Examining the relationship between diet-induced acidosis and cancer

Increased cancer risk is associated with select dietary factors. Dietary lifestyles can alter systemic acid-base balance over time. Acidogenic diets, which are typically high in animal protein and salt and low in fruits and vegetables, can lead to a sub-clinical or low-grade state of metabolic acidosis. The relationship between diet and cancer risk prompts questions about the role of acidosis in the initiation and progression of cancer.

Cancer is triggered by genetic and epigenetic perturbations in the normal cell, but it has become clear that microenvironmental and systemic factors exert modifying effects on cancer cell development. While there are no studies showing a direct link between diet-induced acidosis and cancer, acid-base disequilibrium has been shown to modulate molecular activity including adrenal glucocorticoid, insulin growth factor (IGF-1), and adipocyte cytokine signaling, dysregulated cellular metabolism, and osteoclast activation, which may serve as intermediary or downstream effectors of carcinogenesis or tumor promotion.

In short, diet-induced acidosis may influence molecular activities at the cellular level that promote carcinogenesis or tumor progression. This review defines the relationship between dietary lifestyle and acid-base balance and discusses the potential consequences of diet-induced acidosis and cancer occurrence or progression.

The relationship between diet and cancer is well known [1-3]. Dietary intake exists as the largest external or environmental epigenetic factor capable of driving the development or maintenance of cancer. The American Institute for Cancer Research (AICR) comprehensive global report has compiled numerous studies demonstrating associations between dietary habits and cancer risk [4]. The findings recommend increased or regular consumption of vegetables, fruits, whole grains, and legumes, while discouraging excess consumption of sugary and energy-dense foods and drinks, red and processed meats, and salty processed foods (http://www.aicr.org).

Acidity is a well known factor associated with cancer. Lower pH levels in the extracellular space promote the invasive and metastatic potential of cancer cells [5-14]. Extracellular acidity is mostly generated by tumor cells due to upregulated proton [H+ and lactic acid production [15]. This phenomenon is distinct from ‘acidity’ caused by a net-acid diet. A net-acid diet or acidogenic diet is determined by the balance between acid and base-forming dietary constituents. Most fruits and vegetables are net-base producing foods since the metabolized products are organic anion precursors such as citrate, succinate, and conjugate bases of carboxylic acids [16-18].

The final metabolite of these precursors is bicarbonate anion. Sulfur containing amino acids, methionine and cysteine, typically found in meats, eggs and dairy products, are oxidized into sulfuric acid which is ultimately net-acid producing [16]. Cationic amino acids such as lysine and arginine can be acid producing if their anionic counterpart is chloride, sulfate, or phosphate. However, if the anionic component is a metabolizable organic acid (glutamate or aspartate), there is almost no impact on systemic acidity [17,18]. Other dietary factors are known to influence acid-base status as well. Sodium chloride is reported to be an independent and causal factor for inducing metabolic acidosis in a dose-dependent manner [19,20].

Conversely, potassium salts, and to a lesser degree magnesium, serve as a countervailing effect on net acid excretion and help to promote alkaline balance [21,22].

Acidogenic dietary intake such as high protein consumption can have an immediate effect on increasing net acid production while low protein lacto-vegetarian consumption can result in significantly reduced net acid excretion [23,24]. Short-term dietetic acid loading may cause temporary acid-base disequilibrium, but is quickly compensated and has no measureable clinical effect.

A persistent acidogenic diet, however, raises the likelihood of an increased [H+ surplus and chronically lower levels of serum bicarbonate if compensatory processes become less efficient and are unresolved by dietary adjustments. Potential long-term effects of acidogenic diets are further compounded by the reduction of renal function typically from ageing [16,25-28].

Blood pH from prolonged or chronic acidogenic diets is reported to be near the lower physiological range (7.36-7.38) rather than the higher end (7.42-7.44). Specifically, persistent acidogenic diets have the potential to cause small decreases in blood pH and plasma bicarbonate, but not beyond the normal physiological range. This condition is described as ‘diet-induced’, ‘low-grade’, or ‘chronic metabolic acidosis’ [28-30] or sometimes ‘latent acidosis’ [31].

Diet-induced acidosis is distinct from clinical metabolic acidosis in that clinical metabolic acidosis occurs when factors other than just acidogenic diet contribute a system’s inability to compensate for blood [H+ perturbations, typically resulting in blood pH below 7.35 [32]. The patho-physiological effects of clinical metabolic acidosis are well known [33], while the true pathophysiological impact of long-term, diet-induced acidosis is not well understood. For example, it is unknown if [H+ accumulation from chronic diet-induced acidosis can be stored at the cellular level if it does not play a role in lowering blood pH or is compensated by competent renal or respiratory function.

Studies of the impact of clinical metabolic acidosis on biological systems may still be informative towards understanding the effects of diet-induced acidosis because they examine how acid-base disequilibrium causes physiological stress and influences molecular pathways active in disease processes [34].

It is generally understood that the cancer condition evolves from genetic and epigenetic changes in the normal cell. Both microenvironmental and systemic factors exert selective pressures that aid in the initiation or aggravation of tumors. Acid-base disequilibrium is considered a type of systemic stress. With the understanding that long-term acidogenic diets potentially exert chronic physiological stress, the question proposed here is: Can diet-induced acidosis increase cancer risk or promote existing tumors?