Food properties and dietary habits in colorectal cancer prevention and development

ABSTRACT

Colorectal cancer (CRC) is a very common and lethal disease worldwide. The etiology of the disease includes genetic and environmental factors. Among environmental factors, the dietary habits are considered to be easily changeable regarding preventing the CRC. Although there is still a long road to cover the gaps in knowledge on nutritional determinants and the dietary pattern on the CRC risk, several dietary suggestions and goals could be summarized. Diets high in energy, consumption of red meat or processed meat, food with a high glycemic index (carbohydrates, snack food, frying fast food, and sugar-sweetened drinks, sweets), exceed intake of salt (NaCl), low daily water intake (<4 cups per day) have been linked to an increased CRC risk. In contrast, consumption of white meat, as well as plant and fish oils with a high omega-3 PUFA to omega-6 PUFA ratio might even reduce the occurrence of CRC. A fiber-rich diet can lower the CRC risk up to 50%. Diet rich in vitamin B6, C, D, E, folic acid, selenium, and magnesium has also been considered to reduce the CRC risk. General unhealthy lifestyle which results in overweight and obesity-related syndromes (chronic inflammation, type 2 diabetes) can promote CRC. However, in many cases, the results are inconsistent and depend on multiple interdependent factors, i.e., ethnic, anthropometric, gender, age, hormones, and environment. In addition to dietary habits, all these agents are suggested to modify the risk of CRC.

KEYWORDS:

• Cancer prevention
• Colorectal cancer
• Diet
• Fatty acids
• Food property
• Vitamin

Introduction

Colorectal cancer (CRC) poses a significant threat to public health worldwide. It is the third most commonly detected cancer in males and the second in females.^[1] A further increase in the number of CRC cases due to the expectancy of population growth and the aging of the population is predicted. The prediction for Poland forecasts a substantial CRC increase in 2020 by 12% in female and 13.9% in male.^[2,3]

The CRC incidence rates and related deaths differ at least 25-fold between geographic regions; the highest are recorded in the most industrialized and high-developed countries (Western Europe, Canada, the United States, Japan, and Australia); the lowest incidences are noted for low-developed countries (except South Africa, India, the Middle East, and South American).^[4,5] Etiology of colorectal cancer is complex and involves both genetic and environmental factors. It is still not uncovered why colorectal cancer incidence rates are higher among highly developed societies. However, the assumptions under investigation account for socioeconomic and environmental factors.^[6] For example, in developed countries, many cases of CRC are identified in the pre-invasive stage through screening programs (colonoscopy), whereas in developing countries, large-scale screening programs are usually uncommon.^[4,5,7] There are also vast differences in lifestyle between high- and low-developed countries. Lifestyle differences reflect physical activity, disparities in dietary habits, obesity, and diabetes.^[8] Environmental factors are predicted to influence the development of CRC in 50–80% of diagnosed cases. Most commonly mentioned are dietary habits, whose critical role is attributed to inhibition as well as the promotion of the development and progression of colorectal adenoma and cancer.^[9–11]

The dietary trends adopted today by high-income society worldwide follow ‘the Western dietary pattern’ characterized by high-fat products (dairy, eggs, butter, margarine, mayonnaise, fries, fast foods), high intake of processed meat, as well as consumption of refined grains, sweets, soda, and snacks.^[12] Whereas, the prudent dietary pattern common in low-income countries is related to the predominance of high-fiber plant-based food and low intake of fat.^[13] Moreover, strong determinant for the CRC risk is the body mass index (BMI) closely associated with the dietary pattern.^[14] In general, ‘the Western dietary pattern’ promotes various chronic conditions, i.e. obesity, diabetes, the metabolic syndrome (MetS), overexpression of leptin, and chronic low-grade inflammation. Evidence support a role of these conditions in the activation of several signaling pathways that favor carcinogenesis.^[15,16]

The idea that diet is an important determinant of the risk of CRC has been proposed about 50 years ago, based on the observations conducted in African populations indicating that the low incidence of these cancers is associated with the consumption of a high-fiber diet.^[17] Since then, various dietary habits have been investigated as potential risk factors for CRC.^[18] An epidemic survey conducted by Kesse et al. among black Americans and white Americans unequivocally evidenced that ‘the Western dietary pattern’ followed by black Americans was a strong determinant of higher risk of colorectal adenomas.^[19] The importance of lifestyle and dietary habits for the CRC risk have also been evidenced in the number of epidemiological surveys conducted among migrant populations (i.e. for Japanese migrants to California^[20,21] or migrant groups from Europe or Asia to Australia.^[22,23] Changes in dietary behaviors (i.e. energy excited diet, lack of fiber, consumption of red and proceeded meat) and the related increase in the body mass index have been considered among important factors that increased colorectal cancer rates among migrants.^[24]

The association of CRC with dietary patterns may differ by age as the disease was positively associated with the old-age group (age >50 years) and no association was made in younger study participants.^[25] According to some estimates, dietary pattern contributes up to 50% of CRC cases.^[26] Concerning the CRC risk, diet appears to be particularly important for primary prevention of colorectal cancers. Substantial advances in understanding the importance of specific nutritional elements as modifiable risk determinants for of CRC have been acquired over the last 20 years. Nevertheless, the analyses of the impact of specific foods and nutrients on the CRC risk are associated with several limitations. First and foremost, components in different foods that are eaten together can have potentially a wide range of interactions. Presumably, the changes in many nutrients or food intake could exert an effect on change in incidence rates of CRC. Moreover, different combinations of food intake may have synergistic effects and can interact to increase or decrease CRC risk.

Carcinogenesis in CRC

Carcinogenesis is a multistage transformation and an uncontrolled growth of healthy cells into invasive cancer cells. Different exogenous and endogenous agents (carcinogens) may affect the transition between sequential stages.^[27] Genetic pathogenesis is well known in the CRC.^[28] Colorectal cancer is highly heterogeneous disease, which arises from somatic or germline heritable mutations that can occur anywhere in the colon or the rectum. During the initiation stage, the carcinogen or its active metabolites interact with nucleic acids. Therefore, irreversible changes take place in the genotype of the normal cells leading to its immortality.^[29–31] Carcinogens in colorectal cancer induce two forms of genomic instability in cells.^[32] One is the chromosomal instability (CIN), detected in approximately 85% of all CRCs; the second refers to microsatellite instability (MSI) that results from impaired DNA mismatch repair (MMR), accounting for approximately 15% of all colorectal cancers.^[33–38] However, the CRC nonpolyposis forms are reported to be inherited mutations in no more than 5% of all CRC cases.^[39] Most colorectal cancers grow slowly, and usually transformation from non-cancerous polyps into tumor takes about 10–15 years.^[1]

In fact, the CRC is considered as one of the most preventable cancers. The abnormalities are readily detectable by screening methods and can be removed before they have a chance to turn into cancer.^[40,41] However, because a long period is required for polyps degeneration to carcinoma, and the adenoma to carcinoma sequence is complex, it is difficult to study activation of pro-oncogenic pathways in colorectal hyperplastic polyps or potential chemopreventive agents.^[42] The incidence of cancer increase with age may apply to the accumulation of structural and functional changes in cellular organelles and DNA mutations, which can provide age-related pathologies, and finally cancer.^[43,44] However, food related bioactive compounds may activate or inhibit genes responsible for carcinogenesis and induce or protect cell organelles and DNA damages.^[45] It seems that there is not a single nutrient but rather a combination of nutrients would be responsible for polyps’ progression to cancer.^[46] Moreover, the activity of particular chemical food compounds may depend on the presence or absence of other compounds.^[47] Many authors conclude that the environmental factor that has been documented to increase the risk of CRC can be preventable.^[47–50] Major diet habits investigating the potential factors that can stimulate or prevent CRC development are discussed below.

Fatty acids – procarcinogenic and anticarcinogenic effects

Fats (triglycerides) are essential in the human diet. Fats consist of many different fatty acids, which constitute important energy source and may have unique biological properties and health effects.^[51,52] Many scientific surveys have questioned whether fat is a culprit in causing the CRC. However, studies evaluating the influence of fatty diet or particular types of fat on colorectal cancer risk have revealed inconsistent results. Some reports describe no association between dietary fat intake and CRC risk; others presented a positive correlation between dietary fat intake with CRC incidences.^[53–55] There is some evidence from clinical and epidemiological surveys that the effect of fatty diet on the CRC is associated with the concentration of fatty acids in adipose tissues, erythrocytes or plasma.^[56–58] Moreover, the composition of specific fatty acids in the diet may promote the pathogenic process or protect from colorectal carcinogenesis.^[59]

Fatty acids – total intake

Several possible hypotheses concerning the disadvantage of the effect of fat on colon carcinogenesis have been suggested. High-fat diets may promote cancer because they have a high caloric content and the high caloric intake per se. Fundamental risks associated with the high-calorie intake is the development of overweight and obesity. Various mechanisms may contribute to cancer initiation and progression in excess body weight. In brief, the obesity is clearly linked with some pathogenic conditions, which constitute a protumorigenic environment, i.e. hyperinsulinemia, hyperglycemia, hypertriglyceridemia, and chronic low-grade inflammation.^[15,60] Strong co-existence of hyperinsulinemia/hyperglycemia/hypertriglyceridemia and the increased secretion of interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), adiponectin, leptin, tumor necrosis factor alpha (TNF-α), overproduction of reactive oxygen species (ROS), and C-reactive protein (CRP) was documented.^[61–63] These molecules (i) impair the immune system function, (ii) operate in multiple cellular signaling cascades crucial for malignant cell transformation, (iii) promote rapid cellular multiplication, and (iv) inhibit apoptosis of transformed cells and as a result of this leading to cancer development and progression.^[64–66]

Fatty acids – an elevated level of bile acids

An excessive level of fat in a diet often leads to an increased secretion of the bile acids (deoxycholic acid, DOC) into the gastrointestinal tract and leads to high concentration of bile acids in the colon. In human, 5-fold disparities in concentrations of bile acids in stool between people with low- compared to people with high-fat intake were evidenced (7.30 vs. 37.51 nmol/g wet weight).^[66] The possible mechanism for bile acids in colon cancer development is related to the formation of reactive oxygen and nitrogen species at a high concentration level of bile acids.^[67,68] The prediction has been confirmed in a most recent experiment conducted on a mouse model.^[69] In mice fed with a diet supplemented with high levels of bile acid, the colonic neoplasia and tumor progression to colon adenocarcinoma have been observed, whereas in control mice fed with standard diet (with 10-fold lower bile acids level) the colonic neoplasia was not revealed. Between the two cohorts, substantial changes in predominant forms of free radicals (i.e. 8-OH-dG or 8-oxodG) occurred. There is the experimental evidence confirming that free radicals are highly reactive molecules, which can cause damage to lipids and proteins in cellular membranes, or the decrease in the DNA repair capability, and alter the cellular antioxidant defense system.^[68] These disturbances are considered to induce colon cancer precursor oxidative lesions and are recognized as initiation factors of carcinogenesis.^[68–70]

Fatty acids – composition and proportion

In brief, there are two types of fatty acids present in food: saturated (SFAs) and unsaturated (UFAs). Saturated fatty acids differ in length and are categorized as short-chain fatty acids (SCFA), medium-chain fatty acids (MCFA) and long-chain fatty acids (LCFA). Unsaturated fatty acids contain one double bond (monounsaturated fatty acids - MUFAs) or contain more than one double bond (polyunsaturated fatty acids - PUFAs) and are found in cis or trans configuration. Certain polyunsaturated fatty acids are known to serve multiple functions essential in several physiological processes, i.e. regulate the nervous system, brain function, and blood pressure.^[71,72] Moreover, PUFAs are involved in immune regulation and inflammation processes. There are two types of PUFAs, classified as omega-3 (n-3) (i.e. alfa-linolenic acid – ALA, eicosapentaenoic acid – EPA, docosahexaenoic acid – DHA) and omega-6 (n-6) (i.e. linoleic acid – LA, arachidonic acid – AA).^[73] In general, n-6 PUFAs are precursors of proinflammatory signaling molecules, while n-3 PUFAs are important in anti-inflammatory regulation (Table 1).^[71,74]

Table 1. Primary roles of the omega-3 and omega-6 PUFAs in colorectal cancer development.

Polyunsaturated fatty acids (PUFAs)	Major role in cancerogenesis
Omega-3 PUFAs	↓ inflammation	INHIBITION OF CANCEROGENESIS
alfa-linolenic acid – ALA eicosapentaenoic acid – EPA	↓ angiogenesis
	↓ metastases
	↓ cell proliferation
Omega-6 PUFAs	↑ inflammation	PROMOTION OF CANCEROGENESIS
linoleic acid – LA	↑ angiogenesis
arachidonic acid – AA	↑ cell proliferation
	↑ apoptosis

↑ - increase/activation; ↓ - decrease/inhibition.

The idea that composition of fatty acid fractions in a diet is associated with the risk of CRC has been proposed with regard to the observations conducted in Alaskan Eskimos. They tend to have a high-fat diet (with a high amount of fish omega-3), however, a low rate of colorectal cancer.^[75] Typically, animal products (i.e. red meat, milk) are rich in saturated fatty acids (SFAs), whereas plant and fish products are rich in unsaturated fatty acids (UFAs). The primary dietary sources of omega-3 PUFAs are green leafy vegetables, flaxseed, and rapeseed oils, while corn and sunflower oils are rich in omega-6 PUFAs.^[71]

There is convincing evidence that increased concentrations of the trans-fatty acids and animal fat promote human colon cancer growth. Likewise, long-term consumption of polyunsaturated fatty acids is involved in the etiology of colorectal cancer.^[76–78] The recommended dietary ratio of omega-6 PUFAs to omega-3 PUFAs is 1/4:1.^[59] However, in last two decades, qualitative nutritional changes in dietary habits (i.e. ‘Western diet’) brought a sharp increase in omega-6 PUFA consumption. The omega-6 PUFA/omega-3 PUFA proportion is within the range of 10:1 or even 20:1.^[79] Imbalance in omega-6 and omega-3 PUFA ratio is reported as an etiological proinflammatory determinant and promotion cancer factor.^[80,81] The protective effect of omega-3 consumption on colorectal cancer risk was evaluated in a Polish-case-control study; the CRC risk decreases already at the moderate fish intake of 1–2 serving weekly.^[82]

Many randomized control trials found possible evidence that PUFAs are often subjected to peroxidation process in which free radicals are created.^[83] Imbalance in omega-6 and omega-3 PUFA ratios is reported as the etiological risk of alterations in indices related to the metabolic syndrome, a complex physiological disorder associated with prolonged inflammation directly linked with pathological levels of C-reactive protein, interleukin-6, tumor necrosis factor-alfa, and other factors identified with CRC carcinogenesis.^[84–86] Recently, Yang et al.^[87] showed that fatty acid profiles differed between normal and cancerous tissues in the same CRC patients and concluded that the metabolism of PUFAs might play a significant role in the evolution of inflammation driven tumorigenesis in the CRC. The protective effect of an increased intake of omega-3 PUFAs (EPA and DHA) accompanied by low consumption of omega-6 PUFAs might be related to modulation of cyclooxygenase-2 (COX-2) activity, the enzyme responsible for the formation of pro-inflammatory prostaglandins.^[88–90] Other postulated mechanisms of the protective role of omega-3 PUFAs in colorectal carcinogenesis prevention may involve the decreased risk of microsatellite instability (MSI), the enhancement of DNA repair systems mismatch pathways or the inactivation of antiapoptotic genes, i.e. Bcl-2 family genes.^[91,92]

Dairy products

Milk and other dairy products are essential components of human diet worldwide. These products provide carbohydrates, protein, fat, minerals, and vitamins. The relationship between intake of dairy products and the CRC risk is conflicting. Several epidemiological survey studies have suggested that dairy foods correlate negatively with the risk of colorectal cancer, in both men and women.^[93–95] However, null or positive associations have also been reported.^[96,97] It is entirely possible that high consumption of dairy products, including milk, cheese, butter, margarine and ice cream, may have a pro-carcinogenic effect due to an overall high dietary saturated fat intake.^[98] For example, about 31% of saturated fat in the United States and 50% in Sweden come from dairy products.^[99,100] Also, dairy products may contain toxic pesticides, recognized as potentially carcinogenic contaminants.^[101] There is convincing evidence that milk products contain insulin-like growth factor-1 (IGF-1). The high circulating concentration of IGF-1 in serum enhances insulin resistance, promote oxidative stress, and inflammation, contributing to the development, proliferation and spread of cancer cells.^[102]

In contrast, some ingredients of dairy products such as the calcium, vitamin D, conjugated linoleic acid (CLA), or butyric acid generated by probiotic bacteria are hypothesized to reduce the CRC risk. On a molecular level, calcium is known to prevent the CRC by influencing intracellular pathways leading to normal colonocyte differentiation.^[103,104] In an animal model, calcium has been linked to reduced number of K-ras gene mutations in colorectal malignancies.^[105] The anti-cancer effect of calcium function is also attributable to the stimulation of apoptosis that occurs in transformed cells of the colonic epithelium.^[83,106] The other protective effect of calcium is related to binding bile acids and free fatty acids (i.e. deoxycholic and lithocholic acids). As a result of binding, the level of toxic concentration of bile acids is reduced, the exposure of the colonic epithelial cells to these carcinogens is shorten and weaken, at this moment proliferative effects of bile acids in intestinal mucosa cells are limited.^[83,95] Several epidemiological surveys have evidenced that the growth of tumors is reduced by a long-term calcium supplementation.^[107,108] It has been suggested that calcium decreases the colonic content of harmful metabolites (i.e. diacylglycerol) produced by some genera of bacteria colonizing the colon (Bacteroides, Clostridium). The proliferation potential of chemicals produced by these bacteria, via the activation of cellular transduction pathways in the colonic epithelium, has been documented.^[109,110] However, beneficial gut microorganisms (Lactobacillus and Bifidobacteria) have been reported to exhibit a protective effect on the CRC development.^[110] These probiotic bacteria appear in fermented products such as yogurt and they exert an indirect effect on colon tumor cell proliferation through their fermentation products, one of which is butyrate. The critical role of butyrate in the prevention of colonic inflammatory process has been documented.^[111–113] Butyrate is a major energy source for colon epithelium. It acts by enhancing the apoptosis of transformed colonic cells as well as inhibits angiogenesis by regulating vascular endothelial growth factor (VEGF) overexpression.^[112,114]

Another chemopreventive component of dairy products is Conjugated Linoleic Acid (CLA), the most common omega-6 fatty acid. Its antioxidant and anticancer properties have been discovered during the scrutiny examining rats fed with fried hamburgers.^[115] Also, the potential preventive role of CLA is associated with immune system enhancement.^[116–118]

The epidemiological evidence funded by the World Cancer Research Fund as a part of the Continuous Update Project revealed increased intake of dairy products (400 g per day) has a preventive effect in colorectal cancer etiology.^[119]

Red meat, white meat, and processed meat

Meat is a high-protein and high-fat food. Various meats contain different proportions of saturated (SFAs) and unsaturated (UFAs) fats, i.e. red meat (beef, lamb, pork) is rich in saturated fat whereas white meat (chicken, fish) has higher levels of unsaturated fat.^[71] The associations between the meat consumption and the CRC risk are conflicting. There is evidence suggesting that long-term consumption of red meat significantly increases the CRC risk, especially in the distal colon.^[120–122] In some study, the correlation between the red meat consumption and risk of colorectal cancer has been inconsistent.^[123] Also, there is evidence that the frequency of red meat intake is more important than total amount of meat consumed for the CRC risk.^[124] The meta-analyses of Chao et al. revealed the firm association of colorectal cancer with red meat consumption. However, age and total energy intake considerably modify the relationship.^[125] An unclear relationship is reported between the risk of CRC and poultry consumption.^[126] Several surveys evidenced that the consumption of white meat, i.e., fish did not increase the CRC risk.^{[120,127,128]} In 2015, the World Health Organization (WHO) experts indicated the meat processing method is an important mediator of carcinogenesis in the colon.^[129] The risk of colon cancer is strongly and positively associated with the frequent eating of high temperature processed meat products, i.e. smoked, fried or grilled meat (beckon, ham, hot dogs).^[130] Several hypotheses may explain the potential carcinogenic effect of meat diet on the CRC initiation and progression.

Nitrites and/or nitrates are traditionally added to cured and processed meat products to increase their quality and safety, i.e. to prevent pathogenic bacterial growth and the development of botulinum toxin.^[131] Heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs) are chemicals formed when meat is processed using high-temperature methods.^[132]

It has been proven that protein-rich meat leads to an increase in endogenous N-nitroso compounds (NOCs) in the intestinal tract and increases fecal NOC levels.^[133] In several epidemiologic studies, nitrites/nitrates/heterocyclic amines have been identified as carcinogens.^[134] However, these chemicals, are not carcinogenic per se but must be metabolized by a family of cytochrome P450 enzymes to potentially genotoxic and carcinogenic substances which negatively impact on genomic cell stability in colon mucosa.^[135] These mutagens are produced when meats are heated (pan frying, grilling, smoking above 180°C for extended periods of time).^[136] High-temperature meat processing technologies increase the level of at least 17 highly carcinogenic heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs).^[132,137] Also, processed meats often contain specific additives (i.e. salt, sodium nitrite) released into the colon which could irritate the colon cells, disturb cellular metabolism and enhance cell proliferation.^[138,139]

Numerous investigators documented that proteins are subjected to the direct or indirect reactions with reactive oxygen species (ROS) and with secondary by-products of oxidative stress, respectively.^[43,140,141] During protein oxidation, three main protein damages/modifications can occur by: (i) the formation of specific amino acids, (ii) protein cleavage or (iii) cross-linking. These damages/modifications change the proteins property and lead to alteration of their functions with a broad range of consequences in enzymatic activity, i.e. change in cell-to-cell interactions, changes in cellular uptake routes, inactivation of DNA repair enzymes, and damage of DNA replicating enzymes.^[140] The accumulation of oxidatively modified proteins or products, which contain reactive groups, i.e. carbonyls, has been reported in some carcinomas.^[141]

Protein fermentation by the gut microflora releases toxic ammonia, amines, phenols, and indoles. Normally, these substances are detoxified, and physiological levels of these compounds in human colonic contents are low. However, high consumption of dietary meat increases the concentration of toxic metabolites identified as disruptive for human colonocytes.^[130,142] There is some evidence that protein composition and the degree of their digestibility rather than the amount of protein intake is essential pro-mutagenic DNA adducts in the colon.^[143] It has been shown that red meat proteins are digestible only up to 90%, whereas white meat in 98%. The poor protein digestibility is related to structural peculiarities such as modifications to amino acids or cross-linking of amino acid chains.^[144]

Therefore, digestion-resistant proteins of red meat result in more protein reaching the colon for bacterial fermentation and increase amounts of toxic metabolites in the feces.^{[130,143,145]} Few studies highlight the promotive effects of protein fermentation products, like ammonia, phenols, and p-Cresol, presumably because of their toxicity to the mucosa.^[146,147] Santarelli et al.^[148] proposed the “indirect mechanism” to explain the higher risk of colorectal cancer in patients with high red and/or processed meat intake. The authors conclude that general unhealthy lifestyle of meat consumers, i.e. high caloric diet, low fruit and vegetable consumption, drinking of alcohol beverages, and smoking can promote CRC.

Some studies suggest that substituting red meat with other sources of digestible proteins (legumes, poultry, fish) might reduce the risk of colorectal cancer.^[149,150] Several recent investigations have revealed that dietary nitrate (NO³⁻) and nitrite (NO²⁻) inorganic anions (naturally found in vegetables, grains, and fruits) can have divers potentially advantages effects on cellular processes via the nitrate‐nitrite‐nitric oxide pathway.^[151,152] Currently, nitric oxide (NO) is identified as an active hormone, with several biological functions; it is involved in regulation of vascular homeostasis, blood pressure, regulation of energy and lipid metabolism.^[153] Pre‐clinical studies showed the potential protective role of nitrate and/or nitrite against type 2 diabetes, ischemia‐reperfusion injury, reduced arterial stiffness, reduced inflammation and intimal thickness.^[154,155] Moreover, in the review article, Lidder and Webb^[151] gave evidence for inhibition of disadvantages dietary nitrate effects via interactions with some nutrients, i.e., vitamin C, polyphenols and fatty acids. These ingredients are common in nitrate‐rich Mediterranean diet based on fruit, vegetables, and fishes considered as cancer protective.^[149,150] In addition to high proteins and saturated fatty acid (SFA) content, the high level of heme iron is associated with the mutagenic property of red meat. The high level of heme iron can promote the cell proliferation via the increase in the uptake of iron by cells and cytotoxicity of fecal water.^[156]

Food preservatives – salt and monosodium glutamate

Salt (sodium chloride, NaCl) is necessary to regulate extracellular volume, the maintenance of acid-base balance, neural conduction, renal function, cardiac output, and myocytic contraction.^[157] The World Health Organization (WHO) recommend less than 87 mmol Na/day (<5 g NaCl/day) intake of sodium in order to prevent chronic diseases, however, our intake of NaCl is considerably excited, i.e. in the USA it is 8.2–9.4 g NaCl/day, in the UK is 9.4 g NaCl/day, and Asian countries higher than 12.0 g NaCl/day.^[158] It is because the salt is commonly used in many food processing technologies to preserve microorganisms’ development and is added to processed meat products (i.e. ham, bacon, hot dogs, sausage). In dairy products (cheese, butter, condensed and evaporated milk, frozen desserts, ice creams) and baking products (bread cookies, cakes, pastry, pizza, breakfast cereals) salt acts as color-, fermentation-, flavor- and texture-control agent.^[159] There is experimental and epidemiological evidence that dietary sodium chloride can increase the risk of gastric and rectal cancer.^[160,161] The NaCl toxicity mechanism is suggested to be associated with the increase in the number of in the S-phase cells. It is the part of the cell cycle in which the cell DNA is synthesized.^[162] Excessive NaCl concentration in the gastric mucosa can result in the “molecular switch” being turned permanently on, facilitating uncontrolled divisions of the cell, leading to carcinogenesis or tumor development.^[163] In contrast, using the rat models Parnaud et al.^[164] showed that consumption of processed red meats and a bacon-based diet rich in NaCl might even reduce the occurrence of colorectal cancer, probably because of a twofold increase in the rats’ water intake.

Due to the sensory role of sodium in food and its specific functionality (regarding flavor, the degradation of bitterness, or enhancement of sweetness), the reduction of daily salt (sodium) intake seems to be an enormous task ahead of dietary strategies.^[165] The accepted strategy is to replace sodium with potassium salts. The reason is that potassium chloride limit saltiness and also invokes metallic and bitter tastes. To change the dietary sodium content, the overcome of many barriers (mental, technological) is needed; however, it seems to be difficult.^[158,165] The recommended solutions are (i) to use salt substitutes (herbs, spices, lemon juice), (ii) focus on self-cooking with fresh ingredients instead of eating processed meals. In particular, Mediterranean herbs and spices (i.e. parsley, saffron, thyme, basil, rosemary, oregano, sage) are of great proven advantages.^[166] Low-sodium vegetables (i.e. cruciferous) are also suggested to reduce salt-related inflammation and cancer risks. Cruciferous plant species (cauliflower, broccoli, cabbage, brussels sprouts) accumulate sulfur-containing chemicals, known as glucosinolates, responsible for characteristic aroma and bitter taste.^[167] During chewing and digestion, the glucosinolates are broken down to divers biologically active chemicals (indoles, thiocyanates, and isothiocyanates) with proven anticancer properties.^[168]

Monosodium glutamate (MSG) is non-essential amino acid, commonly found in nature.^[169] MSG is classified as the food additive and is widely used in the food industry as a flavor and taste enhancer. The evidence for disadvantages reaction in humans after MCG large doses use is unclear; however, links between MSG and asthma, headaches and other syndromes make a clear attribution to higher than the natural level of MSG.^[170] Recently, Hata et al.^[171] documented that the MSG-induced diabetic mice are highly susceptible to (AOM) azoxymethane-induced colorectal carcinogenesis. They suggest MSG indirect effect in CRC via the metabolic conditions associated with diabetes (hyperinsulinemia, hypercholesterolemia, hyperglycemia, hypercholesterolemia). The acute metabolic complications of diabetes usually induce chronic inflammation in the microenvironment of precancerous lesions for CRC and may contribute to the growth of the lesions.^[15,172]

Fiber-rich products (vegetables and fruits)

The fiber-rich products as whole grains, beans, vegetables, and to the lesser extent fruits are important when considering their excellent abilities in effective prevention against the CRC.^[173] Chemically, dietary fiber consists of non-starch polysaccharides (NSP) and resistant starch. Fiber is indigestible by humans and helps to carry the digestive contents along the intestinal tract. It appears that fiber decreases the risk of CRC by accelerating the transit of gastrointestinal contents, and reducing the colonic exposure time to multiple exogenous and endogenous carcinogens originated from food. The fiber is already known to encourage the gut microbiota for anaerobic fermentation of undigested carbohydrates.^[172,174] This fermentation results in higher production of short-chain fatty acids and lower level of toxic products of bacterial protein fermentation.^[174,175] Fiber-rich products favor the production of the butyrate, the mediator of anti-inflammatory response in colonic epithelial cells. In addition, the fiber-rich plant origin products contain diverse phytochemicals (i.e. polyphenols, flavonoids, carotenoids, terpenes, vitamins) as well as minerals.^[176,177] These molecules are involved in various metabolic pathways, including several engaged in prevention of oxidative DNA damage, DNA correction mechanisms in cells or binding of carcinogens. As a consequence, the dietary fiber contributes to anticancer protection (Table 2).^[25]

Table 2. Suggested anticancer activity of fiber-rich products.

Suggested anticancer activity of fiber-rich products

Encourage the gut microbiota for anaerobic fermentation of undigested carbohydrates Increase production of short-chain fatty acids during fermentation Decrease production of toxic products of bacterial protein fermentation Favor production of the butyrate, the mediator of anti-inflammatory response Contain phytochemicals which are involved in prevention of oxidative DNA damage, DNA correction mechanisms in cells or binding of carcinogens

Vitamins and minerals

Vitamins are essential nutrients playing vital roles in body metabolism and their role in various diseases development, including cancer have been intensively studied recently.^[178] The other anticarcinogenic component of food, mainly found in dairy products is believed to be vitamin D, important in calcium homeostasis and metabolism. However, the current data on vitamin D status are inconclusive and more randomized controlled study are needed to appreciate the role of vitamin D in altering the risk of CRC. In general, the relationship has been shown between low vitamin D levels and the risk of development and growth of colon cancer.^[179–182] The recommended daily intake of calcidiol for sufficient decrease in the CRC risk is 1000 International Units.^[183] The study of Grau et al.^[184] revealed the reduction in CRC risk among women who were receiving both calcium and vitamin D supplements.

In some experimental study on rats, the vitamin D deficiency modulated the expression of proteins (i.e. cyclin D1) involved in control and coordination of mitotic events and cell cycle.^[185–188] The overexpression of these proteins is frequently observed in the colorectal mucous membrane and have been suggested to increase the cancer risk.^[189,190] Some reports indicate that low total intake of vitamin D may induce the differentiation and apoptosis in the normal colorectal epithelium cells as well as in cancer cells in humans, and thus may contribute to tumorigenesis.^[191–193]

Vitamin C is mentioned as useful in protecting against the CRC. Plausible biological mechanisms to explain vitamin C involvement in CRC risk is by inhibiting the nitrosation process and reducing the endogenous N-nitroso compounds (NOCs) formation.^[194,195] The role of these compounds in several cancers, including the CRC has been established.^{[143,196,197]} In cancer case–control studies, the high risk of CRC was clearly associated with high consumption of food high in nitrates and proteins (i.e. meat), and low intake of vitamin C.^[142,198] Similarly, vitamin E (alpha-tocopherol) is reported to be involved in the CRC risk reduction by involvement in binding N-nitroso compounds (NOCs). Accordingly, the protective effects of a diet high in fresh vegetables and fresh fruits on the CRC are presumably related to the vitamin C and E content in these products.^{[194,199–201]}

Many studies indicate the role of folic acid in the reduction of CRC risk, up to 40%.^[202–204] Folic acid has to be supplied by food, as it is not synthesized in the human body. Naturally, folic acids or folate are compounds of vegetables (mainly leafy), fruits, grains, nuts, beans, dairy product, eggs, and meat. A presumable biological mechanism of defensive role of folic acid is related to the DNA repair process that correct mistakes occurring during DNA replication. It is accepted that folic acid is necessary for methylation of DNA. Methylation is believed to play a crucial role in many cellular processes (i.e. chromosome stability) and errors in methylation are believed to have devastating consequences for many metabolic pathways, including carcinogenesis.^[205,206]

Next, there is convincing evidence that vitamin B6 deficiency may increase the CRC risk. Vitamin B6 is a critical coenzyme active in hundreds of metabolic reactions; it is required in amino-acid metabolism, glucose metabolism, lipid metabolism, as well as is involved in the expression of individual genes.^[207] Therefore, the vitamin B6 may suppress the CRC carcinogenesis by various pathways, i.e. reducing the inflammation process, oxidative stress, N-nitroso compounds (NOCs) formation, lowering the cell proliferation and angiogenesis.^[208,209] In vivo and in vitro observations highlight that high intake of magnesium and selenium may reduce the CRC risk.^[210] Intracellular magnesium homeostasis is necessary for proper metabolic cell function.^[211,212] Therefore, lack of magnesium is linked to various chronic metabolic irregularity (i.e. insulin resistance, inflammation) that may favor carcinogenesis.^[212,213]

Water and soft drinks

Consuming adequate amounts of water has been found to play a significant role in the CRC prevention. The reduction of CRC risk by 33–42% is related to drinking more than 4 cups of water daily.^[214,215] The advantage of the increase in water intake for decrease CRC risk is related to water involvement in a numerous process, e.g. digestion, absorption, molecules transport, elimination of waste products and toxins, and proper intestine function.^[216] Low daily water intake leads to reduced fecal output and constipation.^[217] The prolonged bowel transmit time and increased mucosal contact with fecal-related carcinogens are critical steps in the initiation of cancer development in the colon and rectum.^[218,219] The concept was confirmed in the animal models, showing that decreased bowel transit time was correlated with the development of colorectal neoplasm.^[220]

The water quality is an important issue for human health. The epidemiological studies in Japan and China have found the association between the CRC risk and the contamination of drinking water with chemical pollutants, anaerobic bottom sediments or excessive growth of algae.^[221,222] The quality of water sources used in gardening is also important.^[223] Moreover, the potential carcinogens in drinking water are high levels of naturally occurring trace elements and radioactive substances, i.e. arsenic in naturally mineralized water or by-products of drinking water chlorination, i.e. chloroform and carbon tetrachloride.^[224,225]

In ‘the Western diet’, many non-nutritive substances are regularly consumed, among them are beverages (tea, coffee, soft drinks). The opinions of tea and coffee drinking with CRC risk are inconsistent. No association of greater coffee and tea intakes with risk of colorectal cancer has been assessed.^[226] Some investigations have suggested that several constituents, i.e. caffeine and chlorogenic acid from coffee, the catechin found in green tea and black tea polyphenols have shown chemoprotective effects and can even reduce colonic tumor formation.^[227,228] The decrease in the CRC risk has been associated with gender and population group, especially with European women.^[229] In fact, coffee or tea is a complex mixture that contains hundreds of various composition and concentration molecules, which are influenced by geographical origin and growing conditions, diseases and symbiosis (pest and fungi), roasting and drying processes, storage conditions or even serving techniques, and all these factors can contribute to the overall therapeutic benefits.^[230]

Adverse health effects have been related to soft drinks, the carbonated, sugar-sweetened beverages, often containing artificial flavorings and other ingredients.^[231,232] The consumption of sugar-sweetened drinks increases total energy intake and contribute to excess weight. Evidence for the relationship between increased overweight and obesity-related syndromes and health problems (chronic inflammation, type 2 diabetes) and the increased risk of cancers, including CRC have been extensively documented.^[15,172] For more than 30 years, the recommended alternative was replacing sugar-sweetener with non-caloric sweetener – aspartame.^[233] Since then, the evidence for a relationship between long-term aspartame use and the increase in lymphomas/leukemias in animal models have been reported.^[233,234] It is thus highly probable that similar carcinogenic events could occur in humans as a result of regular intake of aspartame; however, further investigations focusing on the safety of aspartame and its breakdown products (aspartic acid, methanol, phenylalanine) are required to provide conclusive evidence.

Conclusion

Although there is still a long road to cover the gaps in knowledge on nutritional determinants and dietary pattern on the CRC risk, several dietary suggestions and goals could be summarized. In brief, diets high in energy, consumption of red meat or processed meat, rich in food with high glycemic index (carbohydrates, snack food, and frying fast food) and rich in omega-6 PUFAs which causes the imbalance in omega-6 PUFAs to omega-3 PUFAs ratio has been linked to an increased CRC risk. In contrast, consumption of white meat, as well as plant and fish oils rich in omega-3 PUFAs might even reduce the occurrence of colorectal cancer. Higher intake of dietary fiber lowers the CRC risk up to 50%. Diet rich in vitamin D, E, and C, selenium, and magnesium, adequate amounts of daily water intake, healthy bowel motility, have been considered to reduce the CRC risk. However, in many cases, the results are inconsistent and depend on multiple interdependent factors, i.e., ethnic, anthropometric, gender, hormonal, environmental, and lifestyle. In addition to dietary habits, all these agents are suggested to modify the risk of CRC.