017[4] arrived, in my opinion, to a clear and straightforward explanation of the Warburg effect. They introduced a proposal in which the augmented lactate formation, initiated by gene mutations, is the reason and purpose of the Warburg effect and that dysregulated lactate metabolism and signalling are the key elements in carcinogenesis. According to their proposition, therapies to limit lactate exchanging and signalling within and among cancer cells should be priorities for discover.

We see the proposition made by San-Millán and Brooks[4] as a major breakthrough in the research for the cure of cancer. We also agree with their view that lactate is necessary for all the major steps in carcinogenesis.

However, I beg to differ from these authors in relation to the initiation of the process. Instead of gene mutation we postulate that chronic stress is the major risk factor and the initial inductor to the whole process of cancer.

Stress as the Major Risk Factor for Cancer

For a better understanding, in conformity with our postulation, stress is defined here as any risk factor leading to dysregulation of the autonomic nervous system. This may be related to chronic sympathetic dominance through sympathetic over-activity or withdrawal of the parasympathetic system.

Some examples of risk factors for cancer linked to altered autonomic function: Psychological stress; Age; Tobacco; Radiation; Infection; Exposure to some chemicals and persistent organic pollutants; and Genetic predisposition (e.g.: Familial dysautonomia). 

Moreover, recent studies have confirmed the important role of the autonomic nervous system in cancer by demonstrating that the denervation of the primary tumor suppresses cancer growth and metastasis.[5, 6]

This evidence is supported by the longstanding hypothesis that chronic stress can influence tumor growth and progression.[1,7 ] It has been shown that sympathetic nervous neurotransmitters can affect both cancer cell growth and tumor vascularization.[8] Recent reviews have discussed the role of the nervous system in cancer and metastasis.[9, 10]

Related to the subject, a recent meta-analysis involving a total of 46 studies with more than a million patients confirms that high resting heart rate is independently associated with increased risk of all-cause mortality in the general population. Its results suggest the risk is increased by 9% and 8% for every 10 beats/min increment of resting heart rate. Higher resting heart rate is a marker of an imbalance between the vagal and the sympathetic tone, and dysfunctional autonomic nervous system, playing a central role in the pathogenesis of numerous adverse health conditions.[11]

Stress and the Development of Lactate / Lactic Acid

The sympathetic dominance leads to a raised catecholamine (adrenaline/epinephrine and noradrenaline) release accelerating glycolysis metabolism, therefore increasing lactic acid and lactate concentration in blood and tissues.

The higher lactate concentration in blood the greater is the risk of death.[12]

The first to observe the influence of adrenaline on lactic acid production was Carl F Cori in 1925.[13] Together with his wife Gerty Cori, they received a Nobel Prize in 1947 for their discovery of how glycogen - a derivative of glucose - is broken down and resynthesized in the body.

John R. Williamson confirmed in 1964 the effects of adrenaline infusion on the increased production of lactate in isolated heart tissue, up to five times the normal production.[14]

According to an article published in 1982[15] the support for a direct participation of catecholamines in the development and/or maintenance of lactic acidosis includes:

1.         The common association of stress and lactic acidosis;

2.         The rise in plasma lactate concentration during adrenaline infusion;

3.         The precipitation of lactic acidosis by adrenaline intoxication and phaeochromocytoma;

4.         the vasoconstrictor effects of catecholamines leading to tissue anoxia and lactic acid production.

However, according to new findings, hyperlactatemia is not a consequence of anaerobic glycolysis, tissue hypo-perfusion, or cellular hypoxia, as believed in the past. Such hyperlactatemia is probably indicative of a stress response, with increased metabolic rate and sympathetic nervous system activity.[3]

The relationship between stress and increased lactic acid/lactate concentration was recently discussed by us as having a causal role for atherosclerosis[16, 17] and for acute myocardial infarction. [18]

Notes

1.         Hyperlactatemia is defined as a mild to moderate persistent increase in blood lactate concentration (2-4 mmol/L) without metabolic acidosis, whereas lactic acidosis is characterized by persistently increased blood lactate levels (usually >4-5 mmol/L) in association with metabolic acidosis;

2.         Lactic acidosis results from increased production of lactate, the final product in the pathway of glucose metabolism. Lactate and lactic acid are not synonymous. Lactic acid is a strong acid which, at physiological pH, is almost completely ionized to lactate.

Acidic Environment and Lactic Acid

The extracellular pH of tumour tissue is often acidic, and acidic metabolites, e.g., lactic acid seem to be its main cause.[19]

Thus, hindering the outflow of catecholamine may consequently decrease the lactate production with effects on the acidic environment, basifying the extracellular pH in tumor tissues.

Ketogenic Diets for Cancer

The use of Ketogenic diets (high fats/low carbs), in prevention or in treatment of cancer is supported by our present hypothesis due to the following reasons:

1)         High carbohydrate diets cause greater sympathetic nervous system activation while fat ingestion does not result in any appreciable changes;[20]

2)         High carbohydrate diets may increase significantly the activity of serum lactate;[21]

3)         The Ingestion of monosaccharides (simple sugars like glucose, fructose and galactose) may have the effect to raise blood lactic acid with this increase being most marked and lasting longest after fructose, that is largely used today as sweetener in soft drinks, fruit punches, pastries and processed foods.[22,23]

Melanie Schmidt and colleagues, in their clinical study about ketogenic diet from 2011,[24] share with us some old but important information about carbohydrates and cancer:
“Since 1885, when E Freund observed that patients with malignant disease can develop spontaneous hyperglycaemia, there has been episodic interest in the association of the altered glucose metabolism with the path of nutrition and neoplasia in man. As early as 1924, Händel and Tadeuma summarized the findings in those days as: ‘a diet rich in carbohydrates has a pronounced stimulating impact on tumour growth’.”

Therefore, according our hypothesis, high carbohydrate diets and simple sugars may represent potential risk factors for cancer.

Cardiac Glycosides: The Fundamental Drugs Against Cancer

Studies using cardiac glycosides like digitalis, an old heart drug, have shown properties of induction of apoptosis and inhibition of proliferation of cancer cells. The use of cardiac glycosides also resulted in a large reduction in mortality of cancer in patients taking these drugs when given at low concentration doses.

In our view the beneficial use of cardiac glycosides in prevention or in therapy of cancer is derived from their neuro-hormonal effects through the inhibition of the sympathetic nervous system and by strengthening the parasympathetic system, avoiding in this way a raise in catecholamine release and acceleration of glycolysis metabolism, therefore, reducing lactate production. [25]

Dedication

I dedicate this paper to my friend Prof Dr Paul J. Rosch, Chairman of the Board at the American Institute of Stress. Paul Rosch is one of my great mentors in medical science and who brought knowledge, advices and inspiration to our researches on the link stress and lactate leading to cancer.

References

1.         Rosch, Paul J. "Stress and cancer: A disease of adaptation?."Cancer, stress, and death. Springer US, 187-212.  at https://link.springer.com/chapter/10.1007%2F978-1-4684-3459-0_18#page-1. 1979.  

2,         Thomas N Seyfried and Laura M Shelton.  Cancer as a metabolic disease. Nutrition & Metabolism 7:7 at http://www.nutritionandmetabolism.com/content/7/1/7. 2010.

3.         Mercedes Garcia Alvarez, Paul Marik, Rinaldo Bellomo. Stress hyperlactataemia: present understanding and controversy. The Lancet Diabetes & Endocrinology, http://thelancet.com/journals/landia/article/PIIS2213-8587(13)70154-2/fulltext  November 29, 2013.

4.         Iñigo San-Millán and George A. Brooks. Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg Effect. Carcinogenesis,, Vol. 38, No. 2, 119–133;  https://academic.oup.com/carcin/article/38/2/119/2709442/Reexamining-cancer-metabolism-lactate-production. 2017.

5.         Claire Magnon, Simon J. Hall, Juan Lin, Xiaonan Xue, et al. Autonomic Nerve Development Contributes to Prostate Cancer Progression. Science Vol 341 http://science.sciencemag.org/content/341/6142/1236361 12 July 2013.  

6.         Chun-Mei Zhao, Yoku Hayakawa, Yosuke Kodama et al. Denervation suppresses gastric tumorigenesis. Sci. Trans. Med. 6; 250ra115:  http://stm.sciencemag.org/content/6/250/250ra115  201.4

7.         Carlos ETB Monteiro, Cancer, Atherosclerosis and Sympathetic Dominance. Positive Health Online, Issue 223 http://www.positivehealth.com/article/cancer/cancer-atherosclerosis-and-sympathetic-dominance  July 2015.  

8.         Jason Tilan and Joanna Kitlinska. Sympathetic Neurotransmitters and Tumor Angiogenesis – Link Between Stress and Cancer Progression. Journal of Oncology, V 10; Article ID 539706. 2010.

9.         Claire Magnon. Role of the autonomic nervous system in tumorigenesis and metastasis, Molecular & Cellular Oncology, 2:2, e975643; 2015.

10.       Katarina Ondicova, Boris Mrave. Role of nervous system in cancer aetiopathogenesis. Lancet Oncol , 11: 596–601: 2010.

11.       Dongfeng Zhang, Xiaoli Shen, Xin Qi. Resting heart rate and all-cause and cardiovascular mortality in the general population: a metaanalysis. CMAJ  http://www.cmaj.ca/content/early/2015/11/23/cmaj.150535  November 23, 2015.

12.       Regnier MA, Raux M, Le Manach Y, et al. Prognostic significance of blood lactate and lactate clearance in trauma patients. Anesthesiology, 117; 1276–88: 2012.

13.       Cori CF and Cori GT. The mechanism of epinephrine action IV: The influence of epinephrine on lactic acid production and blood sugar utilization. J Biol Chem, 84: 683-98:  http://www.jbc.org/content/84/2/683.full.pdf+html 1929.

14.       Williamson JR. Metabolic effects of epinephrine in the isolated, perfused rat heart. J Biol Chem, 239: 2721-29;  http://www.jbc.org/content/239/9/2721.full.pdf  1964.

15.       Schade DS. The role of catecholamines in metabolic acidosis. Ciba Found Symp; 87:235-53: 1982.

16.       Carlos ETB Monteiro, Acidity Theory of Atherosclerosis -- History, Pathophysiology, Therapeutics and Risk Factors – A Mini Review. Positive Health Online, Issue 226   http://www.positivehealth.com/article/heart/acidity-theory-of-atherosclerosis-history-pathophysiology-therapeutics-and-risk-factors-a-mini-revie   November 2015.

17.       Carlos ETB Monteiro, 'Stress as Cause of Atherosclerosis – The Acidity Theory' published in Chapter 10 of the book “Fat and Cholesterol Don’t Cause Heart Attacks and Statins Are Not The Solution” https://www.amazon.com/Cholesterol-Cause-Attacks-Statins-Solution/dp/190779753X   2016.

18.       Carlos ETB Monteiro, “Stress as Cause of Heart Attacks - The Myogenic Theory”. Published at the Journal Wise Traditions in Food, Farming, and the Healing Arts, Fall 2014. Reproduced by Positive Health Online, Issue 222  http://www.positivehealth.com/article/heart/stress-as-cause-of-heart-attacks-the-myogenic-theory  May 2015.

19.       Kato Y et al. Acidic extracellular microenvironment and Cancer. Cancer Cell International, 13:89  http://www.cancerci.com/content/13/1/89  2013.

20.       Tentolouris et al. Differential effects of high-fat and high-carbohydrate isoenergetic meals on cardiac autonomic nervous system activity in lean and obese women. Metabolism, 52(11);1426-32:  http://www.metabolismjournal.com/article/S0026-0495(03)00322-6/fulltext  Nov 2003.

21.       Marshall MW and Iacono JM. Changes in lactate dehydrogenase, LDH isoenzymes, lactate, and pyruvate as a result of feeding low fat diets to healthy men and women. Metabolism. Feb;25(2):169-78.1976.

22.       Harold T. Edwards, Edward H. Bensley, David B. Dill and Thorne M. Carpenter. 1944. Human Respiratory Quotients in Relation to Alveolar Carbon Dioxide and Blood Lactic Acid After Ingestion of Glucose, Fructose, or Galactose. Journal of Nutrition Vol. 27 No. 3: 241-251, March 1944.

23.       Hallfrisch J. Metabolic effects of dietary fructose. FASEB J, Vol 4; 2652-2660. at https://www.ncbi.nlm.nih.gov/pubmed/2189777  Jun 1990.

24.       Melanie Schmidt et al, Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: A pilot trial. Nutrition & Metabolism, 8:54,  http://www.nutritionandmetabolism.com/content/8/1/54  2011 

25.       Carlos ETB Monteiro. Cardiac Glycosides at Low Concentration Providing Neuro-Hormonal Effects.: The Final Solution Against Cancer?. Positive Health Online, Issue 241, http://www.positivehealth.com/article/cancer/cardiac-glycosides-at-low-concentration-providing-neurohormonal-effects-the-final-solution-against-c  October 2017.