Dietary adjustments are often used for the treatment and prevention of diseases. Cancer is no exception: proper nutrition can serve not only as a preventive measure, but also increase the effectiveness of therapy. Here we propose to highlight the “taste preferences” of cancer cells and to understand how individual nutrients can help fight tumors.
Since the early 1980s, leading health organizations have issued dietary and lifestyle recommendations to reduce individual cancer risk. These recommendations are based on the results of meta-analyses of epidemiologic studies (in other words, analyzing the long-term experience of millions of people who have eaten in one way or another). These recommendations are universal and easy to follow: they do not require calorie counting, strict control of food composition, but only offer a general scheme and principle of nutrition to maintain a healthy weight
Nutritional recommendations, which are usually aimed at reducing the likelihood of cancer: the daily diet should include fruits, vegetables, legumes, whole-grain cereals. If possible, you should limit the consumption of red meat, sugar, sweet carbonated drinks and alcohol. Following these tips will help you maintain a healthy weight throughout your life and reduce your individual risk of developing cancer.
This kind of advice applies to healthy people, whereas there are no standardized nutritional recommendations for people with cancer. At the same time, the nutrition of patients can greatly influence the success of therapy for malignant lesions. Why can't universal dietary recommendations be made for people with cancer? The answer to this question follows from the principles according to which all tumors develop. Initially, the cell that in the future will give rise to a tumor is no different from its neighboring cells. As mutations accumulate, normal cells can gradually evolve to acquire the features of cancer cells. In 2000, among the many features of cancer, the legendary Hallmarks of cancer review outlined the key features that define the biology of a tumor cell.
The most important feature of all cancer cells is genome instability, which results in the enormous genetic diversity of tumors. Despite a number of properties inherent to all cancer cells, each tumor has a unique set of mutations that determine its aggressiveness, growth rate, and the effectiveness of therapy. The genetic diversity of tumors is a major obstacle to universal nutritional recommendations for patients.
Recently, researchers have been actively studying the effect of nutrients on tumor progression and treatment efficacy. Most of the experimental work is done on animal models, but there are a few clinical studies as well. We suggest readers to get acquainted with the peculiarities of tumor cell metabolism. We will try to understand how the substances consumed with food can affect the tumor and its environment. And finally, we will try to answer the question: can diet help in the fight against cancer?
Metabolism
In order to understand the intricacies of cancer cell metabolism, let us briefly recall the basic principles and terms of bioenergetics. Metabolism is a set of chemical transformations in the cell, which are aimed at obtaining energy and necessary substances. Just look at the countless number of reactions that metabolism involves! All metabolic pathways can be divided into biodegradation (catabolism) and biosynthesis (anabolism). Catabolism produces energy in the form of macroergic compounds (such as ATP) as well as NADH, NADPH and FADH2, coenzymes involved in redox reactions. Anabolic processes use the stored energy to synthesize molecules necessary for cell life: fats, nucleotides, proteins, and carbohydrates.
Metabolism is closely linked to nutrition: every day we consume nutrients that, on the one hand, participate in catabolic reactions and supply energy to cells, and on the other hand, are necessary for the synthesis of our own molecules. The carbohydrates, proteins and fats we consume are broken down in the digestive tract to monomeric units: carbohydrates to monosaccharides (glucose, fructose, etc.), fats to fatty acids and glycerol, proteins to amino acids. These molecules enter the cells of the body and take part in metabolic processes.
In a cancer cell, the activity of some metabolic enzymes or entire metabolic pathways is often increased, which means that tumor cells may have different nutrient requirements than normal cells. These features can be taken into account in tumor treatment: the exclusion of certain food components from the patient's diet will lead to a decrease in their content in the blood plasma, and therefore in the environment of cancer cells, which will adversely affect their reproduction. In addition, some food elements can directly affect antitumor immunity, which should also be taken into account when formulating the diet.
Glucose
Glucose is the main source of energy for living organisms. In the normal human diet it is found both in free form and as part of oligo- and polysaccharides (e.g. sucrose, lactose and maltose). One of the most important bioenergetic pathways in the cell is glycolysis - a sequence of chemical reactions resulting in the production of 2 molecules of pyruvic acid, 2 molecules of ATP and 2 molecules of NADH from 1 molecule of glucose. The pyruvic acid can then be involved in the tricarboxylic acid cycle (Krebs cycle), a biochemical process in the mitochondria that supplies NADH and FADH2 which ultimately makes possible the synthesis of ATP through oxidative phosphorylation. In this process, approximately 36 molecules of ATP can be produced from 1 molecule of glucose, which is much more energetically advantageous than glycolysis alone. As a consequence, most cells actively utilize the tricarboxylic acid cycle and oxidative phosphorylation for energy production.
However, there are many known cases where, for various reasons, cells shift the balance toward glycolysis, using this pathway as their primary energy source by inhibiting tricarboxylic acid cycle enzymes or activating glycolysis enzymes.
It has long been known that tumor cells actively use glycolysis (oxygen-free oxidation of glucose outside the mitochondria) despite its relatively low efficiency in terms of energy gain. This phenomenon was discovered by Otto Heinrich Warburg in 1924. Warburg himself believed that impaired cellular respiration was the primary cause of tumor development. However, it turned out that cellular respiration in most tumor cells is not disturbed, but simply suppressed due to active glycolysis. It is now clear that active glycolysis provides an advantage to tumor cells. First, glycolysis proceeds without oxygen, and appears to be largely an adaptation to the hypoxia(oxygen deficiency) that develops as tumor cells are removed from blood vessels. Part of this problem is also addressed by the fact that cancer cells can promote angiogenesis - the sprouting of blood vessels into the tumor through the production of angiogenic factors such as VEGF (Vascular endothelial growth factor). Secondly, active glycolysis is associated with the formation of a large amount of lactic acid, which leads to acidification of the environment, thereby promoting tumor invasion by destroying normal cell populations and degradation of the extracellular matrix.
At the same time, one cannot ignore the fact that the Warburg effect is observed not only in tumor cells, but in general in all actively proliferating cells. Glucose is one of the main sources of carbon in the cell, and its complete oxidation in the tricarboxylic acid cycle goes against the needs of the proliferating cell. Some portion of glucose, or rather its metabolites, must be diverted to the pathways of biosynthesis of amino acids, nucleotides, and fatty acids. The pentose phosphate pathway, an alternative glucose oxidation pathway, plays an important role in the production of nucleotide and amino acid precursors, as well as NADPH, which is necessary for fatty acid synthesis, and is also key in supporting cancer cell growth.
Thus, glucose is particularly required by cancer cells due to their active proliferation; it serves not only as an energy source but also as an important precursor for the synthesis of amino acids, nucleotides and fatty acids. However, in addition to the direct role of glucose in cellular metabolism, the effect of insulin on tumor cells is also an important physiological aspect.
It is well known that an increase in blood glucose levels causes the pancreatic beta cells to secrete the hormone insulin. Insulin, in turn, interacts with insulin receptors on cell surfaces. The interaction of insulin with its receptor leads to the activation of phosphatidylinositol-3-kinase (PI3K), a key enzyme of the PI3K/AKT/mTOR signaling pathway: PI3K operation makes possible the phosphorylation of protein kinase Akt, which leads, on the one hand, to the translocation of glucose transporters to the cell membrane (and consequently to increased glucose uptake by cells) and, on the other hand, to the activation of protein kinase mTORC1, a crucial regulator of cellular metabolism and growth.
The PI3K/AKT/mTOR signaling pathway plays an important role in cancer cells, which can actively express insulin receptors and, by receiving signals upon their stimulation, increase growth and proliferation rates.
Reducing blood glucose levels in patients is considered as one of the potential dietary strategies in cancer therapy. This approach would limit the availability of glucose to cancer cells and lower insulin secretion by pancreatic beta cells. How can patients' blood glucose levels be lowered? Of course, reducing the caloric content of food will lower blood glucose levels, but such a method cannot be optimal because it will jeopardize the patient's overall condition. A much more favorable strategy may be the ketogenic diet, which involves limiting carbohydrate intake while increasing the proportion of fat in the diet. Indeed, there is evidence from preclinical studies and a small number of clinical trials that suggest such a diet may contribute to favorable disease outcomes - for example, in glioblastoma. However, it's important to note that some tumor types, on the contrary, are fatty acid-dependent, which means that a diet rich in fat may mediate a pro-carcinogenic effect, as we'll discuss a little further on.
But what about other carbohydrates?
In addition to glucose, there are many other carbohydrates in our daily diet. For example, fructose, one of nature's most common sugars, is found in food both free and as part of oligosaccharides such as sucrose. Epidemiologists have linked the increased consumption of sugary beverages to the rising incidence of cancer. Moreover, it appears that even moderate consumption of fructose (equivalent to one can of soda a day) has negative effects and may promote tumor growth, as observed in experiments with mice for colorectal cancer. Glucose is efficiently absorbed by epithelial cells of the small intestine due to special proteins that transport glucose and sodium ions together. At the same time, fructose transport is mediated by the passive transporter GLUT5 and is therefore less efficient. As a result, much of the fructose consumed passes through the small intestine and into the large intestine. In the case of colorectal cancer, fructose becomes one of the potential nutrients for tumor cells: indeed, cancer cells in the colon actively express both GLUT5 and fructose-metabolizing enzymes. Glucose and fructose are similar in terms of molecular structure, but in terms of their metabolism they are slightly different. In the case of glucose, the first stage of glycolysis is the phosphorylation of glucose with ATP consumption and formation of glucose-6-phosphate, and the activity of hexokinases (enzymes that carry out this reaction) depends on the concentration of glucose-6-phosphate in the medium: the more product for the enzyme, the less active it is. This phenomenon is an example of negative feedback, an important aspect of the regulation of the activity of metabolic pathways. Fructose, on the other hand, is primarily phosphorylated by fructokinase to fructose-1-phosphate (Fr-1-F), also with ATP expenditure, but in this case the activity of the enzyme is independent of the product concentration. This means that the kinase will phosphorylate all available fructose, regardless of how much Fr-1-F has already been made. Consequently, when the concentration of fructose is elevated, the cell will spend a lot of ATP to phosphorylate it. In response to decreased ATP levels, the glysolysis enzyme phosphofructokinase (PFK) is activated and, in addition, the products of Phr-1-F cleavage eventually enter the glycolysis reactions. Thus, fructose increases glycolysis, which is to the advantage of cancer cells: in the case of colorectal cancer, the activation of glycolysis promotes the induction of fatty acid synthesis necessary for tumor growth.
It should be noted that fructose, although it promotes tumor growth in colorectal cancer, is not necessary for the growth and survival of normal cells, so pharmacological inhibition of fructose transporters and enzymes involved in its metabolism (e.g., fructokinase) may prevent the progression of colorectal cancer. And of course, eliminating fructose from a patient's diet may also have a beneficial effect on the course of the disease. However, there is still not enough clinical data to support this.
Another curious example is mannose, a monosaccharide that is also frequently found in the diet both in free form and as part of polysaccharides. Mannose is taken up by the same transporters as glucose, but then accumulates in cells as mannose-6-phosphate and is hardly metabolized further. At the same time, mannose-6-phosphate inhibits some enzymes of glycolysis (hexokinase and glucose isomerase), as well as glucose-6-phosphate dehydrogenase - the first enzyme of the pentose phosphate pathway, an alternative way of glucose oxidation. Thus, the accumulation of mannose-6-phosphate entails suppression of glucose metabolism, which negatively affects cancer cell viability. However, not all tumors are sensitive to mannose. The fact is that cells have an enzyme mannose-6-phosphate isomerase (PMI), which catalyzes the conversion of mannose-6-phosphate into fructose-6-phosphate, a metabolite of glycolysis. It would seem that the accumulation of mannose-6-phosphate ceases to be a problem for the cell, but the fact is that different tumors have different PMI activity, and if its activity is reduced in some tumor cells, mannose will inhibit tumor growth. It turns out that colorectal tumors typically have very low levels of PMI, and indeed, in a mouse model of colorectal cancer, mannose-containing supplements have been shown to significantly suppress tumor growth and have no adverse effect on the health and weight of the mice. It is possible that mannose supplementation will increase the effectiveness of colorectal cancer therapy in humans as well, but clinical studies have not yet been conducted.
Fatty acids
Fatty acids are the most important source of energy in the cell, especially for “energy-consuming” tissues like skeletal and cardiac muscle tissue. The oxidation of fatty acids (which mainly occurs during the β-oxidation process) produces NADH and FADH2, as well as acetyl-CoA, substances necessary for ATP synthesis by oxidative phosphorylation. Moreover, if we compare fatty acids and carbohydrates, we find that, relative to their dry mass, fatty acids provide more ATP than carbohydrates, which means that they are better suited for the role of a reserve nutrient (fatty acids are stored in the form of triglycerides in adipose tissue). Of course, it could not be that there are no tumor cells that actively use fatty acids as a source of energy and repair equivalents. Indeed, processes where the cancer cell switches to β-oxidation have been described, as well as individual tumors for which the main energy source is fat rather than carbohydrates.
For example, fatty acid oxidation has been shown to be critical for breast cancer cells as they detach from the matrix. The ducts of the mammary glands are lined with a layer of epithelial cells that give rise to tumors. In the early stages of breast cancer development, tumor cells detach from the matrix, leave their niches, and begin to proliferate in the lumen of the hollow glandular structures, filling them. Epithelial cells have epidermal growth factor receptors (EGFR) on their surface. When EGFR is stimulated, among other things, the PI3K/AKT/mTOR signaling pathway is activated, which leads to growth, proliferation, and promotes glucose uptake and suppression of apoptosis. Contact with the extracellular matrix is very important for the epithelial cell. If the cell loses contact with the matrix for any reason, EGFR expression drops and, as one consequence, the cell becomes deficient in glucose. Normally, this series of events would lead to ATP deficiency, oxidative stress, and finally to anoikis - cell death, which occurs in response to detachment from the matrix. But the tumor cell is not so simple and actively tries to escape apoptosis. The activity of a number of oncogenes in this case contributes to the activation of fatty acid oxidation, which provides the cell with energy and prevents cell death.
Another important example of the role of fatty acids in cancer cells is related to nicotinamidadenine dinucleotide phosphate (NADPH), a substance that has two main functions. On the one hand, it is involved in protecting the cell from toxic reactive oxygen species (ROS) by enabling the regeneration of the antioxidant glutathione (GSH), which is particularly important for the survival of cancer cells under conditions of metabolic stress. On the other hand, NADPH is required for the synthesis of fatty acids and nucleotides necessary to support cell growth and proliferation, which is an integral part of tumor cell biology. Often, cancer cell growth is limited by NADPH levels, hence changes in cancer cell metabolism must take this important aspect into account. How are fatty acid oxidation and NADPH production related? The main product of fat oxidation is acetyl-CoA, which enters the Krebs cycle and is converted to citrate. Citrate can remain volitionally in the Krebs cycle, or it can leave the mitochondrion and escape into the cytoplasm. There it will be converted to isocitrate, which is a substrate for NADP-dependent isocitrate dehydrogenase. This enzyme oxidizes isocitrate, with hydrogen transfer to NADP+ and the formation of NADPH, which is required by cancer cells. For example, in glioma cells in which fatty acid oxidation is inhibited, NADPH levels are significantly reduced, leading to the accumulation of AFCs and, consequently, cell death.
From these examples, we see that in some cases fatty acids promote survival and metastasis of tumor cells. This means that for individual patients, a low-fat diet may be beneficial. At the same time, a ketogenic diet, which we discussed in the glucose chapter, may cause unanticipated pro-carcinogenic effects and promote tumor growth. Thus, the dietary regimen of patients should be individually tailored to tumor stage, tumor location, and metabolic features.
Amino acids
Proteins are known to take part in most cellular processes: they maintain the shape of the cell, ensure its mobility, control the work of genes, regulate metabolic processes and much more. Amino acids are the building blocks for proteins. Surprisingly, while there is a huge variety of proteins, they are all built from a fairly limited set of amino acids.
Proteins enter the body with food, after which they are degraded to individual amino acids in the gastrointestinal tract. The mixture of amino acids is absorbed in the small intestine, enters the bloodstream, and is distributed to every cell in the body. In the cells, amino acids are already used to synthesize their own proteins, which are necessary for the normal functioning of the body. It is important to note that some of the amino acids the cells of our body can synthesize themselves (so-called substitutable amino acids), and some must necessarily come from food (essential amino acids). So, amino acids that have entered the cell can become part of proteins, but what is more interesting for us is the fact that individual amino acids can perform special metabolic functions. In the following, we will look at the role of specific amino acids in cancer cell metabolism, as well as possible dietary strategies for patients with cancer based on the restriction or bio-supplementation of these amino acids in the diet.
Methionine
Methionine is an essential amino acid for human cells. However, cancer cells require more methionine for their growth compared to normal cells. The fact is that methionine performs a number of regulatory functions. There are special sensors in the cell, which in response to high levels of methionine (or, more precisely, its derivative S-adenosylmethionine) can activate the mTORC1 protein kinase. This protein kinase is extremely important for cancer cells: it activates the process of protein synthesis and, as a consequence, accelerates cell growth and division. In addition, S-adenosylmethionine is the main donor of methyl groups in the cell, i.e. it provides methylation. Methylation of DNA and histones (proteins bound to DNA) allows certain genes to be “turned on” and “turned off”. Changes in the methylation status of histones and DNA regulate gene expression and contribute to tumor growth and development. Since 1990, there have been animal studies demonstrating that restricting methionine intake improves the outcome of tumor treatment. More recently, the first clinical trial has shown that reducing the amount of methionine in patients' diets can slow tumor progression . Thus, dietary restriction of methionine in people with cancer is a very promising approach. It is important to clarify that dietary restriction of certain amino acids can only be accomplished through “artificial” diets in which the main source of protein food is protein drinks/bars that do not contain certain amino acids. This was the dietary pattern of the patients who participated in a clinical trial of a low methionine diet: 75% of the protein food was protein drinks without methionine.
Serine
The amino acid serine is involved in many metabolic processes: in the synthesis of nucleotides and lipids; it can be converted into pyruvate and enter the Krebs cycle, and so on. Serine belongs to the substituted amino acids and can be synthesized in normal cells from glucose and glycine (the simplest amino acid). For cancer cells, which actively use glycolysis and, consequently, are in urgent need of glucose, the synthesis of serine from glucose will certainly result in losses in the amount of ATP and the rate of reproduction. That is why we can say that for tumor cells serine is an essential amino acid, that is, it must necessarily come from outside. The pathway of serine synthesis from glycine is also highly undesirable for cancer cells, as glycine is directly involved in nucleotide synthesis, which means that the conversion of glycine into serine again jeopardizes the rate of division of cancer cells. Thus, limiting serine intake may indeed help in tumor therapy. The effectiveness of such a diet has already been shown in experiments on mice, but no clinical trials have yet been conducted .
Arginine
In normal cells, arginine is able to be formed de novo, i.e. it is a substitutable amino acid. In tumor cells of melanoma, hepatocellular carcinoma and prostate cancer, arginine synthesis is severely reduced. This is due to low levels of the enzyme argininosuccinate synthetase, which is involved in the formation of arginine. It turns out that some cancerous tumors require arginine intake from the outside (arginine is an essential amino acid for the cells of these tumors). “Arginine dependence” of tumors can be exploited for therapy, with both pharmacological approaches and simple dietary restriction of arginine. The pharmacological reduction of arginine in cancer cells is already known from scientific studies: for example, drugs that reduce arginine levels in the plasma of patients have been effective in the treatment of hepatocellular carcinoma and melanoma.
However, arginine may adversely affect antitumor immunity. The most important cells involved in tumor control are T-lymphocytes. Arginine is actively taken up by activated T cells, then metabolized, resulting in increased cell survival and enhanced anti-tumor T-cell response. In a mouse model of skin cancer, an increase in dietary arginine intake led to a decrease in tumor size, promoting survival of the mice .
NK cells (Natural killer cells), immune cells capable of destroying tumor cells, play an equally important role in antitumor immunity. Studies have shown that dietary arginine intake increases the number and activity of NK cells, and, conversely, arginine deficiency depresses the work and vitality of natural killer cells, which can negatively affect the fight against tumors.
Thus, arginine is necessary for both some tumors to grow and for immune cells fighting the tumor. Apparently, only large-scale clinical trials will help to understand in which cases it is worth excluding or, conversely, increasing the content of arginine in the diet to maximize the effect of therapy.
Cystine and cysteine
One of the most important functions of the amino acid cysteine in the cell is to protect against reactive oxygen species (e.g. hydrogen peroxide) that damage DNA, lipids and proteins, causing oxidative stress in the cell. Cancer cells, compared to normal cells, experience severe oxidative stress and require large amounts of cysteine. Indeed, for some tumor cells, a decrease in cysteine levels is detrimental: the cells “burn” due to accumulated reactive oxygen species. Cysteine is formed from the non-classical amino acid cystine, which enters the cell from blood plasma. Drugs that reduce plasma cystine levels inhibit the growth of tumors with a mutant epidermal growth factor receptor (e.g., non-small cell lung cancer) in mice. Theoretically, it is possible to achieve a reduction in plasma cystine levels in patients by adjusting diet, without the use of drugs, but this approach has not yet been investigated.
Histidine
The degradation of histidine in the cell wastes tetrahydrofolate, a cofactor that is essential for nucleotide synthesis and therefore determines the rate of division of cancer cells. The more histidine that enters the cancer cell, the more tetrahydrofolate is spent on histidine breakdown and the slower the cell divides. The use of histidine along with food may help in the therapy of some types of tumors. In particular, this dietary approach may become particularly effective when treating cancer with the chemotherapeutic agent methotrexate (often used to treat malignant blood disorders). Methotrexate disrupts the synthesis of tetrahydrofolate, which leads to a halt in nucleotide synthesis and the death of cancer cells. It turned out that the effectiveness of treatment of leukemia with methotrexate is markedly increased when the amino acid histidine is added to the diet - this was shown in a mouse model.
Folic acid supplements
Finally, we want to pay attention to vitamins. Vitamins are essential for many biochemical reactions and must be ingested with food. There is a common misconception that taking vitamin supplements can serve as a defense against cancer and other diseases. In fact, vitamins should be taken exclusively with food, and supplementation is generally not recommended for healthy people (with some rare exceptions). Taking supplements on a regular basis can be not only ineffective, but also harmful, especially for people with cancer. Let's look at an example of how supplemental vitamin intake promotes tumor growth.
Folic acid (folate, vitamin B9) is an essential substance for nucleotide synthesis. Tumor cells divide rapidly and need large amounts of nucleotides for DNA synthesis, so they actively consume folate. As early as 1948, folic acid supplements were known to promote the growth of certain types of tumors. Today folic acid metabolism is a pharmacological target for cancer therapy: the previously mentioned chemotherapeutic drug methotrexate disrupts folate metabolism and inhibits nucleotide synthesis pathways. It should be emphasized that antifolate therapy for cancer is still purely pharmacological and does not involve dietary adjustments.
However, the potential negative effects of folate in tumor progression do not end there. A number of studies have shown that the presence of unmetabolized folic acid in the blood, associated with its excess intake, was associated with a decrease in the number and activity of NK cells. The previously mentioned NK cells are immune cells, one of whose main functions is to protect the body from cancer cells. Consequently, a decrease in the number and suppression of NK cell activity may result in an increased risk of cancer formation and progression, although there have been no specific studies on the effects of high doses of folate on antitumor immunity.
Thus, vitamins are essential for maintaining bodily functions, but excessive intake of some of them may lead to negative consequences, including tumor progression, as in the case of vitamin B9. Perhaps a diet low in folate would be beneficial for some patients.
Conclusion
In conclusion, we would like to reiterate that there is no one-size-fits-all diet for people with cancer. This is due to the fact that tumors vary greatly in their metabolism. The listed dietary approaches cannot yet be used universally, because before any of them can be introduced for each type of cancer, its localization and stage of the disease, large-scale clinical trials must be conducted to confirm the safety and efficacy of the new treatment method. However, due to promising research results, dietary modifications are a promising approach to cancer treatment. We are confident that in the near future, controlling the composition of patients' diets will become an important part of cancer therapy and will help save many lives. In the meantime, let's just try to eat right and lead a healthy lifestyle. Be healthy!