3. Nutritional facts about macronutrients in cancertrnres.com/ebook/uploads/mehdipour/T_13104450203 Mehdipour.pdf · Nutritional facts about macronutrients in ... 1Department of Community

Transworld Research Network 37/661 (2), Fort P.O. Trivandrum-695 023

Kerala, India

Bridging Cell Biology and Genetics to the Cancer Clinic, 2011: 59-82 ISBN: 978-81-7895-518-6 Editor: Parvin Mehdipour

3. Nutritional facts about macronutrients in cancer

Saeed Pirouzpanah1 and Fariba Koohdani2

1Department of Community Nutrition, School of Health and Nutrition Tabriz University of Medical Sciences, Tabriz, Iran; 2Department of

Nutrition and Biochemistry, School of Public Health and Institute of Public Health Research, Tehran University of Medical sciences, Iran

Abstract. Cancer has received increased attention in different societies in recent years. The dietary components have been proved to have important modulator impact on different stages of tumourigenesis and even have remarkable role in improving the prognosis of cancer. Macronutrients (protein, fat and carbohydrates) are believed to represent calorie to the cells and additionally could promote some physiological pathways attributing to increase risk of cancer. Consumption of protein and calorie is of much debate that lower consumption of protein and calories is the common nutritional problem facing many cancer patients and higher magnitude could support the burden of tumourigenesis. Numerous studies have evaluated the role of glycemic index or glycemic load on cancer risk producing inconsistent results and also the association between dietary fat and cancer development still remains controversial. This chapter review several evidence on tumourogenic effect of macronutrients and their constituents in dealing with tumour development.

Correspondence/Reprint request: Dr. Saeed Pirouzpanah, Department of Community Nutrition, School of Health and Nutrition, Tabriz University of Medical Sciences, 5166614711 Tabriz, Iran E-mail: [email protected]

Saeed Pirouzpanah & Fariba Koohdani 60

Introduction The development of cancer is a complex multistage phenomenon with intricate etiology. Neoplasm is associated with numerous anomalous, biological alterations and defects in fundamental cell regulatory mechanism. Cancer results from aberrant and multiple accumulative changes in DNA damages that cause the net impaired in regular cell functions, metabolism, proliferation, differentiation and survival and eventually attributed to loss of normal tissue organization, and tissue invasion, spreading throughout the body and interfering with the normal function of intact tissues. Indeed, many biomolecules involve critically in cell signaling, regulation of cell cycle, and programmed cell death, where abnormalities in their activities led to tumour development. Importantly, the original progenitor cell does not have initially the acquired abnormalities. Several stages have been developed along with a progressive series of molecular changes to bring about tumour clonality. Different sorts of impaired biological mechanism involved in the etiology. One of the fundamental causes of changes is the interplay between molecular factors and the life style-related factors (e.g., dietary factors). A great deal has been focused about the intervening effects of dietary factors on inducing molecular defects responsible for many human cancers. Translating the empirical understandings of this interplay into practical dimension in cancer prevention and treatment could possibly provide appropriate considerations to pave the way toward overcoming crucial prognostic factor of disease. Diet and nutrients Series of data from numerous studies have shown that diet as a major compartment of lifestyle-related factor may play a crucial role in tumourigenesis. Interestingly, many researchers thrived to unravel an effective intervening approach on broader dimensions from initiation of tumourigenesis toward advance stages of tumourigenesis [1, 2]. In this regard, to our knowledge, dietary-related factors could have potent roles from commencing the neoplastic cells toward advance phases of cancer [1, 3]. Several increasing body of evidence corroborated that every factor could have relative protective or noxious impact on different cellular aggravating mechanism and consequently on extremely unharness proliferation attributed in cancer [4]. In fact, many attempts are focused to find out a dietary pattern in which could be protective against cancer with invasive nature come out from diverse multifactorial etiology [5, 6]. However, there are many

Nutritional facts about macronutrients in cancer 61

promising roles attributed to numerous dietary factors such as total calorie, protein, carbohydrate intakes and fatty acid composition of diet with respect to prevention and treatment implications against cancer, which recently various studies intriguingly reassure a possible link between life-style related factors and tumourigenesis [1, 7, 8]. In the context of this chapter we uncovered and review the attributed role of some dietary factors on biological mechanism involved in cancer prevention and treatment. Calorie There are several epidemiological evidence supporting the theory that diet plays an important role in the initiation, promotion and progression of many common cancers [3, 4, 9]. It is frequently addressed that imbalance calorie intake and a sedentary lifestyle profoundly associate with acquisition of adiposity over time and so-called as obesity [10, 11]. This feature is considered as an active predisposing risk factor for developing some malignancies such as endometrium, breast (postmenopausal), colon, esophagus, renal cell, pancreas, gallbladder and liver cancers [10, 12]. Long term appropriate physical activity and controlled calorie intake may have effect on some metabolic and hormonal alterations, which might cause negative energy balance and influence the procedure of adiposity [13]. Thereafter, reduction in adipose tissue, mainly visceral fat, could influence adipose derived hormones, which in part identified as adipokines. Adipokine profile predominantly consist of cytokines, where secrete from macrophage entrapped within fatty tissue and some originated from adipocyte itself [14]. Results of various researches suggest that chronic existence of adipokines could potentially interfere with cell responses to insulin and may attenuate insulin sensitivity in which subsequent insulin resistance could be clinically manifested [15]. Furthermore, obese individuals are prone to insulin resistance. In other sense, reduced fat mass is also accompanied with a reduction in circulating estrogen levels as a result of a reduction in aromatase activity [12, 16]. Hence, high circulation insulin level have been linked to lower expression of sex hormone binding globulin (SHBG) and subsequently increased free estrogens and testosterone. Therefore, weight loss may associate with decreased insulin level and increased SHBG concentration which could protect proliferating cells in hormone-responsive tumours from exposing high free estradiol and testestrone in blood. Decreased visceral adiposity may also come along with increased insulin-like growth factor binding protein-1 (IGFBP-1) and reduced free insulin-like growth factor-1 (IGF-1) that might preclude the possibility of cell division and invasiveness [12]. Weight loss is also associated with a reduction in inflammatory


cytokines and prostaglandins, and may have effect on several factors of oxidative stress and subsequent DNA damages [17]. O'Callaghan et al., have recently shown that a 13-month weight loss intervention is associated with increased telomere length in the rectal tissue biopsies [18]. Therefore calorie restriction (CR) might preclude telomere shortening, which might contribute in prevention of many age-related unhealthy processes. The provided result in our previous report on a group of patients with breast cancer (BC) led to a new idea about the possible association between calorie intake and the risk of hypermethylation of tumour suppressor genes. We found out that high energy consumption might associate with the hypermethylation status of RARbeta2 gene in breast tumours [19], suggesting that tumours with unmethylated gene and subsequent expression of RARbeta2 as tumour suppressor gene might be more pronounced in BC patients consuming lower calories. Waterland has proposed that the beneficial effect of CR on colorectal cancer (CRC) risk is mediated through decreasing IGF-1 [20]. During adolescent the blood level of IGF-1 is high and suggested that CR can modify and influence the methylation patterns later in life [20]. Indeed, exposure to energy restriction during childhood and adolescence could possibly have more effect on lower risk of developing CRC. Hughes et al. (2009), proposed that severe transient energy restriction during adolescence due to famine during World War II is inversely associated with the risk of having a CpG island methylator phenotype (CIMP) tumour later in life [21]. From their findings, it is revealed that adolescence may be a critical and effective period of life span for epigenetic changes owing to environments that influence the risk of developing malignancy [21, 22]. The CR has long been known to suppress tumour growth in laboratory rodents [3]. Some sorts of developing tumours show a greater response to CR, and small proportion of tumours are resistant to the effects of CR in human studies [23]. The role of high IGF-1 level is anticipated to counterpart in carcinogenesis through stimulated PI3K pathway and repression of phosphatase tension human homology (PTEN) as molecular biomarkers that might significantly predict the responsiveness of a tumour to CR [23, 24]. Physiological impaired regulation of growth hormone secretion and also elevated IGF-I levels is common in acromegalic patients, which might be associated with the elevated risk of tumourigenesis [12]. Nutrition is one of the major regulators of circulating IGF-1levels [3]. Fasting in humans is a kind of CR in physiologic condition could markedly reduces serum IGF-1concentration [3]. Kalaany and Sabatini suggested that genetic alterations in PIK3CA or PTEN can predict the response of tumours to CR [24]. Indeed, two sets of tumour could be classified as CR-sensitive and


CR-resistant tumours based on the existent mutation on these genes [24]. Their provided clues suggest that variant levels of PI3K activation in tumours may take part in their differential. From their findings, it is postulated that signaling pathways other than PI3K may take part in mediating the effects of CR in more advanced tumour stages [24]. In a meta-analysis on experimental animal studies carrying out interventional energy restriction consistently show that CR in itself protects against the development of mammary tumour in mice, irrespective of the macronutrients combination or other relevant study condition [25]. The CR may have negative association with the frequency of some mutation and may cause interference with impaired mechanisms such as the increased activity of FOXO pathways, inflammation and proliferation in the pre-neoplastic lesions and normal neighbor cells [3]. Rapid recurring of surgical injuries needs adequate calorie and protein intakes, likewise the principles of diet therapy for wound healing [11]. However, it is suggested that during post-surgical healing and chemotherapy adequate amount of calorie is essential [26]. Even sufficient calorie and weight gain could support long lasting chemotherapy and subsequent well prognosis of the disease. However, it shouldn’t be forgotten that calories are important for healing, fighting infection, and providing energy for normal cells. Nevertheless, the optimal body weight is recommended for patients during the therapy, X adiposity and relevant obesity might be attributable to non-responsiveness of tumour cells during chemotherapy [11]. Even so, the role of CR and other related dietary manipulations in cancer might be potentially correlated with different range of tumour regression in animal model and human studies, identifying the metabolic and molecular mechanisms responsible for the CR-dependent cancer preventive effect is unclear and it has the potential to lead researches to focus on CR-based therapies [12]. Macronutrients Consumption of diets that are adequate for energy, but low in red meat and fat has been recommended as an important preventive approach to decrease the risk of cancer [27], and have remarkable benefits to reduce cancer incidence by as much as 30% to 40% by an appropriate dietary guidelines (Table 1) [27]. In contrast, ingestion of vegetables, fruit, plant-derived oils such as olive and flaxseed oils, and marine fish and their oils was associated with reduction in cancer risk.


Table 1. Cancer prevention recommendations (population goals; individual guidelines) from the 1997 World Cancer Research Fund/American Institute of Cancer Research expert report [6, 28].


Table 1. Contined


Protein Essential amino acids (lysine, threonine, methionine, phenylalanine, tryptophan, leucine, isoleucine and valine) could provide substrate for normal metabolic requirements from protein rich food sources in diet [26]. In intact cells, amino acid could be utilized as catabolic substrate to yield acetyl group in order to produce energy through Kreb’s cycle. Amino acids also participate in the composition of structural and functional proteins in cells that could support cells integrity to live [29, 30]. In moderate restricted protein diet (<0.75 g of protein/kg body weight/day), which is consumed as common in vegetarian dietary pattern, significant lower serum concentrations of total and free IGF-1 is reported [12]. Moreover, reducing protein intake in individuals who consume strict CR with high protein intake (>1.65 g of protein/kg body weight/day) might have a 25% reduction in serum IGF-1 (from 194 ng/mL to 152 ng/mL), suggesting that the proportion of protein to calorie intake could play major role on circulating IGF-1 levels in humans relative to CR alone [12]. Protein intake was associated with increase in serum IGF-1 level, whereas calorie intake was associated with an increase in serum IGF-I concentration only in lean men with a body mass index <25 kg/m2 [12], suggesting the increased incidence of two adiposity-independent common cancers, such as prostate and premenopausal BC and high protein consumption. It is important to note that the recommended daily allowance for protein intake in healthy adults is 0.83 g/kg of body weight/day [24]. It is presumed that some noxious substances exist in protein and may take part in genotoxicity and carcinogenicity [31, 32]. Thus, high meat and processed meat intakes were linked in part to developing the neoplasm and initiation of cancer in epidemiologic studies [29]. Even though, the presence of adequate level of amino acids is vital for normal cells, it is extremely essential for tumour cells to compensate their sever demands for un-controlled proliferation. The main cancer type that has been linked with high meat intake is CRC, based on a considerable number of reports [29]. Sandhu et al. (2001), suggested that a daily increase of 100 g of all meat or red meat is associated with a 12–17% increased risk of CRC, and a daily increase of 25 g of processed meat is associated with 49% increased risk, suggesting greater undesirable impact of processed meat in tumourigenesis [33]. Consistent conclusion was also drawn by Norat et al. (2002), supposed that individuals in the highest quartile of red meat consumption correlated with a 1.35-fold increased risk of CRC, while those in the highest quartile of processed meat intake showed a 1.31-fold increased risk [34]. Larsson and Wolk (2006) bring out the similar result (1.28-fold increased CRC risk for the highest as


compared with the lowest red meat intake, and 1.20-fold increased risk for processed meat) [35]. However, the reviews concluded that there was no significant association between total meat intake and CRC risk [30]. Whereas, there is consensus that cancer risk might associate with higher consumption of animal protein [22]. There is also possible explanation that the relationship between cancer risk and formation of neoplasm may be linked with dietary pattern, type of meat preparing and invisible fat exist in meat [30]. There are some possible mechanistic evidence about the correlation between meat consumption and cancer. These factors were possibly linked to high-fat content of meats, the production of mutagenic aldehydes, DNA alkylating agents such as heterocyclic amines (HCAs) and/or polycyclic aromatic hydrocarbons (PAHs) during overheated and direct flame-exposed cooking (barbeque, grilling, frying and so forth), the formation of carcinogenic N-nitroso compounds (NOCs) either within meat per se or as a preservative, and the promotion of lipoperoxidation and/or cytotoxicity by haem iron [30]. It is also suggested that the high fat content and also calorie density of protein in meat are in attribution with the increased likelihood of obesity, which is highlighted as a major risk factor for some cancer [30]. Results of a cohort study from Finland suggest that the risk of BC was increased (80%) in individuals consuming fried meat (highest versus lowest tertile RR, 1.80; 95% CI, 1.03-3.16), whereas other meat consumption was not correlated with BC [36, 37]. In a nested case-control study among the Iowa Women’s Health Study cohort [22], the risk of BC risk was high among regular consumers of well-done and fried meats (more than 4-fold) in compared with whom consuming medium or rare meat. Conjugated linoleic acids (CLAs) are a bundle of polyunsaturated fatty acids (PUFAs) with positional and geometric conjugated isomers of linoleic acid usually found in the cis-9, trans-11 isomers [30]. The CLAs are found predominantly in dairy products and tissues derived from ruminant animals. Rumen bacteria in part are responsible for producing CLAs due to partial hydrogenation of PUFAs [26]. There is emerging clues about possibly anticarcinogenic properties of CLAs, but their mode of action is poorly understood [26]. In animal studies, CLAs inhibit carcinogenesis, possibly through modulating immune function [38]. It is proposed that CLAs could be catalyzed by cyclooxygenase (COX) and may decrease the production of potent proinflammatory mediators and eventual cause to increase immune function [39]. It is underlined that t11-CLA inhibited the COX-2 pathway and t10, c12-CLA inhibited the lipooxygenase pathway [40]. Some evidence showed that CLAs are also capable to induce apoptosis but relevant molecular signaling which is not clarified thus far, based on human data [39].


In addition, Ip et al. (2003) indicated that CLA might inhibit angiogenesis in vivo, in part, through mediating the CLA-induced decrease in serum vascular endothelial growth factor (VEGF) and mammary gland VEGF and flk-1[41]. The way of cooking and food preparation are important factors to keep essential ingredients intact to some extent and precluding from production of toxic compounds in protein rich foods such as meat [30, 32]. Fat content of animal sources is a causing factor of undesirable sources in the process of cooking and storing the food. Removal of visible fat and cooking method will also be important for reducing the possible sources of risky components [29]. Carcinogenic heterocyclic amines (HCAs) are DNA alkylating agents can induce mutations in DNA following activation by various hepatic xenobiotic metabolizing enzymes [31]. There are various enzymes involved in catalyzing HCAs, including cytochrome P450, glutathione S-transferase, UDP-glucuronosyltransferases, sulfortransferases and N-acetyltransferases. Various responses to the presence of HCAs and toxicity among individuals could be possibly explained by the existence of single nucleotide polymorphisms (SNPs) in these enzymes in which could intervene with the metabolism of HCAs [32]. Thus, in the condition of carrying SNPs variation, overcooked meats may bring about hazardous impact on developing cancer [32]. In this case, preparing meat in the presence of other mutation modulating agents such as fiber and phytochemicals may be a convenience way to reduce the possibility of DNA damages. There is evidence suggesting that a diet high in dietary fiber sources such as wheat bran may reduce the absorption of HCAs and therefore reduce possibly the carcinogenic effects of HCAs [30, 32]. Carter et al. (2007) suggested that epigallocatechin-3-gallate, and caffeine (tea) may suppress HCA-induced colonic lesions and cell proliferation in the colon [42]. Cruciferous vegetables and polyphenol rich fruits and vegetables contain vitamins and phytochemicals modulating the activity of certain xenobiotic metabolising enzymes. Hence, they can interfere with the methabolism of HCAs and reducing the induction of activated mediators of HCAs [30]. The ability of vitamins C and E are well-established to inhibit the formation of carcinogenic N-nitroso compounds (NOCs) in meat per se and in nitrite-preserved meat. Vitamin C also consider as antioxidant counterparts in reduction of nitrite transformation to NOCs. These nitric based compound significantly produced through microbial flora of gut and other tissues proning factors to produce the N-nitroso derivatives (such as mouth, esophagus, stomach, intestines, colorectal, uterus, bladder and so on) [43, 44]. In an animal study, Koohdani and Mehdipour suggest that the number of a chromosomal defects as micronuclei might be elevated by exposure to nitrite meanwhile the rats nourished with high level of sodium


chloride, suggesting high nitrite content of processed meats often contain high salt in a meal and may increase the possibility of genotoxic effects [45]. Urethane is a potent carcinogenic by-product of fermentation and exist at considerable levels in fermentated dairy product such as cheese [44]. It is indicated that the expression of Ki-67 antigen might be increased by urethane in lung tissue and likely be more aggravating while nitrite ion coexist in food [44]. The major sources of nitrite provision is addressed markedly to foods and drinks which are polluted and cultivated utmost in the exposure of chemical fertilizers and natural sources of nitrite [26]. Some additives and spices may also provide the circumstantial amount of NOCs to access of living cells, if they are consumed regularly in common dietary pattern. Meat is also useful source of highly bioavailable zinc, as well as providing vitamin B6, B12, vitamin D, calcium, folate and selenium [28]. Each of these micronutrients may have beneficial effects in cancer protection, via different mechanistic pathway. Linos et al. (2008), have shown that the exogenous hormones content of meat, e.g., diethylstilbestrol, have been used worldwide for growth stimulation in cattle, and residual amounts of these components in beef may have implications in carcinogenesis [22]. They also explained a possible mechanism related to induction of oxidative stress by dietary iron consumption. In animal studies, it is shown that dietary iron may enhance estrogen carcinogenicity possibly by promoting free radical damage to DNA [22]. In some case-control studies, high rate of mutation in the HFE gene has been indicated among BC patients, which is a well-known genetic characteristic in the etiology of hereditary hemochromatosis [46]. This finding indirectly implicates iron overload in BC pathogenesis. Iron in meat exists in the form of heme and readily bioavailable form of iron and significantly contributes to stored body iron [22]. Hence, the link between dietary protein intake and premenopausal BC risk might be explained in part by contribution of iron-related genetic variation and dietary iron consumption during adolescence and the effect of red meat appears to be independent of animal fat intake. Eventually, several lines of evidence have support a conclusion that high meat intake, processed meat, and fried and flame direct-exposed cooking methods for red meats may increase the hazard of certain cancers development [30, 32]. Besides, it is important to reinforce the nutritional impact of amino acids and several micronutrients to meet normal metabolic demand of human body [37]. It is mostly achievable to provide some possible approaches to maintaining a moderate intake of meat, alongside selecting healthy dietary pattern to eat (e.g., low fat meat, plant-source protein, unprocessed food, modulating the cooking methods and so forth) to reduce


cancer risk and also possibly pave the way in part to restrict the tumour growth during therapeutic intervention [30]. Dietary fat Dietary fat with high energy density could bear out about 9 kcal/gr of fat in common dietary pattern [26]. The average amount of dietary fat intake in normal dietary composition recommended around 15-30% of total energy intake[26]. However, some dietary pattern consists of more than suggested magnitude. Although genetic predisposing factors and different pattern of environmental features influences the risk of cancer development, several investigators have discussed the effect of different levels of total fat intake and different levels of total energy intake [12, 25]. However, no clear conclusion is available on whether the effect of fat intake on tumour incidence is adjusted by the level of calorie intake. However, there is consensus that CR retained by reducing the intake of fat which might be more effective in achieving the goals related to energy restriction compared to the effect of reducing carbohydrates [25]. Consistently, Freedman et al. (1990), find out that the effect of dietary fat was comparable to total calorie intake toward independently increased mammary tumour incidence (2/3 the magnitude of the calorie effect) in both Sprague-Dawley rats and mice [47]. However, World Cancer Research Fund/American Institute for Cancer Research [9], reported that limited data exist to suggest possible link between intake of foods containing animal fat and increased risk of CRC. Several studies have attempted to show that dietary fat may in part have role in increasing the risk of cancer development particularly in breast, ovary, esophagus, colorectal and prostate cancer, but it still remains to be elusive. Data from animal studies and some case–control studies propose that high intake of total fat elevate BC risk, but results from prospective cohort studies are inconsistent [1, 48]. Total fat Decreasing dietary total fat intake is a plausible target in most studies to meet the preventive approach in development of BC [49]. The epidemiological case-control studies (WCRF/AICR, 2007) showed a positive association between total fat intake and BC risk but no supportive association was reported in the Women Health Initiative’s (WHI) randomized controlled trial [49, 50]. In this regard, some biological plausibility was anticipated to reveal the related risk to lipids as follow: It has been known that the required bile acids to digest fat in humans may promote the development of some


cancers [48]. Specifically, the metabolism of secondary bile acids (deoxycholic acids) from primary bile acids by anaerobic bacteria in the large bowel is known to be toxic and mutagenic to cellular systems and may cause damage to intercolonic membranes or intracellular mitochondrial function cancer cells. In addition, it has also been hypothesized that elevated concentrations of transforming growth factor-b1 (TGF-b1), a cytokine predominantly responsible for regulating the growth of epithelial cells, may aid in the progression of related cancer cells [48]. Inflammation and fat have been shown to increase TGF-b1in cancer risk. Another hypothetic implication is the participation of lipids in the excess of energy intake which could help to draw the conclusion about fundamental effect of energy intake [48]. If total fat intake has an impact on cancer risk (such as CRC), the contribution of caloric intake and/or dietary pattern with high content of energy by fat could explain this phenomenon in part. However, this issue was not consistently described by different studies [25, 48]. The acquisition of body fat in premenopause women and consecutive levels of adding estrogen in comparison to gonadal secretion of estradiol would be less important in attributing to risk for BC [51]. For postmenopausal women, it is believed that adiposity is a risk factor for hormone related cancers due to extragonadal estrogen synthesis mediated by adipose tissue. Thus, the role of nutrition-related factors on promoting the body fat accumulation and maintenance appears more preponderant in postmenopausal women, where the estrogenic agonist role of extragonadal hormone profile is important [51, 52]. Importantly, several studies showed increased survival in BC patients with low intake of total fat [7, 48]. Although there are still inconstant results brought about different epidemiological methods, total fat content of a regular diet has been suggested to be low as 15-30% to decrease possibly the chance of cancer development [6, 28]. In addition to total fat, various studies draw the conclusion that dietary fatty acid composition might have greater role in cancer risk. Saturated FA Based on the existence of double bounds between two carbon in the chemical structure of fatty acid chain, fatty acids in regular diet consist saturated, monounsaturated and polyunsaturated total fat [26]. There are many kinds of naturally occurring saturated fatty acids, which differ by the number of carbon atoms, ranging from 3 carbons (propionic acid) to 36 (Hexatriacontanoic acid). Some foods consist of high proportion of saturated fatty acids include dairy products (particularly cream, cheese, butter and ghee);


animal fats such as suet, tallow, lard and fatty meat; cottonseed oil, coconut oil, palm kernel oil, chocolate, and some prepared foods with high fat [26]. Serum saturated fatty acid is generally higher in smokers, alcohol drinkers and obese people [53]. Some studies show that high saturated fat intake might be associated with greater BC risk. This result was particularly addressed by Sieri et al. (2008) [53] that the highest quintile of saturated fat intake contribute in greater risk compared with the lowest quintile and showed that for a 20% increase in saturated fat consumption expected marginally to increase the risk magnitude at OR=1.02 (95%CI, 1.00-1.04). In menopausal women, the positive association with saturated fat was confined to nonusers of hormone therapy. In consistent, Bingham, et al (2003) showed a significant relationship between SFA and BC risk [54]. Thus, it was concluded that the effect of SFA was similar to that of total fat. The similar effects of these FA on CRC are also comparable to total fat. n–6 polyunsaturated fatty acids PUFA that contain the latest double binds in n-6 position of the end of fatty acid chain categorized as n-6 PUFA. They are more often occurred in regular diet as linoleic and arachidonic acids development [26], and hypothesized that could likely increase the risk of neoplastic development [26]. Although there are series of data from recent case-control and cohort studies that they were not drawn any conclusion and explaining the link between n-6 FA consumption and risk status of cancer, the impact of long time n-6 FA intake on the risk remains to be elucidated [48]. It is hypothesized that n-6 PUFA could take part in promoting the production of proinflammatory mediators and oxidation due to presence of several double bounds in FA chain. Despite the non-conclusive results from several studies, these reasons could support hypothetically the probable tumourogenic effect of longitude consumption of n-6 PUFA on neoplastic changes in some tissues [26, 48]. n–3 polyunsaturated fatty acids Fish oil is the main animal sources of eicosapentaenoic acid (EPA; 20:5, n−3) and docosahexaenoic acid (DHA; 22:6, n−3). Seafood and especially fatty fish (trout, salmon, tuna, mackerel, sardine, herring, and so on) are major dietary sources in most populations [26]. Alpha-linolenic acid (ALA) is a n-3 PUFA and fundamentally provided by some plant sources, e.g., seeds and nuts. EPA and DHA can be synthesized by humans from dietary ALA,


but with low efficiency [26]. Although there is sufficient evidence from in vitro and animal studies that these n-3 PUFA can reduce the progression of tumours in various tissues, hormone-related ones, the evidence from several epidemiologic studies is still in debate [55]. There is limited statistically significant data reported for ALA connecting with cancer risk [56]. In a cohort study based on serum FA evaluation proposed a marked decreased CRC risk in men and a non-significant increased risk in women [57]. Siere et al. (2008) found out that BC risk of development is in inverse association with PUFA [53]. Leitzmann et al. (2004) found out that EPA and DHA intakes could be related with lower risk of prostate cancer (PC) [58]. This result is consistent with that of a Japanese study, which showed a negative relation between PC mortality and serum n-3 PUFA (mainly EPA and DHA) [59]. Hence, a high intake of EPA and DHA was associated suggestively with a decreased risk of total and advanced PC [58]. In animal models, it has been reported that high n–3 PUFA containing diet precludes colon tumourigenesis compared with a Western diet with high fat content [60]. However, some studies were not capable to support this hypothesis [48, 61]. The heterogeneity of the findings cannot be explained. But, there are presumptions could support the biological plausibility related to n–3 PUFA on reducing the risk of cancer: (1) the anti-inflammatory effect via introducing pro-inflammatory mediators with relative neutral inflammatory function and suppression of COX 2 enzyme and cytokine production, (2) the anti-apoptotic effect and up-regulating effects on expression of proliferative, antioxidant contributing genes, 3) n-3 PUFA interfere in androgen receptor-mediated events (inhibit 5a-reductase, the expression of PSA protein and the androgen receptor-mediated transcription gene) and alteration of cell signaling, 4) inducing the expression of peroxisome proliferator-activated receptors gamma and modification of membrane phospholipids composition [56, 62, 63]. Although meat appears to be a risk factor in the case of CRC, replacing meat by fish meat might have reducing effect on the risk of cancer. In addition, the recent studies strengthen the probability of a causal relationship between fish intake and CRC [30]. Moreover, two recent cohort studies and experimental models draw a conclusion suggesting a favorable effect of n–3 PUFA on CRC risk and recommended that an intake of ≥500 mg combination of EPA and DHA daily is necessary for a significant risk reduction (20–25%) [48]. Consistently, it is relevant that Asian populations had high amount of n-3 PUFA intake and their average intakes ≥1.500 mg/day may help significant decrease on BC risk (50%) [48].


Dietary n–6 to n–3 PUFA ratio Several researchers have come to a relative consensus that a high ratio of n–6: n–3 PUFA is associated with an increased risk of CRC, PC and BC [61, 63]. From a prospective study data (Shanghai Women's Health Study), Murff et al. (2010) showed that the ratio of n-6 to n-3 PUFA ratio may be positively associated with CRC and BC among Chinese women [61, 64]. If the intake of EPA and DHA is increased as recommended above, the ratio is likely to improve. In the Health Professionals Follow-Up Study, Leitzmann et al. (2004), proposed that linoleic acid (LA) to ALA is inversely correlated with the risk of advanced BC, whereas, LA to EPA plus DHA was positively associated with risk of advanced BC [58]. They concluded that our result suggest that a high ALA intake is associated with an increased risk of advanced BC. In contrast, high EPA and DHA intakes may be associated with a decreased risk of total and advanced PC [58]. Nevertheless no precise conclusion put forth by epidemiological studies, it is recommended that a diet with a ratio of n-6 to n-3 essential fatty acids (EFA) of approximately 1-3 could be acceptable to prevent some chronic disease. Trans fatty acids In case-control and cohorts showed an increased risk of PC for the highest exposure to trans 16: 1, 18: 1 and 18: 2 [65], and 18: 1 11 trans and 18: 2 9 cis 12 trans [66] and trans 18: 1 and total trans FA [48, 67]. However, another cohort study failed to support any association [68]. Liu et al. (2007) suggest that, the polymorphic genotype of QQ/RQ at RNAsel (R462Q) may consider as predisposing factor to deficient proapoptotic activity. Interestingly, this genotype may consider as predisposing risk factor to PC in the case of exposure to total trans FA, trans 18: 1, trans 18: 2 intakes [65]. Indeed, Trans isoform of FAs are generated in ruminant meats and dairy products as a result of fermentation of FA via bacterial micro flora exist in ruminant gut. Monounsaturated FA There are too limited data to support any conclusion about monounsatuared FA (MUFA). The desirable effect might be attributed to: 1) the presence of leuropein, a phenolic compound in olive oil capable of inducing of phase I and II enzymes, 2) the Mediterranean dietary pattern is rich source of MUFA and associated with lower risk of atherosclerosis and cancer risk. Double bond present in unsaturated FA (PUFA and MUFA) is


vulnerable to oxidation and could potentially take part in oxidative stress. MUFA in comparison to PUFA had a double bond and have lower opportunity to oxidation [26]. Thus, consuming the MUFA rich diet (containing olive oil) underlines the beneficial importance in prevention of many chronic disease, e.g., some sorts of cancer [48]. Carbohydrate Carbohydrate is one of the major macronutrients in composition of food that yield considerable calorie through metabolic reactions [26]. They are categorized as: 1) monosaccharide-glucose, fructose (fruit sugar) and galactose which are rarely present in the nature as monosaccharide and combined with other one to build disaccharides and polysaccharides, 2) disaccharides such as sucrose (sugars), lactose (milk sugar) and maltose (malt sugar) widely consumed in the dietary pattern of Western countries. Polysaccharides such as starch consist of monosaccharide units joined by glycosidic links and are polymer of monosaccharides [26]. Starch is a polysaccharide stored by plant as granules in plant-derived food and build up a significant part of calorie from carbohydrate source in food [26]. Carbohydrate intake may influence BC risk by affecting insulin resistance and plasma levels of insulin and glucose [1]. Numerous studies have evaluated the role of glycemic index (GI) or glycemic load (GL) on BC risk producing inconsistent results. GL and GI are dietary characteristics that are useful for estimating the effect of dietary carbohydrates on the insulin response physiologically. The overall GI, a ranking system for carbohydrates according to their effect on blood glucose concentrations, reflects the average quality of carbohydrates consumed. The total dietary GL, the sum of the GLs for the total serving of all carbohydrate-containing foods consumed per day reflects both the average quantity and quality of carbohydrates [69]. Diets high in GI and GL have been associated with different range of chronic disorders such as obesity, diabetes mellitus, hyperlipidemia, heart disease, and stroke [70]. In cohort studies, an association between GI and overall cancer risk was seen among overweight individuals [70]. Increased risk of pancreatic cancer was proposed among cases with frequent consumption of foods high in sugar, hyperinsulinemia and the condition of insulin resistant [70]. Overweight and obesity are accompanied by higher fasting serum and free IGF-1. In particular, insulin promotes the production and activity of IGF-I that may increase cell proliferation and may inhibit cell apoptosis [71]. Hyperinsulinemia affects the production of sex hormones such as androgens and estrogens and decrease the production of SHBG that accompany with


elevated level of free sex hormones in circulation, which may be associated with cancer growth. In the Syrian hamster model, estrogen treatment resulted in kidney tumour, whereas antiestrogens reduced tumour formation [15]. The epidemiologic evidence suggests that a possible link between insulin and growth factors is directly come along with some evidence in CRC. It has also been proposed that high-GI and high-GL diets may promote weight gain over time. Being overweight or obese has been associated with esophageal adenocarcinoma and CRC from several meta-analyses evidence [69]. Dietary fiber is the major ubiquitous polysaccharide found in fruits and vegetables and has been suggested to reduce BC risk through an effect on estrogen signaling or via the insulin growth factor system. Some case-control studies have shown negative association between dietary fiber intake and BC risk, whereas it was not conclusively support by prospective cohort studies [1, 8]. Some researchers tried to reveal the hypothetic link between consumption of total dietary fiber and BC risk through the expression status of estrogen and progesterone receptors (ER and PR), which could involve in tumourigenesis and progration of tumour. However, they did not reach to a significant result and suggest that different plant foods might be differentially associated with BC [1]. Some studies show that other nutrients in addition to fiber exist in plant derived food (i.e. folate) that their insufficient intake might contribute in carcinogenesis of BC via repressing some tumour. Suppressor genes [19, 72]. We found out that folate deficiency may be involved in hypermethylation status of RARbeta2 and ERalpha genes and suppressed ER expression analyzed by immunohistochemistry in BC tumours [72]. Thus, ER and PR downregulation histologically in BC tumours might be attributed to folate deficiency that it could be additionally implicated by dietary fiber derived from vegetables and fruits. Therefore, it could be noticed that carbohydrate particularly mono- and di-saccharides show high GI and GL and could be involved in hyperinsulinemia, increased IGF-1 and subsequent tumour growth. Digesting recommended amount of starchy carbohydrate in the form of breads and cereals with high fiber content would reverse these associations and have more beneficial effect on health besides providing other essential nutrients to human body. Conclusion The promising role of dietary factors has been identified in the etiology of cancer. Several lines of evidence support the fact that dietary energy restriction could convey beneficial considerations for prevention by controlling the healthy pattern of genomic content during life-long and also inducing repression on tumour development. Therefore, it is hypothesized


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