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Physiological Mechanisms: Underlying High Salt Diets and Cancer…

Introduction:

I recently received a question from Bill, “I would also like to know what the purported mechanism for low sodium and low cancer is?

Let me first preface this question with my original blog that that precipitated the question.  Dr. Jansson sent me in his unpublished book manuscript on May 10, 1997 (Found here: http://thepaleodiet.com/a-rare-and-never-before-published-book-chapter-concerning-salt-and-cancer/). Accordingly, the information in his book is now more than 20 years old and unfortunately, Dr. Jansson died 23 May 1998.  Dr. Jansson’s book runs about 300 pages in length, is hand typed, double spaced, and contains the following 10 Chapters:  

  1. Background to the potassium/sodium hypothesis
  1. Human diet before modern times
  1. Diet and dietary carcinogens and anticarcinogens
  1. Non-dietary carcinogens and anticarcinogens
  1. Aging and cellular and total body potassium and sodium
  1. Hypo- and hyperkalemic diseases and cancer
  1. Altitude and cellular potassium and sodium and cancer
  1. Animal experiments
  1. Earlier studies of relations between potassium, sodium and cancer
  1. Conclusions, explanations and recommendations

 

Contained in Dr. Jansson’s book are numerous references that he uses to explain cellular mechanisms of action underlying the epidemiological evidence that he summarizes demonstrating the relationship between dietary sodium (Na+), potassium (K+) and cancer.  Clearly, since I have not obtained permission to publish his book from his heirs, it would not be ethical for me to release it yet.  However, I can tell you that many of the cellular mechanisms involving sodium, potassium, cancer initiation and promotion, that Dr. Jansson discusses, were well known 20 years ago by cancer scientists and oncologists.  These mechanisms are virtually identical to those same ones that Dr. Jansson had previously described in his scientific publications (1-8).   

I would like to point out that Dr. Jansson’s work with sodium, potassium, and cancer was not exclusively unique to his scientific publications or those of his scientific colleagues.  Two other well-known cancer scientists, Maryce Jacobs and Roman Pieta independently published an extensive review chapter (9) on the same topic while exhaustively reviewing almost all human studies (epidemiology and case reports), tissue (cell culture) studies, animal studies as well as mechanisms of action.  These authors conclusions were as follows: “Generally, a high potassium to sodium ratio is associated with decreased cancer incidence.  Conversely, a higher sodium to potassium ratio with a higher absolute sodium concentration is associated with a higher risk of cancer” (9).   

Sodium, Potassium and Cancer: Early Studies and Mechanisms of Action.

It has been long recognized that modifications in the cell surface are implicated in the oncogenic and mitogenic processes, including changes in ion transport, membrane permeability, transmembrane potential, and intracellular ion concentrations (3, 6, 9,10-16).  Cone and colleagues have pointed out that the chronic lowering of the transmembrane potential initiates the mitogenic process, and that environmental events which reduce the activity of the Na+/K+ pump in the cell surface membrane initiate and sustain mitosis (10-16).  The notion that elevated intracellular Na+ concentrations are increased in cancer cells, whereas K+ concentrations are reduced, has been demonstrated in tissue studies as well as in vivo data from a variety of human and animal experiments (9, 17-20).

One of the challenges in the interpretation of these early experiments was the technology that was employed to measure intracellular Na+, K+ and other ions.  Generally, these ions were determined by technologies (flame emission photometry, atomic absorption analysis, electron probe X-ray microanalysis) that necessitated penetration of the cell wall and required correction for the contaminating presence of extracellular fluid ions which introduced large errors in the data (21).   Accordingly, the clues to the etiology of cancer provided by these early ion experiments went largely ignored by later cancer workers who focused upon more complex hormone, cytokine (localized hormones) and immune mediated mechanisms of cancer.

Nevertheless, a new technology (presently called 23NaMRI, previously called 23NaNMR) was developed by FW Cope between 1965-1970 (22-23) which for the first time allowed for accurate intracellular ionic concentration measurements in muscle, brain, and kidney tissues without disrupting cellular membranes and without contaminating the internal cellular ion content with extracellular fluid ions.  Unfortunately, the clout of this powerful new technology went largely unappreciated by cellular physiologists until the early 1980’s when it finally began to gain acceptance as a method for non-invasive and non-destructive determination of intracellular sodium in viable cells and tissue (21, 24). Only a relative few cellular biologists began to examine intracellular Na concentrations in cancer cells using 23NaMRI (21, 24).  Hence, the notion of altered ionic concentrations in cancer cells remained largely unrecognized by most oncologists and cancer scientists.  Further, specific studies of salt loading in humans and accurate measurements (23NaMRI) of intracellular Na+ and K+ concentrations in various human tissues would still lie in the future.

Sodium, Potassium and Cancer: Recent Studies and Mechanisms of Action.

The first study to investigate salt loading and examine intracellular sodium concentrations (via 23NaMRI) in any human body tissue was performed in 1994 by Resnick and colleagues (25) who were interested not in cancer, but in hypertension.  In both, hypertensives and normal subjects fed high salt diets (200 meq/day) for two months, significant increases in erythrocyte (red blood cell) intracellular Na+ concentrations occurred (25).   

Interestingly, blood plasma concentrations of Na+ are regulated by the kidney within a very narrow range (135-145 mmol/L) that is stable within 2 to 3 mmol/L over 3 year periods in humans (26), and only show transient elevations during increased periods of elevated salt consumption (27, 28).  Accordingly, the prevailing dogma in the scientific literature had been that increased dietary Na+ intakes were acutely (within hours or days) removed from the bloodstream (plasma) and excreted by the kidney into the urine via commensurate increases in water retention.  Hence, when dietary Na+ is increased from low to high levels, total body Na+ and water increase until daily Na+ excretion again equals intake.   

This dogma had prevailed in the scientific literature for over 50 years, but should have started to crumble with the Resnick et al. (25) study (using 23NaMRI data) which indicated that erythrocytes retain Na+ intracellularly when plasma concentrations of Na+ are temporarily elevated.  The implications of the Resnick et al. study (25) are suggestive that Cope’s (22, 23) original hypothesis (22, 23), first formulated in 1965-70, was correct in suggesting that many body tissues (muscle, kidney, brain) tend to retain Na+ ions when plasma concentrations are acutely elevated.  Plasma concentrations of Na+ shortly return to normal ranges after dietary intakes are elevated (27, 28), but tissue intracellular concentrations do not (29-32).    

Perhaps, the most important insight of these new developments is the recognition that certain body tissues, particularly skin, skeletal muscle, erythrocytes and other tissues (29, 33-38) act as reservoirs to retain Na+ intracellularly, long after transient plasma changes in Na+ concentrations occur.  This important new data implicates dietary salt as being integral in the etiology of autoimmune disease (38, 39 -41), cardiovascular disease (42-45), chronic inflammation (38, 39, 42, 46-57) and now alarmingly in multiple types of cancer (58-67), as previously outlined by Jansson (1-8) Jacobs (9) and others more than 20 years ago.   

Mechanisms Underlying Cancer from Salt Ingestion

Cancers generally maintain five developmental stages: 1) initiation, 2) promotion, 3) malignant conversion, 4) invasion and 5) metastasis (68).  In virtually every developmental stage of cancer, inflammation plays a crucial role (68-75).  Although numerous genetic and environmental factors underlie cancer development and progression, it is clear that elevated dietary salts act at all five developmental stages of cancer to promote and initiate cancer via salt’s promotion of inflammation, tumor-genic growth factors and pro-carcinogenic modulation of the innate and adaptive immune systems.

DNA Damage, Repair and Salt

Cells have evolved mechanisms which constantly monitor DNA for any damage or breaks in its integrity and then proceed to repair the broken or damaged DNA (74, 75).  DNA damage occurs during acute inflammation and subsequently accumulates during chronic inflammation.  DNA repair mechanisms are important in countering damage to DNA, but are not always successful, often times leading to cancer promotion (74, 75).

Burg and colleagues have demonstrated that a high salt environment increases the number of DNA breaks both in cell cultures and in vivo (76-78).  Acute elevations of osmolality from 300 (the normal concentration in plasma) to 500-600 mosmol/kg H2O by adding NaCl causes DNA strand breaks both in tissue and in vivo experiments which persists even after the cells have adapted to higher salt environments (77, 78).   

High salt diets can cause tissue (skin, muscle, erythrocyte, brain, kidney) intracellular concentrations of Na+ to increase beyond plasma concentrations of Na+ (29, 33-38).  Accordingly, as long as high dietary salt intakes are continued, then the higher concentrations of Na+ found in the tissue reservoirs of Na+ (skin, muscle, erythrocytes, brain and other tissues) will put them at increased risk for DNA damage, inflammation and cancer promotion not only from increased DNA breaks but also from its associated pro-inflammatory milieu (74, 76).  

          

Reactive Oxygen Species (ROS) and Salt   

In biological systems ROS (superoxide, hydrogen peroxide, hydroxyl radicals) can be produced intracellularly from exogenous sources (diet, tobacco smoke, pollutants, radiation, drugs, and salt consumption) reacting with cellular contents.  ROS are also formed endogenously as a normal product of oxygen metabolism and maintain important roles in cellular signaling and homeostasis.  During times of environmental stress (high ultraviolet radiation, pollutants, high salt intake, etc.), ROS concentrations may increase dramatically which can significantly damage cell structures. This process is referred as oxidative stress and produces chronic inflammation (74, 75) which may lead to cancer (79, 80).   

Elevations of salt in tissue culture studies as well as in vivo animal models indicate that chronic increases in salt consumption can have deleterious health effects by increasing ROS production (81-88).   Increased ROS production in turn acts synergistically to promote DNA damage and a pro-inflammatory microenvironment conducive to cancer formation (74, 79, 80).  

Vascular Endothelial Growth Factor (VEGF) and Salt

Angiogenesis, the creation of new vessels from established vasculature is crucial to tumor growth and metastasis.  Angiogenesis is regulated by multiple factors, of which VEGF plays a principal role.  Various approaches to inhibit the VEGF signaling pathway by directly targeting VEGF itself or by blocking its receptors have been developed and have become established techniques for treating a wide variety of cancers (89-93).  VEGF causes angiogenesis in tumors via multiple mechanisms including the activation of specific signaling pathways (NFAT5 and AKT/PI3k) (59, 94).

At least two human studies have demonstrated significant increases in circulating concentrations of VEGF-C following consumption of high salt diets (95, 96).  The human data corroborates animal experiments also showing that high salt diets elevate VEGF-C (97-99).  High salt cellular environments have recently been demonstrated to directly induce the expression of VEGF in breast cancer cells via a number of mechanisms including the NFAT5 signaling pathway (59).  Studies of breast cancer patients have indicated a strong correlation between the genetic expression of NFAT5 and the development of breast cancer (100). This accumulating information clearly indicates that a high salt environment promotes angiogenesis in tumor cells.   

Salt Induced Warburg Metabolism in Cancer Cells

One of the defining characteristics of all cancer cells, unlike normal cells, is that they utilize a seemingly inefficient metabolism of glucose, producing large amounts of lactate as opposed to synthesizing ATP.  This abnormal metabolism of glucose by all cancer cells is called aerobic glycolysis and was first identified by Otto Warburg in 1924 (101, 102) and hence, it is called the “Warburg Effect” of cancer cells (60, 101, 102).   

Although the exact causes of the “Warburg Effect” of all cancer cells are unclear, high osmotic stress in the solid tumor microenvironment is considered to be one of the most important factors (60, 77, 78).  As I have previously shown, a high salt diet transiently increases plasma Na+ concentrations (25, 27) which causes elevated concentrations of salt in almost all of the body’s tissues including skin, muscle, erythrocytes, brain, and kidney (23, 25, 33-38) that creates high osmotic stress (77, 78) in these tissues.

Amara and colleagues have demonstrated that a high salt environment exaggerates the Warburg Effect in breast cancer cells by increasing osmotic stress (60).  Accordingly, dietary salt may act to promote cancer cell proliferation in various tissues by enhancing the Warburg Effect in actively growing tumors.

Salt Induced Pro-Cancer Activation of Macrophages

Macrophages are a type of white blood cells that engulf and digest cellular debris, foreign substances, microbes, and cancer cells.   A subtype of these cells, called M1 macrophages, encourage inflammation and promotes cancer, whereas those macrophages that decrease inflammation and encourage tissue repair are called M2 macrophages (61, 103-104).  High salt environments activate M1 macrophages to produce a pro-inflammatory M1 state (40, 104) that promotes cancer while simultaneously inducing a M2 environment with poor phagocytic ability to engulf and remove cancer cells (61).  Accordingly, the epidemiological evidence indicating that a high salt diet promotes cancer (1-9) is consistent with the molecular physiologic evidence.

Salt and T Cell Activation

A high salt environment not only activates macrophages of the innate immune system to promote cancer, but it also activates CD4+ T helper (Th) cells (46) which form an essential part of the antigen specific, adaptive immune system whose function is governed by micro-environmental cues (105).  Local tumor inflammatory conditions cause a number of immune cells, including CD4+ T helper (Th) cells to be recruited to the local tumor site (58).  A high salt environment induces CD4+ T helper (Th) cells to differentiate into Th17 cells (39, 51) which then secrete the pro-inflammatory cytokine (IL-17) within the tumor micro-environment (46, 58).  IL-17 induces angiogenesis in the tumor microenvironment by causing increased secretion of VEGF which leads to enhanced tumorigenicity and cancer metastasis (51, 73).  Mechanistically, high salt environments promote the activation of CD4+ T helper (Th) cells into Th17 cells and the subsequent secretion of the pro-inflammatory cytokine (IL-17) via the NFAT5, the p38/MAPK, the AKT/PI3k and the SGK1 signaling pathways (39, 51, 59, 94).

High salt diets not only promote cancer via their activating and pro-inflammatory effects upon CD4+ T helper cells and the formation of Th17 cells (46, 58), but also upon their impairment of regulatory T cells (Tregs); key elements of the adaptive immune system.  Tregs normally produce anti-inflammatory properties via secretion of the immuno-suppressive IL-10 cytokine (58).  High salt environments have been demonstrated to promote interferon release from Tregs and abolish their normal anti-inflammatory and immunosuppressive effects (106, 107).  Once again, high salt environments appear to adversely affect Tregs via their effect upon the SGK1 signaling pathway (106). The suppressive effect of high salt environments upon Tregs function supports the conclusion from epidemiological studies (1-9) that a high salt, low potassium environment represents a key nutritional factor that promotes and initiates cancer.

Conclusions

The average U.S. diet (per day) contains 3,584 mg of sodium (Na+) and 2795 mg of potassium (K+) yielding a K+/Na+ ratio of 0.77 (108).   WAKE UP READERS! This ratio (below 1.00) should fundamentally shake you, as it demonstrates the dysfunction and disease promoting effects of the typical U.S. diet.  Few natural, unsalted foods maintain K+/Na+ ratios less than 1.00.  From my prior blog and spreadsheet (109), which extensively examines the sodium (Na+) and potassium (K+) content of more than 1200 plant and animal foods (unadulterated without added salt), two key conclusions are revealed:  

1) It is difficult or impossible when eating natural, non-salted, foods to consume more than 2300 mg of Na+ per day, and  

2) It is virtually impossible when eating real, non-salted foods to consume less potassium than sodium. Non-salted, natural foods, contain 5 to 10 times more potassium than sodium (109).  In the typical U.S. diet, we eat about 23% more sodium than potassium (108).

 

Consequently, this data provides indisputable information regarding the ancestral nutritional conditions (high potassium, low sodium) that conditioned the human genome, but also the genomes of all terrestrial vertebrates as well as the genomes of all simple celled organisms, as life on earth evolved from unicellular organisms into multicellular organisms including fish, amphibians, terrestrial dwelling reptiles, birds, mammals and hominins (us).

All cells in human, mammalian and terrestrial species have evolved a cellular mechanism called the sodium (Na+)/potassium (K+) ATP-ase pump.  The Na+/K+ ATP-ase pump maintains the internal cellular ionic environment at rest by pumping Na+ out of the cell to maintain a low internal cellular Na+ environment, but also to keep the internal cellular potassium environment high (110, 111).    

Further, terrestrial and aquatic vertebrates have evolved kidneys which filter blood to remove excessive blood (plasma) stores of Na+, but also serve to maintain high blood concentrations of K+ in blood (plasma) (112, 113).   This is the natural physiological state of affairs under which virtually all life on earth evolved – a low intracellular sodium environment and a high potassium intracellular environment (114, 115).

The regular inclusion of mined, artificial salt into the human diet, which has only occurred regularly in the past 10,000 years (333 human generations) (116, 117), represents a fundamental nutritional disruption for which our genomes have no recourse except disease (1-9, 25, 27, 29, 34, 58-67), physiological dysregulation (38, 39, 41, 42, 46-57), and premature aging and senescence (118-121).

The contemporary Paleo Diet is not necessarily about pleasing our modern palettes and penchants for unlimited salt, sugar and refined carbohydrates, but rather it is about emulating the dietary characteristics of our pre-agricultural ancestors (116, 117).  A lifetime dietary intake of what is typically perceived as an innocuous salt intake/addiction is actually a high salt/low potassium diet (115).  This abnormal nutritional condition (high salt intake/low potassium intake) puts all people at increased risk for most chronic diseases of civilization and premature death.

 

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About Loren Cordain, PhD, Professor Emeritus

Loren Cordain, PhD, Professor EmeritusDr. Loren Cordain is Professor Emeritus of the Department of Health and Exercise Science at Colorado State University in Fort Collins, Colorado. His research emphasis over the past 20 years has focused upon the evolutionary and anthropological basis for diet, health and well being in modern humans. Dr. Cordain’s scientific publications have examined the nutritional characteristics of worldwide hunter-gatherer diets as well as the nutrient composition of wild plant and animal foods consumed by foraging humans. He is the world’s leading expert on Paleolithic diets and has lectured extensively on the Paleolithic nutrition worldwide. Dr. Cordain is the author of six popular bestselling books including The Real Paleo Diet Cookbook, The Paleo Diet, The Paleo Answer, and The Paleo Diet Cookbook, summarizing his research findings.


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