Nutrition and Colon Cancer

Chapter 36

Nutrition and Colon Cancer Daniel D. Gallaher1 and Sabrina P. Trudo2 1

University of Minnesota, St. Paul, MN, United States, 2University of Arkansas, Fayetteville, AR, United States

I INTRODUCTION Colorectal cancer is the third most common cancer and third leading cause of cancer death in both men and women in the United States [1]. Approximately 71% of new cases arise in the colon and 29% in the rectum [1]. Epidemiologic evidence from migrant populations suggests there are some modifiable environmental risk factors, such as diet, in the etiology of colorectal cancer [2]. Hence, extensive research has probed the relationship between dietary components and altered colorectal cancer risk. Given that the majority of cases arise in the colon and evidence suggests some differences in etiology between colon and rectal cancers [3
5], this chapter will focus on the emerging evidence of dietary impacts on the risk of colon cancer. Many approaches have been developed to examine how diet influences risk of colon cancer. Broadly, these include case
control studies, prospective cohort studies, intervention trials using putative intermediate markers of colon cancer risk, animal studies, and cell culture studies. Each approach has advantages and limitations. Epidemiologic studies, such as case
control and cohort studies, are observational studies that primarily demonstrate associations between two variables (e.g., a particular dietary component or dietary pattern and colon cancer risk). Observational studies are thus most useful for generating hypotheses or providing support to findings from intervention or animal studies. However, since they directly examine humans consuming their normal diets, epidemiologic studies are invaluable in identifying potentially beneficial or harmful foods or dietary patterns. Prospective cohort studies are typically considered stronger than case
control studies due to less susceptibility to recall and selection bias. In addition, data from multiple cohort and case
control studies are often

combined to yield statistically stronger conclusions due to the combined larger number of study subjects, among other strengths of this approach; however, a primary drawback is that not all published cohort and case
control studies on a given topic provide sufficient data to be included in the meta-analysis. Another approach for examining the role of nutrition in the etiology of colon cancer is the intervention trial. The advantages of these studies are that foods or dietary patterns being studied are well controlled and there is no question about applicability to humans. However, this approach requires an outcome measure other than the development of cancer, since trials are necessarily of shorter time than the induction period for colon cancer. Currently, there is no unequivocally validated intermediate marker for colon cancer. Recurrence of colon adenomas (polyps) after their removal has been used, but studies of polyp recurrence are long and expensive. Further, even polyps are not completely validated as a marker of colon cancer risk. However, there is reason for optimism, as some studies suggest the possibility that molecular markers collected from either rectal swabs [6] or fecal samples [7] may provide the long sought validated marker of elevated risk of colon cancer. Animal studies represent a complementary approach that allows a more mechanistic examination to the study of diet and colon cancer. Although questions about the applicability of findings from animals to the human situation must continually be considered, there is no doubt that findings from animal studies provide insight into colon cancer in humans. Animal studies are often the best approach to examine how consuming different dietary components influence initiation events such as biotransformation of carcinogens, DNA adduct formation, DNA repair, and apoptosis, as well as postinitiation events such as changes in signaling pathways and eventual tumor formation.

Nutrition in the Prevention and Treatment of Disease. DOI: http://dx.doi.org/10.1016/B978-0-12-802928-2.00036-9 © 2017 Elsevier Inc. All rights reserved.

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Cell culture studies are frequently employed for the study of how isolated compounds influence cancer cell growth and signaling pathways, among other aspects of carcinogenesis. Nonetheless, they are severely limited in that whole foods requiring digestion cannot be examined nor can food components that are normally metabolized after consumption. Consequently, for the purposes of this chapter, we shall focus on only animal, case
control, prospective cohort, and intervention studies related to nutrition and cancer. In discussion of the animal studies, we shall focus on those studies using whole foods and their effect on morphological endpoints of colon cancer, either adenomas (benign tumors that may progress to cancer), adenocarcinomas (cancerous tumors), aberrant crypt foci (ACF, believed to be precancerous lesions), or mucindepleted foci (MDF, a subpopulation of ACF which are suggested to be highly dysplastic and are more immediate precursors to tumors than ACF) [8]. A representative image of ACF and MDF is shown in Fig. 36.1. For discussion of human studies, we will focus similarly on studies using colon cancer as the endpoint, with the exception of intervention trials. Emphasis will likewise be on studies of whole foods with a few exceptions. The majority of these studies have investigated diet components that can be grouped into five categories: Fruits, Vegetables, and Legumes; Meats; Milk and Dairy Foods; Whole Grains; and Beverages. For each category we will summarize the proposed impact on colon cancer risk, including putative biological mechanisms for influencing cancer risk, and review the relevant animal and human data. Fig. 36.2 provides a representation of the process of carcinogenesis, and will provide a basis for understanding at what point(s) different diet components can influence this process.

II FRUITS, VEGETABLES, AND LEGUMES Proposed mechanisms for influencing cancer risk. It has been hypothesized that plant foods protect against cancers such as colon cancer [9]. Thousands of phytochemicals have been identified in fruits, vegetables, and legumes, many of which are capable of modulating various processes related to colon cancer development. For example, apoptosis (or programmed cell death) is a means by which cells with DNA damage can be safely eliminated instead of becoming cancerous. Flavonoids that are found in many fruits and vegetables induce apoptosis in a variety of models [10,11]. Other phytochemicals that induce apoptosis include proanthocyanidins (apples, chocolate, grapes, berries, other fruits), resveratrol (grape skins, peanuts), isothiocyanates (derived from cruciferous vegetables like broccoli and cabbage), and limonene (citrus fruits, cherries) (reviewed in Refs. [10,12]).

FIGURE 36.1 (A) Aberrant crypt foci (ACF) and (B) mucin-depleted foci (MDF) in rat colon. ACF are visualized by staining whole mounts of colon with methylene blue. MDF are ACF that show no mucin staining using high-iron diamine alcian blue. Normal crypts stain black.

Second, many of the naturally occurring compounds in plant foods also interfere with oxidative processes by acting as antioxidants or increasing antioxidant activity. Antioxidants inhibit or mitigate the damage to cells from reactive oxygen species (ROS) that can lead to carcinogenesis. Compounds shown to be antioxidants or to increase antioxidative activities include vitamin C, vitamin E, provitamin A and other carotenoids, flavonoids, proanthocyanidins, isoflavonoids (soy), isothiocyanates and indoles (cruciferous vegetables), and resveratrol (see reviews [10,12,13]). A third major process modulated by phytochemicals is the metabolism of carcinogens. Several groups of biotransformation enzymes metabolize carcinogens by typically first exposing functional groups on the parent compound, referred to as phase I metabolism and, secondly, conjugating the metabolite with another molecule, called phase II metabolism. The net effect is usually a safer

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FIGURE 36.2 An overview of the pathway of chemical carcinogenesis. Indirect carcinogens can be detoxified through phase I and phase II metabolism, although for a few compounds, phase II metabolism can lead to carcinogen activation (dotted line). However, some indirect carcinogens are activated by phase I metabolism, leading to mutations in DNA through formation of DNA adducts. DNA repair mechanisms can remove the adducts. If mutation is extensive, this can result in cell death through apoptosis. However, if the DNA is not repaired correctly, and DNA replication occurs, this can lead to a permanent mutation, forming an initiated cell. Additional mutations or promoters of cell proliferation can lead to hyperproliferation and potentially a tumor. Adapted from G.A. Belitsky, M.G. Yakubovskaya, Genetic polymorphism and variability of chemical carcinogenesis, Biokhimiya 73 (2008) 675
689, http://www. protein.bio.msu.ru/biokhimiya/contents/v73/ full/73050675.html.

and water soluble product that can be excreted. The cytochrome P450s (CYPs) are generally involved in the first step and the second step is mediated by conjugating enzymes such as glutathione S-transferases (GSTs), UDP-glucuronosyltransferases (UGTs), N-acetyltransferases, and sulfotransferases (SULTs). However, carcinogen metabolism by these collective enzymes is complex, in that the enzymes have broad substrate specificities and in some instances actually toxify the substrate instead of detoxifying it by the chemistry they mediate (i.e., activate procarcinogens). Given the number of phytochemicals that modulate biotransformation enzyme expression and activity, a widely investigated hypothesis is that diet could optimize biotransformation activity toward net detoxification of carcinogens. For example, CYP activity is influenced by isothiocyanates, furanocoumarins, and phenolic compounds [14,15]; GST activity is modulated by isothiocyanates and cruciferous vegetables [15,16]; many flavonoids, isoflavonoids, polyphenols, and some carotenes modulate UGT activity [17]; and evidence indicates that flavonoids and isoflavonoids inhibit several SULTs [18]. A fourth cancer-related process that is modulated by phytochemicals is inflammation. During promotion, cytokines and chemokines can serve as tumor growth factors and

tumor survivor factors; proinflammatory cytokines can also regulate epithelial-mesenchymal transition and thus influence invasion and metastasis [19]. Flavonoids, proanthocyanidins, isothiocyanates, and resveratrol have demonstrated antiinflammatory activity [12,19]. Additionally, many plant foods are rich in folate, a water soluble B-vitamin. Folate aids in methylation of DNA, and methylation patterns are key in epigenetic regulation of gene expression. Finally, fruits, vegetables, and legumes provide fiber which may prevent colon cancer by increasing bulk of stool, decreasing transit time through the gut, and diluting carcinogens [20]. Animal studies. Few studies have examined the effect of whole fruits on colon carcinogenesis. Carcinogen-treated rats fed freeze-dried blueberries, blackberries, plums, or mangos, at 5% of the diet, had large reductions in ACF compared to the control group [21]. A similar finding was reported with freeze-dried black raspberries [22] and with whole apples [23]. Although feeding dried plum powder, produced by air drying, did not result in a reduction of ACF [24], feeding a puree of dried plums to carcinogen-treated rats did result in a highly significant reduction of ACF [25]. Thus, studies of fruit feeding have been mostly consistent in showing a reduction in colon cancer risk, although the manner of preparation of the fruit may be important.

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Of the vegetables, cruciferous (Brassica) vegetables, such as cabbage, broccoli, Brussels sprouts, and cauliflower, have received the most attention for their chemopreventive properties. Cruciferous vegetables contain glucosinolates, which are hydrolyzed by the plant enzyme myrosinase after tissue damage, such as by chopping or chewing, to isothiocyanates and indoles, which evidence suggests are the active agents. Cruciferous vegetables fed to carcinogen-treated animals result in significant reductions in ACF [26]. Further, a tendency for reduction in ACF has been found with juices of garden cress [27] and Brussels sprouts [28], but not red cabbage [28]. Finally, carcinogen-treated mice that were fed cabbage had fewer adenomas, a benign tumor that can progress to a cancerous tumor [29]. Allium vegetables, such as garlic and onion, have also been examined. This family of vegetables is notable for high concentrations of organosulfur constituents, such as diallyl disulfide and S-allylcysteine. Studies of carcinogen-treated rats fed garlic have shown a reduction in either ACF [30] or MDF [31], as well as a reduction in tumor incidence [32]. Aged garlic extract reduced large ACF (.4 aberrant crypts/ ACF) [33]. Aged garlic extract is prepared by prolonged extraction of fresh garlic, and is less irritating than fresh garlic. Dried onions also reduced ACF in carcinogen-treated rats [34]. Thus, vegetables from different botanical families, containing very different profiles of phytochemicals, appear to be chemopreventive in animal models. Legumes commonly consumed by humans include soy, beans, peas, lentils, and peanuts. Of these, soy has received the most attention for colon cancer prevention due to evidence that isoflavones present in soy, which have phytoestrogenic activity, may be chemopreventive. Soy, however, is essentially never consumed as the whole bean. It is consumed as a myriad of processed products, including soy flour or protein isolates, tofu, and fermented forms such as tempeh and miso. Soy protein isolate fed to carcinogen-treated rats has reduced tumor incidence [35] and ACF number [36,37]. Soy flour has also reduced ACF number [38]. Interestingly, miso had no effect on ACF number or tumor incidence [39]. However, in contrast, a fermentation product of soybean, black bean, and green bean was found to reduce the growth of tumors resulting from injection of CT-26 colon cancer cells [40]. Few other legumes have been examined. In carcinogentreated rats, garbanzo bean flour [38] and lentils [37] reduced ACF number whereas cooked navy beans had no effect on tumor incidence [41]. Thus, the evidence suggests that soy, as either a protein isolate or whole flour, is chemopreventive in animal models; too few studies have been reported to be confident about the effect of other legumes. Human studies. While in vitro studies, animal studies, and many human intervention trials suggest mechanisms

that are biologically plausible, cohort and case
control studies have been inconsistent regarding protection against colon cancer by plant foods. Most studies through the 1990s reported 30
40% reduction in risk in those with the highest vegetable intake relative to those with the lowest intake [9,42
46]. Accordingly, the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) reported in 1997 that, after critical review of the research literature by experts, the evidence for protection against colon cancer by diets rich in vegetables was “convincing” [47]. Subsequent studies, however, were less supportive. For example, the European Prospective Investigation into Cancer and Nutrition (EPIC) study observed in 2009 an inverse association for usual combined fruit and vegetable intake and colon cancer, however with adjustment for total fiber the risk estimate for colon cancer lost significance when comparing the highest with the lowest quintile of intake [48]. The reassessment of the evidence by the WCRF/ AICR published in the 2011 Continuous Update Project (CUP) report for colorectal cancer indicated limitedsuggestive evidence for risk reduction by fruits and nonstarchy vegetables [49]. Nevertheless, the 2011 CUP report does conclude that there is convincing evidence that foods containing dietary fiber do decrease the risk of cancers of the colon and rectum. Studies investigating the independent association of fruit and vegetable intake with colon cancer since the 2011 CUP have continued to report inconsistent results. After additional investigation in 2015 with longer follow-up within EPIC, study investigators reported that although there was suggestion of lower colon cancer risk with increased fruit and vegetable intake, the study did not support a clear inverse association [50]. EPIC was also used to assess the association with colon cancer of plasma concentrations and dietary intakes of carotenoids and vitamins A, C, and E which are generally found in high levels in fruits and vegetables. The authors concluded that although inverse associations with colon cancer were suggested, all of the inverse associations lost statistical significance after adjusting for multiple comparisons except for retinol [51]; the authors further suggested that the possible inverse association between fruit and vegetable intake and colon cancer may be due to compounds other than those investigated in the study. In the Shanghai Men’s Health Study, a cohort of over 60,000 men, study investigators reported an inverse association between fruit intake and colon cancer, little evidence for an association between vegetable consumption and colorectal cancer, and an inverse association for legume intake [52]. Similarly, a systematic review and metaanalysis of cohort and case
control studies in the Japanese population found insufficient evidence of an association between vegetable intake and colorectal

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cancer risk [53]. Other investigators have pursued more targeted assessment of the intake of specific vegetables. For example, Wu et al. [54] conducted a meta-analysis that included data from 24 case
control and 11 prospective studies to investigate the association of cruciferous vegetable intake and colon cancer risk; statistically significant inverse associations were observed particularly for distal colon cancer in both case
control and prospective studies. Likewise, the meta-analysis by Tse and Eslick [55] that included 33 studies also showed an inverse association between cruciferous vegetable consumption and colon cancer, particularly with broccoli. The 2011 CUP report concluded that garlic probably protects against colorectal cancer [49]; however, no evidence of a protective association was found in a 2014 meta-analysis that included studies specifically investigating allium vegetables (onion, garlic, leeks, etc.) [56]. In sum, the human data on fruits, vegetables, and legumes intake reducing colon cancer risk is inconsistent. The inconsistencies could be related to study design differences in population-based studies such as inconsistent discrimination between effects on proximal versus distal colon, low sample size and case numbers, low or narrow range of intake of plant-based foods in the population studied, types of plant foods consumed in different populations studied, and error in measuring dietary intake. Additionally, a possible explanation for existing discrepancies between animal data and population-based data is that animal studies frequently use purified phytochemicals as the interventions and there may be differences in net effects between phytochemical treatment versus treatment with the intact food source (see review by Liu [57]). Plant foods contain thousands of bioactive constituents that may interact or counteract each other as normally consumed in whole foods and complex diet patterns.

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Nonetheless, that individual phytochemicals show promise mechanistically in animal and in vitro studies gives impetus for continued work in identifying the role of plant foods in colon cancer prevention (Fig. 36.3).

III MEAT Proposed mechanisms for influencing cancer risk. There are several components of meat whose consumption can plausibly be linked to enhancing the risk of colon cancer. Cooking meat at high temperature causes formation of heterocyclic aromatic amines (HAAs), which are known carcinogens in rodents [58]. HAA consumption produces chemical modifications of DNA [59], known as DNA adducts. The structures of two HAAs commonly found in foods and their DNA adducts are shown in Fig. 36.4. Formation of DNA adducts is generally considered to be a “necessary but not sufficient” event for tumor formation [60]. Although the failure to detect differences in colon cancer risk between populations consuming well-done meat versus normal meat [61] has caused some to question the role of HAAs in human colon carcinogenesis, a recent study in which dietary HAA intake was estimated for three HAAs found significant positive correlations between intake of several HAAs and colorectal tumors [62]. Thus, whether the HAAs present in grilled meat represents a colon cancer risk in human remains an open question. A second meat component suspected of increasing risk of colon cancer is heme, present in myoglobin, hemoglobin, and various heme proteins, which is suggested to act as a colon cancer promoter [63]. A large cohort study, in which heme iron intake was found to be significantly associated with an increased risk for tumors that carried G.A mutations in the APC gene [64], suggests a mechanism. Since G.A mutations are characteristic of FIGURE 36.3 An overview of phase I and phase II metabolism. Carcinogens can undergo oxidation reactions that allow conjugation with glutathione by GSTs. Alternatively, carcinogens can undergo hydrolysis or reduction reactions, and subsequently be sulfated by SULTs, acetylated by N-acetyltransferases, or glucuronidated by UGTs. The result is a more hydrophilic compound that can be excreted in the bile or urine. Adapted from https:// commons.wikimedia.org/wiki/File: Xenobiotic_metabolism.png.

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FIGURE 36.4 Structure of two foodborne HAAs, 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) and 2-amino-3,4-dimethylimidazo[4,5-f] quinolone (MeIQ) and their DNA adducts N-(deoxyguanosin-8-yl)
PhIP (dG-C8
PhIP) and N-(deoxyguanosin-8-yl)
MeIQ (dG-C8
MeIQ).

DNA alkylating agents [65], heme may promote mutagenesis. However, in a study in which mice were fed hemecontaining or heme-free diets for 18 months, no difference in either DNA alkyl adducts, such as O6-methyl-2-deoxyguanosine, or tumor number were found between the groups [66]. Thus, a mechanism by which heme may increase colon cancer risk remains uncertain. Nitrite and N-nitroso compounds (NOCs) represent yet another class of compounds that are present primarily in processed meats (e.g., grilled bacon) and smoked fish, and have been shown to be carcinogenic in animal studies [67]. Further, nitrates and nitrites, which can give rise to NOCs endogenously, have been classified as probable human carcinogens by the International Agency for Research on Cancer (IARC) [68]. Finally, animal sources of dietary fat, primarily saturated fat, are implicated as a risk factor in epidemiologic studies [69,70]. How saturated fat may promote colon carcinogenesis remains very unclear. However, carcinogen-treated rats fed beef tallow were reported to have greater expression of β-catenin (part of the Wnt signaling pathway) and decreased apoptosis in the colonic mucosa [71], both of which are associated with greater colon cancer risk. Thus, saturated fat may shift intracellular signaling pathways toward a condition of greater cancer risk. Animal studies. A large number of animal studies of the effect of red meat on colon carcinogenesis have been conducted. These include studies where the endpoints

were either colonic tumors [72
74] or ACF [75] and where either carcinogen-treated animals or genetic models [76] of colon carcinogenesis were used. Overall, these studies do not support an effect of red meat on promoting colon carcinogenesis, and in some cases beef was protective [73,74,76]. For example, diets containing either 30% or 60% of freeze-dried beef, chicken, or bacon were fed to carcinogen-treated rats and ACF number determined after 100 days of feeding. These diets were compared to casein-based control diets that used either olive oil or lard as fat sources in order to approximate the fat content of the meat diets. There were no differences in the number of ACF among any of the diets [75]. Pence et al. examined the effect of lean beef versus casein at two levels of dietary fat (5% vs 20%) and two types of dietary fat (corn oil vs tallow) on tumor development in carcinogen-treated rats [74]. After 27 weeks of feeding, total incidence and the number of tumors were lower in the beef-fed rats than the casein-fed rats. To explain why animal studies do not support a promotional effect of red meat whereas epidemiologic studies largely do (discussed below), Pierre et al. proposed that high calcium diets may protect against the promotional effect of red meat [77]. This was based on the observations that most rodent diets are relatively high in calcium, that heme added to the diets of rats promoted colonic epithelial proliferation [78], and that this heme-induced

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proliferation was inhibited by high calcium [79]. This hypothesis was examined in carcinogen-treated rats fed diets containing 60% beef in the context of either a low or high calcium diet. A casein-based diet served as the control. Both ACF and MDF were increased in the lowcalcium beef diet compared to the low-calcium casein diet. However, the high-calcium beef diet did not differ in ACF or MDF from the low-calcium casein group, supporting the hypothesis that calcium suppresses the promotional effect of red meat. Unfortunately, complicating the interpretation of these results was the finding that the high-calcium casein diet had ACF and MDF numbers equivalent to the low-calcium beef diet. The authors suggested that this unexpected finding may be due to the phosphate component of the calcium phosphate used as the calcium source in the diet. Further, a diet of 60% beef represents a concentration of beef in the diet well beyond what would be consumed by humans. In a subsequent study of the interaction of processed meat and calcium on colon cancer risk, carcinogen-treated rats were fed an airexposed picnic ham containing nitrite (47% of the diet), in the context of a very low or high calcium diet [80]. Rats fed the high calcium diet had significantly fewer colonic MDF than those fed the low calcium diet, although the number of ACF did not vary between the two diets. These two studies suggest an important interaction between dietary red meat and calcium in terms of colon cancer risk that warrants further study. Human studies. In the 2011 CUP by WCRF/AICR, the evidence was assessed as “convincing” for intake of red meat and processed meat (smoked, cured, salted, etc.) increasing the risk of colon and rectal cancer [49]. Moreover, on behalf of IARC, a working group of 22 scientists from 10 countries assessed over 800 epidemiological studies of the association between colorectal cancer and red meat and processed meat. They concluded in 2015 that consumption of processed meat is “carcinogenic to humans” with the largest body of evidence concerning colorectal cancer; they additionally concluded that red meat intake is “probably carcinogenic to humans” based on limited evidence in humans [81]. They define processed meat as meat that has been transformed (salting, curing, smoking, etc.) for enhanced flavor or improved preservation, and red meat as unprocessed mammalian muscle meat such as beef, pork, lamb, etc. However, other investigators critically reviewing the epidemiologic data on unprocessed red meat and colorectal and colon cancer contradictorily conclude that the data show weak associations, lack a clear dose
response trend, vary by gender, and are susceptible to the collinearity of meat intake with other dietary and behavioral factors which limits isolation of the independent effects of meat [82
84]; they also suggest that data from epidemiologic studies do not support that there is a clear underlying

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biological mechanism [84]. Interestingly, in a recent analysis of data from two large prospective cohorts (Nurses’ Health Study, n 5 87,108 women; Health Professionals Follow-up Study, n 5 47,389 men) processed red meat was associated with higher risk of distal colon cancer while unprocessed red meat was associated with lower risk after adjusting for calcium, folate, and fiber intake [85]; the authors thus concluded that there was little evidence that unprocessed red meat substantially increases risk of colorectal cancer. In numerous prospective cohort and case
control studies of the association between poultry consumption and risk of colon cancer, results quite consistently indicate no association with colorectal or colon cancer risk [86]. This lack of an association has raised suspicion over the role of HAAs as an underlying mechanism of meat and colon cancer risk because, similar to red meat, poultry cooked at high temperatures is also a source of HAA. Potential challenges to finding consistency across human studies of meat and colon cancer may include accuracy in assessing cooking or processing methods of meats and level of doneness of meats (thus HAA exposure). Additionally, genetic polymorphisms, such as in genes involved in metabolism of HAAs or DNA repair, could modify the risk related to a putative mechanism [87
89].

IV MILK AND DAIRY FOODS Proposed mechanisms for influencing cancer risk. A number of constituents in dairy foods have been investigated for their chemopreventive potential, with calcium and vitamin D having received the most attention. However, lipid components found in dairy fat, such as conjugated linoleic acid (CLA) and sphingolipids, as well as dairy proteins, particularly the whey proteins, have also been studied. Perhaps the earliest suggestion for the chemopreventive action of dietary calcium was put forth by Newmark et al. [90], who suggested that calcium would precipitate fatty acids and bile acids within the colonic lumen, thereby reducing their ability to irritate the colonic epithelium. This irritation was suggested to be the manner in which they act as cancer promoters. This hypothesis received experimental support from studies showing that dietary calcium decreased the solubility of fatty acids and bile acids in the large intestine [91] and thereby reduced the cytotoxicity of the fecal water [92]. The calcium sensing receptor, which is involved in controlling differentiation of colonic epithelial cells, may also play a role. In cell culture studies, calcium increased transcriptional activity of the calcium sensing receptor and induced a less malignant phenotype in colon cancer cells, an effect also noted with 1,25(OH)2D3, the active form of vitamin D [93]. Since the active form of vitamin D functions as a steroid hormone, functioning as a transcription factor bound

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to the vitamin D receptor (VDR), it is understandable that the proposed mechanisms of action of vitamin D involve effects on gene expression. Since many sporadic colon cancers show mutations in the adenomatous polyposis coli gene (Apc) [94], several studies have examined the role of the active form of vitamin D on pathways related to Apc. Inactivation of Apc results in activation of the WNT pathway and accumulation of β-catenin in the nucleus which, through a complex series of events [95], leads to constitutive activation of target genes promoting proliferation of colonic epithelial cells. Subsequent mutations are thought to lead to tumor development. In mice with mutations in Apc, those also carrying a mutation in VDR accumulated more nuclear β-catenin [96], suggesting that 1,25-(OH)2D3 acts to modulate the WNT pathway. Severe deficiency of 1,25-(OH)2D3, created by knocking out 25-hydroxyvitamin D 1α-hydroxylase, the enzyme responsible for its formation, has been shown to induce significant colonic inflammation [97]. Chronic inflammation in the colon has long been known to increase colon cancer risk, as illustrated by the increased risk of colon cancer in patients with ulcerative colitis [98]. Whether the mild to moderate degrees of vitamin D deficiency encountered in human populations also result in colonic inflammation remains to be investigated. CLA is a term for a group of isomers of linoleic acid that contains a conjugated double bond system. Dairy products represent a major dietary source of CLA, with the two major forms being cis9, trans11-CLA and trans10, cis12-CLA. Almost all studies examining the chemopreventive mechanisms of CLA have used purified CLA in cell culture studies. No clear mechanism has emerged from these studies. There is some evidence that cis9, trans11-CLA decreases cyclooxygenase-2 (COX-2) expression in breast cancer cell lines [99], a change associated with reduced cancer risk in the colon. Increased rates of apoptosis are associated with decreased colon cancer risk, and several studies showed induction of apoptosis with CLA [100,101]. Supporting a chemopreventive effect of CLA, a study in carcinogen-treated rats fed bitter gourd seed oil, which contains .50% CLA in the forms of α- and β-eleostearic acids, found statistically significant reductions in ACF and adenomas after 32 weeks of feeding. However, additional studies are necessary to establish the chemopreventive mechanism of CLA. Sphingolipids are a category of structurally diverse lipids having a sphingoid base with long-chain fatty acids attached in an amide linkage and containing polar head groups. They are present in small amounts in most foods but are abundant in dairy products, particularly cream and cheese [102]. Sphingolipids, along with their digestion products (ceramides and sphingosines), are highly bioactive. A mechanism of chemoprevention by sphingolipids has not been conclusively identified, but ceramides are involved in

cancer cell growth, differentiation, and apoptosis [103]; supplementing the diet with sphingolipid increases apoptosis in the colonic epithelium in carcinogen-treated mice [104]. There is also evidence that sphingolipids normalize aberrant Wnt/β-catenin signaling [105], a pathway that is frequently dysregulated in colon cancer. Thus, sphingolipid-induced changes in differentiation and apoptosis, as well as Wnt signaling, are likely to be involved in the chemopreventive action of sphingolipids. Dairy proteins have several distinct properties that make them plausible dietary chemopreventive agents. Caseins, the most abundant group of dairy proteins at 80% of the total, have been shown to bind HAAs [106], which are known carcinogens. A casein hydrolysate was shown to inhibit β-glucuronidase activity [107]. Decreased β-glucuronidase activity has the potential to reduce colon cancer risk, as carcinogens can be inactivated by glucuronidation in the liver and excreted in the bile. However, colonic bacteria express β-glucuronidase activity, which hydrolyzes the glucuronide, releasing the active carcinogen. Inhibiting this bacterial β-glucuronidase activity could thus reduce carcinogen release in the colon. Whey proteins, the second most abundant group of dairy proteins, at 20% of the total, are notable as a rich source of the sulfur amino acid cystine. Feeding whey proteins to rats increases tissue levels of the cysteine-containing tripeptide glutathione [108]. This is significant for two reasons. First, glutathione is a potent intracellular antioxidant and can participate in the elimination of ROS, either directly or as a cosubstrate for glutathione peroxidase, which reduces lipid peroxides. ROS can damage cellular macromolecules including DNA, and high levels of ROS are believed to promote cancer. Second, glutathione is a cosubstrate for GST, an enzyme involved in detoxification of xenobiotics, including carcinogens. Animal studies show an inverse relationship between liver glutathione concentration and colon tumor incidence [72], suggesting that increasing tissue glutathione may be chemopreventive. Animal studies. Tavan et al. [109] reported that carcinogen-treated rats given a diet containing 30% skim milk had a significant reduction in ACF relative to the control group. However, almost no additional studies have been conducted on milk and colon cancer risk in animal models. The focus has been almost exclusively on milk components, both major and minor. Whey proteins, which constitute approximately 20% of milk proteins, reduce tumor formation in carcinogen-treated rats [110] and partially hydrolyzed whey proteins reduce ACF number compared to casein-fed animals [111]. Another major milk component, milk fat, has been examined as two different fractions—the anhydrous milk fat and the milk fat globule membrane. This latter fraction is a protein
lipid complex, rich in sphingolipids, that surrounds the milk fat globules. In carcinogen-treated rats

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the milk fat globule membrane, but not the anhydrous milk fat, reduced ACF number [112], pointing to the potential of sphingolipids as an important chemopreventive compound in milk. This is plausible, as a number of animal studies have demonstrated that sphingolipids show chemopreventive effects [10]. A large number of animal studies have examined the potential for calcium to reduce tumorigenesis. A metaanalysis of the studies through 2005 concluded that high calcium diets reduced tumor incidence in carcinogentreated animals (Relative Risk 5 0.91, p 5 0.03) [113]. Animal studies conducted since 2005 continue to support a role for high calcium diets reducing carcinogenesis. A high calcium diet (5.2 g/kg diet) reduced ACF number in both mice and rats compared to a low calcium diet (1.4 g/kg diet) [114]. A relatively new animal model of colon carcinogenesis is the so-called new Western-Style diet (NWD), which is low in calcium and vitamin D and high in fat, and also has relatively low levels of folic acid, cysteine, and choline bitartrate. Long-term feeding (e.g., 18 months) of the NWD resulted in intestinal tumor formation, primarily in the large intestine [115]. Using this model, 2 years of feeding the NWD with added calcium and vitamin D resulted in no colon tumors compared to 27% of mice fed the NWD [116]. Since both calcium and vitamin D were added, this study cannot determine if either one alone would have had a comparable effect. Regardless, overall, animal studies strongly support a chemopreventive effect of dietary calcium. Relatively few animal studies have been reported of the influence of vitamin D, independent of calcium (i.e., when dietary calcium was adequate), on tumorigenesis or precancerous lesion. In rats given the direct acting colon carcinogen N-methyl-N-nitrosourea and lithocholic acid (which acts as a tumor promoter), there were fewer tumors when 1-(OH)-D3 was also administered [117]. In the Apcmin mouse, a genetic model of colon cancer, intraperitoneal injection of 1,25-(OH)2-D3, the active form of the vitamin, did not reduce the number of intestinal polyps. However, the total tumor load was significantly reduced compared to the control group that was not administered 1,25-(OH)2-D3 [118]. In carcinogen-treated rats, administration of 1,25-(OH)2-D3 prior to administration of the carcinogen reduced tumor formation by 50% [119]. The previously described studies examined supplemental vitamin D. In a study using carcinogen-treated rats, it was found that animals fed a high calcium diet had fewer colonic tumors per rat (tumor multiplicity), compared to a normal calcium diet. However, feeding a high calcium diet that was also vitamin D deficient resulted in the loss of the protective effect of the high calcium diet [120]. These few studies suggest that supplemental vitamin D may reduce colon cancer risk, and that vitamin D is necessary for the chemopreventive effect of high

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dietary calcium. However, in a recent study using both rats and mice with a defective Apc gene (Pirc rat and Apcmin mouse), supplemental vitamin D did not alter either tumor number or tumor multiplicity compared to animals given a normal amount of vitamin D in either species [121]. More recently, a similar study was conducted feeding a range of vitamin D concentrations as well as 25(OH)D3 [122]. In addition to enumeration of tumors at the end of the study, the investigators followed tumor development endoscopically. No protection against development of the final number of colonic tumors was found. Thus, the results from animal studies are inconsistent and do not provide strong support for a chemopreventive effect of supplemental vitamin D. Human studies. Based on evidence primarily from observational studies in Western countries, the WCRF/ AICR concluded in the 2011 CUP report that intake of milk and calcium probably decrease the risk of colon cancer [49]; in regards to foods containing vitamin D, their conclusion was that there was “limited-suggestive” evidence for a protective association. In 2012, Aune et al. [123] published the results of their meta-analyses that included data from 19 cohort studies; total dairy intake and milk intake were each inversely associated with colon cancer in both men and women. No associations were observed for cheese or other dairy products. Subsequently, a meta-analysis that included 15 prospective studies reported an inverse association between milk intake and colon cancer risk, but in men only [124]. The authors speculated that observing the association in men only could be related to the higher incidence of colorectal cancer in men compared with women [124]. Consistent with the majority of studies on the association between dietary calcium and colorectal cancer risk, Zhang et al. [125] reported in 2016 that total calcium intake was associated with reduced risk of colon cancer in a large cohort of 88,509 women and 47,740 men. They also observed that results were similar for different sources of calcium (from all foods or dairy products only) and that the inverse association was linear and stronger for distal colon cancer than proximal [125]. Since the publication of the 2011 CUP report, evidence is still limited regarding vitamin D intake and colon cancer risk; a 2015 systematic review and meta-analysis utilizing six studies found inconsistent associations for colorectal cancer and vitamin D supplementation [126]. While not conclusive, the evidence is somewhat consistent for a protective effect from milk and calcium intake. The human data on vitamin D are not consistent and the relationship to colon cancer warrants further investigation.

V WHOLE GRAINS Proposed mechanisms for influencing cancer risk. Whole grains include a heterogeneous collection of cereals,

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including wheat, corn, barley, oats, rye, and rice, as well as less commonly consumed cereals such as sorghum, millet, and triticale. Whole grains represent the intact grain, containing the endosperm, germ, and bran. The endosperm is largely composed of starch with some protein, whereas the bran contains most of the dietary fiber and many compounds thought to be highly bioactive, including phenolic acids, flavonoids, and vitamin E. The germ is rich in vitamins, minerals, and oil, and also contains a variety of antioxidants, including vitamin E. Unsurprisingly, cereals show great variation in their composition of components thought to have health benefits. For example, oats and barley contain substantial amounts of β-glucans, a viscous and highly fermentable type of dietary fiber, whereas wheat, corn, and rice have little β-glucans. There are similar wide variations in antioxidant capacity among the whole grains. Nevertheless, there are sufficient commonalities among the cereals that it is still useful to consider them as a group in terms of colon cancer prevention. The dietary fiber from whole grains has long been postulated as providing protection from colon cancer by several different mechanisms. One long-standing hypothesis is that dietary fiber reduces contact of potential carcinogens or procarcinogens with the colon, either by dilution of potential carcinogens or procarcinogens due to fecal bulking or by reducing exposure due to a decreased colonic transit time. Another potential mechanism involves the increased production of short chain fatty acids within the colon due to greater quantities of fermentable substrate for colonic bacteria. Of the short chain fatty acids, butyrate has been of particular interest due to many in vitro studies showing that butyrate inhibits growth of cancer cells, causing normalization of cancer cells, or increases cancer cell elimination by increased apoptosis [127]. Yet another potential dietary fiber mechanism is the promotion of the growth of probiotic bacteria (such as bifidobacteria) by fructans (such as inulin). Although increasing probiotic bacteria in the colon by feeding prebiotics reduces colon cancer risk in animal models [128,129], it appears unlikely that humans consuming a normal cereal-containing diet could consume a sufficient quantity of fructans to significantly increase the colonic bifidobacteria population [130]. Therefore, this particular mechanism of chemoprevention may not be relevant to humans not consuming supplements of fructans. Another oft-discussed potential mechanism of chemoprevention by whole grains is the delivery of antioxidants from whole grains. There are two issues with regard to this mechanism. First, the ability of antioxidants to reduce colon cancer risk is still in doubt. Trials in humans and animal models of colon cancer do not provide strong support for a reduction in risk by α-tocopherol, the form of vitamin E commonly found in supplements, although a

mixture of tocopherols shows some promise [131]. For most other natural compounds present in foods, it is uncertain whether the chemopreventive benefit they provide is due to their antioxidant effect or some other property. The second issue is the often poor bioavailability of compounds in cereals with antioxidant activity. For example, ferulic acid, the major phenolic acid in cereals, displays antioxidant activity in vitro [132], but is almost entirely bound within the cereal matrix [133] and therefore poorly available for absorption. Consistent with this is the finding that in diabetic rats, who exhibit elevated levels of oxidative stress, feeding cereal-based diets had no effect on markers of oxidative stress [134]. A number of other compounds found in cereals have been shown, in purified form, to reduce colon cancer risk. These include phytic acid [135,136], sphingolipids [104], and lignans [137] (compounds with a diphenolic ring structure that have phytoestrogen activity). However, whether these compounds, either alone or in combination, contribute significantly to chemoprevention by cereals is difficult to ascertain, in part due to questions about bioavailability. Thus, cereals contain a plethora of bioactive compounds that could explain any observed chemopreventive effects. As with other whole foods, determining which compound or combination of compounds is responsible for chemoprevention is a difficult task. Animal studies. Very few studies have examined the effect of whole versus refined grains on colon cancer risk in animal models. Maziya-Dixon et al. [138] fed red and white flour, in both the whole and refined forms, to mice given a chemical carcinogen. After 40 weeks, mice fed the wheat-containing diets did not differ from the wheatfree control diet tumor incidence. Interestingly, though, mice fed the red wheat diets, regardless of refining state, had significantly lower tumor incidence that mice fed white flour, again regardless of refining state. In other words, it was wheat color, not the state of refinement, which influenced tumor incidence. The importance of wheat color, as opposed to state of refining, was confirmed in a study in carcinogen-treated rats, where feeding red wheat, either whole or refined, reduced colonic ACF relative to white wheat [139]. The importance of wheat color was confirmed and extended in a study where it was shown that carcinogen-treated rats fed refined red wheat had fewer MDF than those fed refined white wheat, when fed only in the late postinitiation stage (when the wheat diets were fed 54 days after carcinogen treatment), as well as less β-catenin, indicating less dysregulation of the Wnt signaling pathway [140]. In another study, whole and refined wheat were fed to rats given HAA as a carcinogen. No difference was found between the groups fed whole and refined wheat in the number of colonic ACF [141], although it should be noted that the number of

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ACF per animal was extremely small. Thus, in the few studies investigating wheat, the evidence suggests that it is the color of the wheat, not whether it is whole or refined, that is most important in terms of chemoprevention. Given the paucity of studies in which whole and refined grains have been directly compared, an alternative is to examine studies in which bran feeding has been investigated. This is an imperfect comparison, as whole grains differ from refined grains by the inclusion of both bran and germ in the whole grain. However, as germ represents only about 2.5% of the whole grain, in the case of wheat, this is likely a useful approach. The vast majority of studies that used cereal bran examined wheat bran, usually at dietary concentrations of 15
20%. Using carcinogen-treated rats, most have found a reduction in colon tumor incidence [142
150]. A study using Min (multiple intestinal neoplasia) mice, which have a mutated Apc gene, similar to the mutation in familial adenomatous polyposis patients, and thus spontaneously develop intestinal tumors, reported fewer tumors after feeding brans of several wheat varieties. The efficacy of tumor number reduction inversely correlated with the orthophenolic content (e.g., ferulic acid) of the wheat from which the bran was derived [151]. In addition, several studies have reported a decrease in ACF in carcinogen-treated rats fed wheat bran, relative to rats fed a fiber-free or low fiber diet [148,152]. A study in carcinogen-treated mice found that a diet of 20% wheat bran reduced adenomas relative to a fiber-free control diet, but had no effect on adenocarcinoma incidence [153]. Several studies have even reported an enhancement in tumor incidence in carcinogen-treated rodents fed wheat bran. Carcinogen-treated mice fed 20% wheat bran, from either soft winter white or hard spring wheat, had a much higher incidence of colon tumors than animals fed a fiber-free diet [154]. Similarly, carcinogen-treated rats fed a 20% wheat bran diet also had a greater number of colonic tumors compared to animals fed fiber-free diet, but this was only observed when the wheat bran was fed during carcinogen administration [155]. Overall, however, studies in carcinogen-treated rodents support a reduction in tumor development with feeding of wheat bran. Fewer studies have been carried out with brans of cereals other than wheat. Oat bran fed to carcinogen-treated rats resulted in a greater number of colonic tumors in the proximal colon, but not the distal colon, compared to a fiber-free control [156]. In Min mice, however, oat bran feeding had no effect on the development of intestinal tumors [157]. Feeding rye bran to carcinogen-treated rats resulted in fewer colon tumors and fewer ACF, compared to the cellulose-fed control group [158]. However, rye bran fed to Min mice resulted in either no effect [157,159] or an increase in intestinal tumors [160]. Barley bran was shown to reduce tumor incidence in carcinogen-treated rats

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compared to cellulose-fed control group [143], whereas corn bran increased colon tumor incidence in carcinogentreated rats [142,161]. Finally, rice bran at 30%, but not 10% of the diet, reduced intestinal tumor number in Min mice compared to a cellulose-fed control group [162], but had no effect in carcinogen-treated rats [142]. Thus, animal studies provide considerable support for protection against colon cancer by wheat, primarily based on studies of wheat bran, although there are indications that the color of the wheat is more important than the state of refinement. For other cereals the studies are highly inconsistent and are too few to ascertain whether they have a chemopreventive effect or may even promote colon cancer. Human studies. The evidence for an association between cereal grains and colon cancer was reported as limited according to the WCRF/AICR report of 2007 [20]; in the 2011 WCRF/AICR CUP report [49], whole grains are folded into the category of foods containing dietary fiber with the conclusion that there is convincing evidence that foods containing fiber decrease colon cancer risk. Specifically looking at whole grains, CUP meta-analyses showed a 16% decreased risk per three servings per day. Since the 2011 CUP report, Kyro et al. [163] reported that intake of whole-grain products, and specifically wholegrain wheat, was associated with lower incidence of colorectal cancer but not colon cancer in a large Scandinavian prospective cohort. However, in a cohort of Norwegian women whole-grain bread was not associated with colorectal cancer, but there was a weak protective association with proximal colon cancer [164]. Two other studies used plasma alkylresorcinols, a biomarker of whole-grain intake, to investigate the association of whole grains with colon cancer [165,166]. Alkylresorcinols are primarily found in the bran of wheat and rye and their concentrations in plasma have been used as an indicator of short-term and medium-term consumption specifically of whole-grain wheat and rye products. Both studies observed an inverse association between plasma alkylresorcinol concentrations and distal colon cancer incidence [165
167]. In sum, there is evidence that whole-grain wheat and rye may reduce colon cancer risk, that the effect may be specific to distal versus proximal colon cancer, and that use of the alkylresorcinol biomarker may increase precision in estimating risk compared to food frequency questionnaires. Further evidence that grains may influence risk of colon cancer includes studies where an increased risk was observed with intake of refined grains [168
170]. However, it should be noted that whole-grain intake is reported to be associated with various factors that could also be related to decreased risk of colon cancer, such as healthy lifestyle, socioeconomic, and dietary factors [171]. Using putative intermediary biomarkers of colorectal cancer, a few intervention trials have been conducted [172
175].

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However, they typically used an isolated grain fraction such as the bran or fiber instead of actual whole-grain foods, or else combined high intake of whole-grain foods with other practices that may have an independent effect (e.g., low fat, high vegetable intakes) and thus make it difficult to assess effects attributable specifically to whole-grain intake.

VI BEVERAGES Proposed mechanisms for influencing cancer risk. Three types of nonnutritive beverages have been studied extensively for potential protective effects against colon cancer (coffee and tea) and harmful effects (alcoholic beverages). The interest in coffee stems from evidence that coffee components such as dieterpenes (cafestol and kahweol) mitigate the genotoxicity of HAAs [176
178]; increase the activities of enzymes that generally detoxify carcinogens (UGTs and GSTs), decrease the activity of some carcinogen-activating enzymes (N-acetyltransferases and SULTs), and decrease HAA-mediated genotoxicity [176
181]. Additionally, cafestol and kahweol have antioxidant properties, and induce γ-glutamylcysteine synthetase (the rate limiting enzyme in glutathione synthesis) [182,183]. Human consumption of Italian-style coffee (or espresso) increases plasma glutathione and unfiltered French press coffee increases glutathione content in colorectal mucosa [184,185]. Moreover, coffee is rich in phenolic acids, flavonoids, and melanoidins, many of which have demonstrated antioxidant properties that can depend on degree of roasting [186
188]. In vitro studies suggest that chlorogenic and caffeic acids found in coffee may decrease cell proliferation, cell invasion, angiogenesis, and metastasis, further supporting the hypothesized chemopreventive potential of coffee [189
193]. Both green tea and black tea have also interested cancer prevention researchers. Theaflavin-2 (black tea polyphenol) exhibits antiinflammatory and proapoptotic activities [194]. Green tea polyphenols inhibit proliferation and invasiveness of colon cancer cells [195], induce apoptosis and demonstrate antioxidant activity [12,196], modulate GST activity [196], and are antiinflammatory [19]. Alcohol, on the other hand, may have detrimental effects. For example, it may enhance penetration of carcinogens by functioning as a solvent; be metabolized to reactive metabolites such as acetaldehyde; produce prostaglandins, lipid peroxidation, and free-radical oxygen species; and/or alter folate metabolism [20,197,198]. Animal studies. Very few studies have examined the effect of coffee on colon cancer in animal models. Mori and Hirono [199] examined the effect of coffee in rats treated with cycasin, a compound derived from the cycad sago palm that is metabolized to the colon carcinogen methylazoxymethanol. In their study, neither coffee nor

cycasin alone induced a significant number of tumors. However, coffee and cycasin combined resulted in a high incidence of tumors, indicating that coffee promoted the carcinogenicity of cycasin. Recently, the influence of organic and conventional coffees, each at three different dietary levels (5, 10, and 20%), as well as 4% powdered coffee (eight coffee groups in all), was examined in carcinogen-treated rats [200]. The authors reported no significant effect of the coffee on ACF number. However, it should be noted that every coffee group had a greater number of ACF than the coffee-free control group, in most cases twice as many, raising the question as to whether further statistical analysis might have led to a different conclusion. In contrast, in a study in which 1% coffee was fed to carcinogen-treated rats, no difference in ACF number was found in the coffee group compared to the control group [201]. Since caffeine alone has been shown to increase tumor number and decrease long-term survival in rats treated with an HAA [202], it may be that the caffeine in coffee promotes carcinogenesis, but that phytochemicals within coffee counteract this effect when the quantity of caffeine is low. Considerably more attention has been focused on the potential chemopreventive effects of tea, both green and black. In a study using an HAA as the carcinogen, green tea, but not black tea, was found to reduce ACF in rats [203]. However, in rats treated with azoxymethane as a carcinogen, the group fed black tea, but not green tea, had fewer adenomas [204]. There were also fewer cancers in the black tea group, but this reduction was not statistically significant. A second study using the colon-specific carcinogen azoxymethane reported that green tea did not reduce the number of ACF [205]. Further, Weisburger et al. [206] reported that extracts of black or green tea given to azoxymethane-treated rats had no influence on tumor development. In contrast, in mice treated with azoxymethane and fed a high fat background diet, mice given 0.6% green tea (0.6 mg tea solids/mL) had significantly fewer ACF relative to mice given only water [207]. White tea, which is the least processed type of tea, and therefore has the greatest quantity of the putative chemopreventive catechins, was found to greatly reduce ACF in rats administered an HAA as the carcinogen [208]. Yet, in a second study by the same investigators, white tea was found to promote the formation of colon tumors in rats administered an HAA [202]. Clearly, the results from animal studies on tea and colon carcinogenesis are highly inconsistent, and no conclusions can yet be drawn as to whether tea, in any form, is chemopreventive. Animal studies examining the effect of fermented beverages such as beer and wine are very few. Feeding beer to carcinogen-treated rats led to a significant reduction in gastrointestinal tumor incidence, but not colon tumor incidence [209]. This finding is consistent with two studies in

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which colonic tumor incidence was unaltered by beer consumption, although it led to a shift in tumor incidence from the right and transverse colon to the left colon [210,211]. However, in a more recent study, feeding freeze-dried beer, which contains no ethanol, nor the volatile components of beer, reduced ACF formation when fed in both the initiation and promotion phases of carcinogenesis [212]. When the freeze-dried beer was fed only in the promotion phase, the effect was somewhat attenuated. Ethanol alone had no effect on ACF formation. In contrast to the situation with beer, in which there are studies of feeding the beverage itself, there appear to be no studies in which wine was fed to carcinogen-treated animals. Studies with extracts from wine have been inconsistent. In one study, feeding an extract of complex polyphenols and tannins from wine did not reduce the number of ACF in carcinogen-treated rats [213]. Interestingly, in two subsequent studies by the same investigators, a polyphenolic extract of red wine reduced adenoma incidence in carcinogen-treated rats [214,215]. Given that the polyphenolic extract differs from wine itself, and that the results with the extracts were inconsistent, no conclusion can be drawn regarding the influence of wine consumption on colon carcinogenicity from animal studies. Human studies. Historically, evidence for a protective association of coffee intake against colon cancer has been somewhat inconsistent. However, there is greater consistency in more recent reports from meta-analyses of prospective cohort and case
control studies, and have mostly been consistent in showing inverse associations between coffee intake and colon cancer risk [216
219]. In particular, the meta-analysis by Gan et al. [218] based solely on prospective cohort studies (19 studies with .22,600 cases combined), showed a threshold $5 cups/day as associated with decreased colon cancer risk, which is similar to the earlier suggestion of a nonlinear relationship and report by Tian et al. [220] that $4 cups/day is associated with decreased risk of colon cancer. Gan et al. posit that a nonlinear relationship is biologically plausible [218] given coffee’s complex mixture of a thousand compounds, some of which may be detrimental (heterocyclic amines, aromatic hydrocarbons, acrylamide, caffeine) as well as the many bioactive compounds discussed earlier. Nonetheless, challenges persist in clearly determining the coffee and colon cancer relationship. For example, subgroups of populations may be more responsive to the effects of coffee, and insufficient measurement of the method of coffee preparation or type of coffee. Instant, filtered, and percolated coffee have negligible amounts of the bioactives cafestol and kahweol (paper filters significantly trap cafestol and kahweol) [221,222]; espresso has intermediate amounts; and Turkish, cafetie`re, and Scandinavian-type boiled coffees have large amounts [223]. Of note, Gan et al. detected

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stronger associations in older studies and put forth the notion that coffee preparation methods may have changed over time [218]. The majority of studies on tea have primarily focused on green tea, and frequently indicated a protective effect, but an assessment of the evidence was deemed limited and inconclusive in the WCRF/AICR 2007 report [20]; there have been no further updates on tea and colon cancer risk by WCRF/AICR. However, studies since 2007 seem to consistently report a protective association. Examples include an inverse relationship reported between green tea intake and colon cancer in a cohort of Chinese women [224]. Also, in a randomized control trial of 136 colorectal adenoma patients, adenomas were removed and patients randomized to 1.5 g green tea extract per day or no supplement for 1 year; there were fewer patients with metachronous adenomas in the supplement group (p , 0.05) and the size of relapsed adenomas was smaller in patients in the supplement group compared to the control group (p , 0.001) [225]. Conversely, in a Singapore cohort there was suggestion of an actual increased risk with green tea for advanced colon cancer in men and no association with black tea [226]. Using urinary biomarkers of tea polyphenols, Yuan et al. observed that in comparing the highest tertile of urinary epigallocatechin to undetected epigallocatechin there was an inverse association with colon cancer [227]; there was a similar inverse relation seen for 40 -O-methyl-epigallocatechin, and the strongest protective effect was observed for regular tea drinkers with high levels of both urinary polyphenols [227]. Lastly, in a cohort of Chinese men, green tea intake was associated with reduced risk of colon cancer in male nonsmokers [228]. However, a metaanalysis by Wang et al. [229] based on prospective cohort studies of green tea showed an inverse association with colon cancer only in the Shanghai population. A subsequent meta-analysis by Zhang et al. [230] of prospective studies of all kinds of tea showed no association between the green tea subtype and colon cancer risk. Alcohol is one of a few dietary exposures with some of the most convincing human evidence for increasing risk of colon cancer [49]. For instance, results of a metaanalysis that included 16 cohort studies indicated that high intake of alcohol increased risk of colon cancer that was equivalent to a 15% increased risk of colon cancer for an increase of 100 g of alcohol per week [231]. A subsequent meta-analysis sought to clarify the doserisk relation of alcohol to colorectal cancer and found a positive association with .1 drink per day, and the association of alcohol drinking with colorectal cancer did not differ by colon and rectal subsites [232]. A recent meta-analysis that utilized 12 case
control and 9 cohort studies that assessed the risk related specifically to beer intake, reported increased risk for colorectal cancer that

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was stronger for rectal (30% increased risk) than colon cancer (5% increased risk) [233].

VII SUMMARY With regard to fruits, vegetables, and legumes intake, there is some suggestion from animal studies of protection against colon cancer by fruit and soy, but not other legumes. The animal-based evidence for protective effects from vegetables is stronger. Evidence from human studies is inconsistent. While animal data are generally not supportive of meat increasing colon cancer risk, there may be an important interaction with dietary calcium, such that meat may promote colon cancer in the context of a low calcium diet. Human studies are more consistent with regard to meat consumption increasing colon cancer risk, although a clear mechanism is lacking. Strong data from animal studies are supportive of a protective effect from calcium, but the animal data is inconsistent for vitamin D and virtually absent for milk and dairy. There is some consistency in the human data regarding milk and dairy intake, and possibly calcium, but not regarding vitamin D. Relatively few studies with whole grains have been conducted in animals. Those examining wheat suggest that wheat color, not refining state (i.e., whole vs refined), is the important factor for reducing colon cancer risk. Studies using only wheat bran are supportive of a chemopreventive potential. There is little support from animal studies for other cereals being protective against colon cancer. Evidence in humans is limited on whole grains, but is generally encouraging of potential protection. Finally, with regards to nonnutritive beverages, few animal studies have been done on coffee and the tea and alcohol data are inconsistent. Likewise, human data are inconsistent for coffee and somewhat inconsistent for tea, but strong or convincing for alcohol increasing risk of colon cancer. While this chapter presented the current state of the evidence for associations between food groups and colon cancer, it cannot be overlooked that foods are rarely eaten in isolation; they are consumed as part of a larger, complex dietary pattern. Interest and methodological developments are improving for assessment of the associations of different overall dietary patterns with colon cancer risk. For instance, a study in the United States (North Carolina) investigating risk modification of colon cancer identified three distinct dietary patterns and compared their associations with colon cancer [234]. The three dietary patterns were “Western-Southern” (high in red meats, fried foods, cheese dishes, sweets), “fruit-vegetable” (high in fruits, vegetables, legumes), and “metropolitan” (salad, seafood, pastas, Mexican foods, turkey, chicken, veal, lamb, cruciferous vegetables, alfalfa sprouts). The “fruitvegetable” pattern was significantly inversely associated

with colon cancer risk in Whites but not in AfricanAmericans. A Canadian case
control study assessed three patterns: Meat-diet pattern (high intake of red and processed meat), Sugary-diet pattern (high intake of fruit pies, tarts, desserts, and sweets), and Plant-based pattern (fruits, vegetables, whole grains); increased risk of colon cancer was observed for the Sugary-diet pattern (proximal and distal) and the Meat-diet pattern (distal) [235]. In a large cohort of women in the United States, a diet pattern characterized by higher meat, fish, and sweetened beverage intake but lower coffee, high fat dairy, and wholegrain intake was associated with colon cancer in those who were overweight or sedentary [236]. For comparison, it was observed in a Japanese cohort that a high dairy, high fruit and vegetable, low alcohol dietary pattern was inversely associated with colorectal cancer, but only rectal cancer upon analyses by subsite; no associations were observed for a Japanese dietary pattern or an “animal food” pattern [237]. Lastly, a meta-analysis that included eight cohort studies and eight case
control studies found an increased risk of colon cancer associated with a “western” diet of high red and processed meat intake, and a decreased risk associated with a “healthy” pattern of high fruit and vegetable intake [238]. There is a general paucity of whole food studies in the body of literature on nutrition and colon cancer, which represents a severe limitation in diet and cancer research. People eat food as opposed to individual constituents or fractions and a presumption that there are no differences between pure individual constituents and intact foods is clearly false in some cases [57]. A greater use of foods in animal and human studies is needed to get us closer to developing appropriate dietary recommendations to make regarding cancer prevention. Additionally, there are relatively few whole food feeding intervention trials in humans. While of necessity they rely on intermediary markers of colon cancer, they could prove valuable in testing or confirming hypotheses and findings from populationbased studies and animal studies [239]. Furthermore, future human studies may need to better account for genetic variation among individuals which can not only impact metabolism of carcinogens (as briefly mentioned earlier) but may impact tolerance, absorption, and metabolism of the putative chemopreventive constituents in the diet [240].

REFERENCES [1] American Cancer Society, Colorectal Cancer Facts & Figures, American Cancer Society, Atlanta, GA, 2011. [2] A.E. Grulich, M. McCredie, M. Coates, Cancer incidence in Asian migrants to New South Wales, Australia, Br. J. Cancer 71 (1995) 400
408. [3] E.K. Wei, E. Giovannucci, K. Wu, et al., Comparison of risk factors for colon and rectal cancer, Int. J. Cancer 108 (2004) 433
442.

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[4] D. Schottenfeld, J.F. Fraumeni (Eds.), Cancer Epidemiology and Prevention, third ed., Oxford University Press, New York, NY, 2006. [5] P. Gervaz, P. Bucher, P. Morel, Two colons-two cancers: paradigm shift and clinical implications, J. Surg. Oncol. 88 (2004) 261
266. [6] S. Lu, Y.S. Chiu, A.P. Smith, et al., Biomarkers correlate with colon cancer and risks: a preliminary study, Dis. Colon Rectum 52 (2009) 715
724. [7] C. Zhao, I. Ivanov, E.R. Dougherty, et al., Noninvasive detection of candidate molecular biomarkers in subjects with a history of insulin resistance and colorectal adenomas, Cancer Prev. Res. (Phila.) 2 (2009) 590
597. [8] A.P. Femia, P. Dolara, G. Caderni, Mucin-depleted foci (MDF) in the colon of rats treated with azoxymethane (AOM) are useful biomarkers for colon carcinogenesis, Carcinogenesis 25 (2004) 277
281. [9] K.A. Steinmetz, J.D. Potter, Vegetables, fruit, and cancer. I. Epidemiology, Cancer Causes Control 2 (1991) 325
357. [10] M.H. Pan, C.S. Lai, J.C. Wu, et al., Molecular mechanisms for chemoprevention of colorectal cancer by natural dietary compounds, Mol. Nutr. Food Res. 55 (2011) 32
45. [11] S. Ramos, Effects of dietary flavonoids on apoptotic pathways related to cancer chemoprevention, J. Nutr. Biochem. 18 (2007) 427
442. [12] M.H. Pan, C.T. Ho, Chemopreventive effects of natural dietary compounds on cancer development, Chem. Soc. Rev. 37 (2008) 2558
2574. [13] J.M. Mates, J.A. Segura, F.J. Alonso, et al., Anticancer antioxidant regulatory functions of phytochemicals, Curr. Med. Chem. 18 (2011) 2315
2338. [14] W.W. Johnson, Cytochrome P450 inactivation by pharmaceuticals and phytochemicals: therapeutic relevance, Drug Metab. Rev. 40 (2008) 101
147. [15] H. Steinkellner, S. Rabot, C. Freywald, et al., Effects of cruciferous vegetables and their constituents on drug metabolizing enzymes involved in the bioactivation of DNA-reactive dietary carcinogens, Mutat. Res. 480
481 (2001) 285
297. [16] B. Pool-Zobel, S. Veeriah, F.D. Bohmer, Modulation of xenobiotic metabolising enzymes by anticarcinogens—focus on glutathione S-transferases and their role as targets of dietary chemoprevention in colorectal carcinogenesis, Mutat. Res. 591 (2005) 74
92. [17] M.R. Saracino, J.W. Lampe, Phytochemical regulation of UDPglucuronosyltransferases: implications for cancer prevention, Nutr. Cancer 59 (2007) 121
141. [18] R.M. Harris, R.H. Waring, Sulfotransferase inhibition: potential impact of diet and environmental chemicals on steroid metabolism and drug detoxification, Curr. Drug Metab. 9 (2008) 269
275. [19] J. Terzic, S. Grivennikov, E. Karin, et al., Inflammation and colon cancer, Gastroenterology 138 (2010) 2101
2114. [20] World Cancer Research Fund/American Institute for Cancer Research, Food, Nutrition, Physical Activity and the Prevention of Cancer: A Global Perspective, American Institute for Cancer Research, Washington, DC, 2007. [21] J. Boateng, M. Verghese, L. Shackelford, et al., Selected fruits reduce azoxymethane (AOM)-induced aberrant crypt foci (ACF) in Fisher 344 male rats, Food Chem. Toxicol. 45 (2007) 725
732. [22] G.K. Harris, A. Gupta, R.G. Nines, et al., Effects of lyophilized black raspberries on azoxymethane-induced colon cancer and

[23]

[24] [25]

[26]

[27]

[28]

[29] [30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

801

8-hydroxy-2’-deoxyguanosine levels in the Fischer 344 rat, Nutr. Cancer 40 (2001) 125
133. M. Poulsen, A. Mortensen, M.L. Binderup, et al., The effect of apple feeding on markers of colon carcinogenesis, Nutr. Cancer 63 (2011) 402
409. Y. Yang, D.D. Gallaher, Effect of dried plums on colon cancer risk factors in rats, Nutr. Cancer 53 (2005) 117
125. D. Seidel, K. Hicks, S. Taddeo, et al., Dried plums modify colon microbiota composition and spatial distribution, and protect against chemically-induced carcinogenesis, FASEB J. 29 (Suppl. 1) (2015) 394. A.Y. Arikawa, D.D. Gallaher, Cruciferous vegetables reduce morphological markers of colon cancer risk in dimethylhydrazinetreated rats, J. Nutr. 138 (2008) 526
532. F. Kassie, S. Rabot, M. Uhl, et al., Chemoprotective effects of garden cress (Lepidium sativum) and its constituents towards 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ)-induced genotoxic effects and colonic preneoplastic lesions, Carcinogenesis 23 (2002) 1155
1161. F. Kassie, M. Uhl, S. Rabot, et al., Chemoprevention of 2-amino3-methylimidazo[4,5-f]quinoline (IQ)-induced colonic and hepatic preneoplastic lesions in the F344 rat by cruciferous vegetables administered simultaneously with the carcinogen, Carcinogenesis 24 (2003) 255
261. N.J. Temple, T.K. Basu, Selenium and cabbage and colon carcinogenesis in mice, J. Natl Cancer Inst. 79 (1987) 1131
1134. A. Sengupta, S. Ghosh, S. Das, Tomato and garlic can modulate azoxymethane-induced colon carcinogenesis in rats, Eur. J. Cancer Prev. 12 (2003) 195
200. T. Chihara, K. Shimpo, T. Kaneko, et al., Inhibition of 1, 2-dimethylhydrazine-induced mucin-depleted foci and O-methylguanine DNA adducts in the rat colorectum by boiled garlic powder, Asian Pac. J. Cancer Prev. 11 (2010) 1301
1304. J.Y. Cheng, C.L. Meng, C.C. Tzeng, et al., Optimal dose of garlic to inhibit dimethylhydrazine-induced colon cancer, World J. Surg. 19 (1995) 621
625, discussion 625
626. H. Jikihara, G. Qi, K. Nozoe, et al., Aged garlic extract inhibits 1,2-dimethylhydrazine-induced colon tumor development by suppressing cell proliferation, Oncol. Rep. 33 (2015) 1131
1140. S. Tache, A. Ladam, D.E. Corpet, Chemoprevention of aberrant crypt foci in the colon of rats by dietary onion, Eur. J. Cancer 43 (2007) 454
458. R. Hakkak, S. Korourian, M.J. Ronis, et al., Soy protein isolate consumption protects against azoxymethane-induced colon tumors in male rats, Cancer Lett. 166 (2001) 27
32. T.M. Badger, M.J. Ronis, R.C. Simmen, et al., Soy protein isolate and protection against cancer, J. Am. Coll. Nutr. 24 (2005) 146S
149S. M.A. Faris, H.R. Takruri, M.S. Shomaf, et al., Chemopreventive effect of raw and cooked lentils (Lens culinaris L) and soybeans (Glycine max) against azoxymethane-induced aberrant crypt foci, Nutr. Res. 29 (2009) 355
362. G. Murillo, J.K. Choi, O. Pan, et al., Efficacy of garbanzo and soybean flour in suppression of aberrant crypt foci in the colons of CF-1 mice, Anticancer Res. 24 (2004) 3049
3055. Y. Ohuchi, Y. Myojin, F. Shimamoto, et al., Decrease in size of azoxymethane induced colon carcinoma in F344 rats by 180-day fermented miso, Oncol. Rep. 14 (2005) 1559
1564.

802 PART | F Cancer

[40] J.S. Chia, J.L. Du, M.S. Wu, et al., Fermentation product of soybean, black bean, and green bean mixture induces apoptosis in a wide variety of cancer cells, Integr. Cancer Ther. 12 (2013) 248
256. [41] G. Bobe, K.G. Barrett, R.A. Mentor-Marcel, et al., Dietary cooked navy beans and their fractions attenuate colon carcinogenesis in azoxymethane-induced ob/ob mice, Nutr. Cancer 60 (2008) 373
381. [42] Y. Park, A.F. Subar, V. Kipnis, et al., Fruit and vegetable intakes and risk of colorectal cancer in the NIH-AARP diet and health study, Am. J. Epidemiol. 166 (2007) 170
180. [43] J. Shannon, E. White, A.L. Shattuck, et al., Relationship of food groups and water intake to colon cancer risk, Cancer Epidemiol. Biomarkers Prev. 5 (1996) 495
502. [44] M.L. Slattery, J.D. Potter, A. Coates, et al., Plant foods and colon cancer: an assessment of specific foods and their related nutrients (United States), Cancer Causes Control. 8 (1997) 575
590. [45] P. Terry, E. Giovannucci, K.B. Michels, et al., Fruit, vegetables, dietary fiber, and risk of colorectal cancer, J. Natl Cancer Inst. 93 (2001) 525
533. [46] G.R. Howe, E. Benito, R. Castelleto, et al., Dietary intake of fiber and decreased risk of cancers of the colon and rectum: evidence from the combined analysis of 13 case-control studies, J. Natl. Cancer Inst. 84 (1992) 1887
1896. [47] World Cancer Research Fund, Food, Nutrition and the Prevention of Cancer: A Global Perspective, American Institute for Cancer Research, Washington, DC, 1997. [48] F.J. van Duijnhoven, H.B. Bueno-De-Mesquita, P. Ferrari, et al., Fruit, vegetables, and colorectal cancer risk: the European Prospective Investigation into Cancer and Nutrition, Am. J. Clin. Nutr. 89 (2009) 1441
1452. [49] World Cancer Research Fund/American Institute for Cancer Research, Continuous Update Project Report. Food, Nutrition, Physical Activity, and the Prevention of Colorectal Cancer, American Institute for Cancer Research, Washington, DC, 2011. [50] M. Leenders, P.D. Siersema, K. Overvad, et al., Subtypes of fruit and vegetables, variety in consumption and risk of colon and rectal cancer in the European Prospective Investigation into Cancer and Nutrition, Int. J. Cancer 137 (2015) 2705
2714. [51] M. Leenders, A.M. Leufkens, P.D. Siersema, et al., Plasma and dietary carotenoids and vitamins A, C and E and risk of colon and rectal cancer in the European Prospective Investigation into Cancer and Nutrition, Int. J. Cancer 135 (2014) 2930
2939. [52] E. Vogtmann, Y.B. Xiang, H.L. Li, et al., Fruit and vegetable intake and the risk of colorectal cancer: results from the Shanghai Men’s Health Study, Cancer Causes Control. 24 (2013) 1935
1945. [53] I. Kashino, T. Mizoue, K. Tanaka, et al., Vegetable consumption and colorectal cancer risk: an evaluation based on a systematic review and meta-analysis among the Japanese population, Jpn. J. Clin. Oncol. 45 (2015) 973
979. [54] Q.J. Wu, Y. Yang, E. Vogtmann, et al., Cruciferous vegetables intake and the risk of colorectal cancer: a meta-analysis of observational studies, Ann. Oncol. 24 (2013) 1079
1087. [55] G. Tse, G.D. Eslick, Cruciferous vegetables and risk of colorectal neoplasms: a systematic review and meta-analysis, Nutr. Cancer 66 (2014) 128
139. [56] B. Zhu, L. Zou, L. Qi, et al., Allium vegetables and garlic supplements do not reduce risk of colorectal cancer, based on

[57] [58]

[59]

[60] [61]

[62]

[63]

[64]

[65]

[66]

[67] [68]

[69] [70]

[71]

[72]

[73]

[74]

meta-analysis of prospective studies, Clin. Gastroenterol. Hepatol. 12 (2014) 1991
2001. R.H. Liu, Potential synergy of phytochemicals in cancer prevention: mechanism of action, J. Nutr. 134 (2004) 3479S
3485S. R.J. Turesky, Formation and biochemistry of carcinogenic heterocyclic aromatic amines in cooked meats, Toxicol. Lett. 168 (2007) 219
227. S. Kim, J. Guo, M.G. O’Sullivan, et al., Comparative DNA adduct formation and induction of colonic aberrant crypt foci in mice exposed to 2-amino-9H-pyrido[2,3-b]indole, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline, and azoxymethane, Environ. Mol. Mutagen. 57 (2016) 125
136. M.C. Poirier, Chemical-induced DNA damage and human cancer risk, Discov. Med. 14 (2012) 283
288. J.H. Barrett, G. Smith, R. Waxman, et al., Investigation of interaction between N-acetyltransferase 2 and heterocyclic amines as potential risk factors for colorectal cancer, Carcinogenesis 24 (2003) 275
282. P.E. Miller, P. Lazarus, S.M. Lesko, et al., Meat-related compounds and colorectal cancer risk by anatomical subsite, Nutr. Cancer 65 (2013) 202
226. R.L. Santarelli, F. Pierre, D.E. Corpet, Processed meat and colorectal cancer: a review of epidemiologic and experimental evidence, Nutr. Cancer 60 (2008) 131
144. A.M. Gilsing, F. Fransen, T.M. de Kok, et al., Dietary heme iron and the risk of colorectal cancer with specific mutations in KRAS and APC, Carcinogenesis 34 (2013) 2757
2766. R. Saffhill, G.P. Margison, P.J. O’Connor, Mechanisms of carcinogenesis induced by alkylating agents, Biochim. Biophys. Acta 823 (1985) 111
145. J. Winter, G.P. Young, Y. Hu, et al., Accumulation of promutagenic DNA adducts in the mouse distal colon after consumption of heme does not induce colonic neoplasms in the western diet model of spontaneous colorectal cancer, Mol. Nutr. Food Res. 58 (2014) 550
558. T.M. de Kok, J.M. van Maanen, Evaluation of fecal mutagenicity and colorectal cancer risk, Mutat. Res. 463 (2000) 53
101. IARC Working Group on the Evaluation of Carcinogenic Risk to Humans, Ingested nitrate and nitrite, and cyanobacterial peptide toxins, Lyon (FR). Retrieved from: ,http://www.ncbi.nlm.nih. gov/books/NBK326544/., 2010. G.A. Kune, S. Kune, The nutritional causes of colorectal cancer: an introduction to the Melbourne study, Nutr. Cancer 9 (1987) 1
4. A.S. Whittemore, A.H. Wu-Williams, M. Lee, et al., Diet, physical activity, and colorectal cancer among Chinese in North America and China, J. Natl Cancer Inst. 82 (1990) 915
926. T. Fujise, R. Iwakiri, T. Kakimoto, et al., Long-term feeding of various fat diets modulates azoxymethane-induced colon carcinogenesis through Wnt/beta-catenin signaling in rats, Am. J. Physiol. Gastrointest. Liver Physiol. 292 (2007) G1150
G1156. G.H. McIntosh, G.O. Regester, R.K. Le Leu, et al., Dairy proteins protect against dimethylhydrazine-induced intestinal cancers in rats, J. Nutr. 125 (1995) 809
816. R.L. Nutter, D.S. Gridley, J.D. Kettering, et al., BALB/c mice fed milk or beef protein: differences in response to 1,2-dimethylhydrazine carcinogenesis, J. Natl Cancer Inst. 71 (1983) 867
874. B.C. Pence, M.J. Butler, D.M. Dunn, et al., Non-promoting effects of lean beef in the rat colon carcinogenesis model, Carcinogenesis 16 (1995) 1157
1160.

Nutrition and Colon Cancer Chapter | 36

[75] G. Parnaud, G. Peiffer, S. Tache, et al., Effect of meat (beef, chicken, and bacon) on rat colon carcinogenesis, Nutr. Cancer 32 (1998) 165
173. [76] H.L. Kettunen, A.S. Kettunen, N.E. Rautonen, Intestinal immune responses in wild-type and Apcmin/ 1 mouse, a model for colon cancer, Cancer Res. 63 (2003) 5136
5142. [77] F. Pierre, A. Freeman, S. Tache, et al., Beef meat and blood sausage promote the formation of azoxymethane-induced mucindepleted foci and aberrant crypt foci in rat colons, J. Nutr. 134 (2004) 2711
2716. [78] A.L. Sesink, D.S. Termont, J.H. Kleibeuker, et al., Red meat and colon cancer: dietary haem, but not fat, has cytotoxic and hyperproliferative effects on rat colonic epithelium, Carcinogenesis 21 (2000) 1909
1915. [79] A.L. Sesink, D.S. Termont, J.H. Kleibeuker, et al., Red meat and colon cancer: dietary haem-induced colonic cytotoxicity and epithelial hyperproliferation are inhibited by calcium, Carcinogenesis 22 (2001) 1653
1659. [80] F.H. Pierre, O.C. Martin, R.L. Santarelli, et al., Calcium and alpha-tocopherol suppress cured-meat promotion of chemically induced colon carcinogenesis in rats and reduce associated biomarkers in human volunteers, Am. J. Clin. Nutr. 98 (2013) 1255
1262. [81] V. Bouvard, D. Loomis, K.Z. Guyton, et al., Carcinogenicity of consumption of red and processed meat, Lancet Oncol. 16 (2015) 1599
1600. [82] L.D. Boada, L.A. Henriquez-Hernandez, O.P. Luzardo, The impact of red and processed meat consumption on cancer and other health outcomes: Epidemiological evidences, Food Chem. Toxicol. 92 (2016) 236
244. [83] D.D. Alexander, C.A. Cushing, Red meat and colorectal cancer: a critical summary of prospective epidemiologic studies, Obes. Rev. 12 (2011) e472
e493. [84] D.D. Alexander, D.L. Weed, P.E. Miller, et al., Red meat and colorectal cancer: a quantitative update on the state of the epidemiologic science, J. Am. Coll. Nutr. 34 (2015) 521
543. [85] A.M. Bernstein, M. Song, X. Zhang, et al., Processed and unprocessed red meat and risk of colorectal cancer: analysis by tumor location and modification by time, PLoS One 10 (2015) e0135959. [86] P.R. Carr, V. Walter, H. Brenner, et al., Meat subtypes and their association with colorectal cancer: systematic review and metaanalysis, Int. J. Cancer 138 (2016) 293
302. [87] A.D. Joshi, R. Corral, K.D. Siegmund, et al., Red meat and poultry intake, polymorphisms in the nucleotide excision repair and mismatch repair pathways and colorectal cancer risk, Carcinogenesis 30 (2009) 472
479. [88] L.M. Butler, R.C. Millikan, R. Sinha, et al., Modification by N-acetyltransferase 1 genotype on the association between dietary heterocyclic amines and colon cancer in a multiethnic study, Mutat. Res. 638 (2008) 162
174. [89] H. Girard, L.M. Butler, L. Villeneuve, et al., UGT1A1 and UGT1A9 functional variants, meat intake, and colon cancer, among Caucasians and African-Americans, Mutat. Res. 644 (2008) 56
63. [90] H.L. Newmark, M.J. Wargovich, W.R. Bruce, Colon cancer and dietary fat, phosphate, and calcium: a hypothesis, J. Natl Cancer Inst. 72 (1984) 1323
1325.

803

[91] M.J. Govers, R. Van der Meet, Effects of dietary calcium and phosphate on the intestinal interactions between calcium, phosphate, fatty acids, and bile acids, Gut 34 (1993) 365
370. [92] M.J. Govers, D.S. Termont, J.A. Lapre, et al., Calcium in milk products precipitates intestinal fatty acids and secondary bile acids and thus inhibits colonic cytotoxicity in humans, Cancer Res. 56 (1996) 3270
3275. [93] S. Chakrabarty, H. Wang, L. Canaff, et al., Calcium sensing receptor in human colon carcinoma: interaction with Ca(2 1 ) and 1,25dihydroxyvitamin D(3), Cancer Res. 65 (2005) 493
498. [94] S.M. Powell, N. Zilz, Y. Beazer-Barclay, et al., APC mutations occur early during colorectal tumorigenesis, Nature 359 (1992) 235
237. [95] K.M. Cadigan, M. Peifer, Wnt signaling from development to disease: insights from model systems, Cold Spring Harb. Perspect. Biol. 1 (2009) a002881. [96] M.J. Larriba, P. Ordonez-Moran, I. Chicote, et al., Vitamin D receptor deficiency enhances Wnt/beta-catenin signaling and tumor burden in colon cancer, PLoS One 6 (2011) e23524. [97] Y. Liu, L. Chen, C. Zhi, et al., 1,25(OH)2D3 deficiency induces colon inflammation via secretion of senescence-associated inflammatory cytokines, PLoS One 11 (2016) e0146426. [98] J.A. Eaden, K.R. Abrams, J.F. Mayberry, The risk of colorectal cancer in ulcerative colitis: a meta-analysis, Gut 48 (2001) 526
535. [99] N.S. Kelley, N.E. Hubbard, K.L. Erickson, Conjugated linoleic acid isomers and cancer, J. Nutr. 137 (2007) 2599
2607. [100] F. Beppu, M. Hosokawa, L. Tanaka, et al., Potent inhibitory effect of trans9, trans11 isomer of conjugated linoleic acid on the growth of human colon cancer cells, J. Nutr. Biochem. 17 (2006) 830
836. [101] H.J. Cho, W.K. Kim, J.I. Jung, et al., Trans-10, cis-12, not cis-9, trans-11, conjugated linoleic acid decreases ErbB3 expression in HT-29 human colon cancer cells, World J. Gastroenterol. 11 (2005) 5142
5150. [102] H. Vesper, E.M. Schmelz, M.N. Nikolova-Karakashian, et al., Sphingolipids in food and the emerging importance of sphingolipids to nutrition, J. Nutr. 129 (1999) 1239
1250. [103] Y.A. Hannun, L.M. Obeid, The ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind, J. Biol. Chem. 277 (2002) 25847
25850. [104] L.A. Lemonnier, D.L. Dillehay, M.J. Vespremi, et al., Sphingomyelin in the suppression of colon tumors: prevention versus intervention, Arch. Biochem. Biophys. 419 (2003) 129
138. [105] M. Garcia-Barros, N. Coant, J.P. Truman, et al., Sphingolipids in colon cancer, Biochim. Biophys. Acta 1841 (2014) 773
782. [106] S. Yoshida, X. Ye, The binding ability of bovine milk caseins to mutagenic heterocyclic amines, J. Dairy Sci. 75 (1992) 958
961. [107] G.R. Gourley, B.L. Kreamer, M. Cohnen, Inhibition of betaglucuronidase by casein hydrolysate formula, J. Pediatr. Gastroenterol. Nutr. 25 (1997) 267
272. [108] G. Bounous, F. Gervais, V. Amer, et al., The influence of dietary whey protein on tissue glutathione and the diseases of aging, Clin. Invest. Med. 12 (1989) 343
349. [109] E. Tavan, C. Cayuela, J.M. Antoine, et al., Effects of dairy products on heterocyclic aromatic amine-induced rat colon carcinogenesis, Carcinogenesis 23 (2002) 477
483.

804 PART | F Cancer

[110] R. Hakkak, S. Korourian, M.J. Ronis, et al., Dietary whey protein protects against azoxymethane-induced colon tumors in male rats, Cancer Epidemiol. Biomarkers Prev. 10 (2001) 555
558. [111] R. Xiao, J.A. Carter, A.L. Linz, et al., Dietary whey protein lowers serum C-peptide concentration and duodenal SREBP-1c mRNA abundance, and reduces occurrence of duodenal tumors and colon aberrant crypt foci in azoxymethane-treated male rats, J. Nutr. Biochem. 17 (2006) 626
634. [112] D.R. Snow, R. Jimenez-Flores, R.E. Ward, et al., Dietary milk fat globule membrane reduces the incidence of aberrant crypt foci in Fischer-344 rats, J. Agric. Food Chem. 58 (2010) 2157
2163. [113] D.E. Corpet, F. Pierre, How good are rodent models of carcinogenesis in predicting efficacy in humans? A systematic review and meta-analysis of colon chemoprevention in rats, mice and men, Eur. J. Cancer 41 (2005) 1911
1922. [114] Y. Liu, J. Ju, H. Xiao, et al., Effects of combination of calcium and aspirin on azoxymethane-induced aberrant crypt foci formation in the colons of mice and rats, Nutr. Cancer 60 (2008) 660
665. [115] H.L. Newmark, K. Yang, M. Lipkin, et al., A western-style diet induces benign and malignant neoplasms in the colon of normal C57Bl/6 mice, Carcinogenesis 22 (2001) 1871
1875. [116] H.L. Newmark, K. Yang, N. Kurihara, et al., Western-style dietinduced colonic tumors and their modulation by calcium and vitamin D in C57Bl/6 mice: a preclinical model for human sporadic colon cancer, Carcinogenesis 30 (2009) 88
92. [117] A. Kawaura, N. Tanida, K. Sawada, et al., Supplemental administration of 1 alpha-hydroxyvitamin D3 inhibits promotion by intrarectal instillation of lithocholic acid in N-methyl-N-nitrosourea-induced colonic tumorigenesis in rats, Carcinogenesis 10 (1989) 647
649. [118] S. Huerta, R.W. Irwin, D. Heber, et al., 1Alpha,25-(OH)(2)-D(3) and its synthetic analogue decrease tumor load in the Apc(min) Mouse, Cancer Res. 62 (2002) 741
746. [119] A. Belleli, S. Shany, J. Levy, et al., A protective role of 1,25dihydroxyvitamin D3 in chemically induced rat colon carcinogenesis, Carcinogenesis 13 (1992) 2293
2298. [120] M.D. Sitrin, A.G. Halline, C. Abrahams, et al., Dietary calcium and vitamin D modulate 1,2-dimethylhydrazine-induced colonic carcinogenesis in the rat, Cancer Res. 51 (1991) 5608
5613. [121] A.A. Irving, R.B. Halberg, D.M. Albrecht, et al., Supplementation by vitamin D compounds does not affect colonic tumor development in vitamin D sufficient murine models, Arch. Biochem. Biophys. 515 (2011) 64
71. [122] A.A. Irving, L.A. Plum, W.J. Blaser, et al., Cholecalciferol or 25-hydroxycholecalciferol neither prevents nor treats adenomas in a rat model of familial colon cancer, J. Nutr. 145 (2015) 291
298. [123] D. Aune, R. Lau, D.S. Chan, et al., Dairy products and colorectal cancer risk: a systematic review and meta-analysis of cohort studies, Ann. Oncol. 23 (2012) 37
45. [124] R.A. Ralston, H. Truby, C.E. Palermo, et al., Colorectal cancer and nonfermented milk, solid cheese, and fermented milk consumption: a systematic review and meta-analysis of prospective studies, Crit. Rev. Food Sci. Nutr. 54 (2014) 1167
1179. [125] X. Zhang, N. Keum, K. Wu, et al., Calcium intake and colorectal cancer risk: results from the nurses’ health study and health professionals follow-up study, Int. J. Cancer 139 (2016) 2232
2242.

[126] R.C. Heine-Broring, R.M. Winkels, J.M. Renkema, et al., Dietary supplement use and colorectal cancer risk: a systematic review and meta-analyses of prospective cohort studies, Int. J. Cancer 136 (2015) 2388
2401. [127] D. Scharlau, A. Borowicki, N. Habermann, et al., Mechanisms of primary cancer prevention by butyrate and other products formed during gut flora-mediated fermentation of dietary fibre, Mutat. Res./Rev. Mutat. Res. 682 (2009) 39
53. [128] B.L. Pool-Zobel, Inulin-type fructans and reduction in colon cancer risk: review of experimental and human data, Br. J. Nutr 93 (Suppl. 1) (2005) S73
S90. [129] D.D. Gallaher, J. Khil, The effect of synbiotics on colon carcinogenesis in rats, J. Nutr. 129 (1999) 1483S
1487S. [130] T.S. Manning, G.R. Gibson, Microbial-gut interactions in health and disease. Prebiotics, Best Pract. Res. Clin. Gastroenterol. 18 (2004) 287
298. [131] J. Ju, S.C. Picinich, Z. Yang, et al., Cancer-preventive activities of tocopherols and tocotrienols, Carcinogenesis 31 (2010) 533
542. [132] M. Srinivasan, A.R. Sudheer, V.P. Menon, Ferulic acid: therapeutic potential through its antioxidant property, J. Clin. Biochem. Nutr. 40 (2007) 92
100. [133] A. Adam, V. Crespy, M.A. Levrat-Verny, et al., The bioavailability of ferulic acid is governed primarily by the food matrix rather than its metabolism in intestine and liver in rats, J. Nutr. 132 (2002) 1962
1968. [134] M. Youn, A. Saari Csallany, D.D. Gallaher, Whole grain consumption has a modest effect on the development of diabetes in the Goto-Kakisaki rat, Br. J. Nutr. 107 (2012) 192
201. [135] S. Norazalina, M.E. Norhaizan, I. Hairuszah, et al., Anticarcinogenic efficacy of phytic acid extracted from rice bran on azoxymethane-induced colon carcinogenesis in rats, Exp. Toxicol. Pathol. 62 (2010) 259
268. [136] M. Jenab, L.U. Thompson, The influence of phytic acid in wheat bran on early biomarkers of colon carcinogenesis, Carcinogenesis 19 (1998) 1087
1092. [137] A.L. Webb, M.L. McCullough, Dietary lignans: potential role in cancer prevention, Nutr. Cancer 51 (2005) 117
131. [138] B.B. Maziya-Dixon, C.F. Klopfenstein, H.W. Leipold, Protective effects of hard red versus hard white winter wheats in chemically induced colon cancer in CF1 mice, Cereal Chem. 71 (1994) 359
363. [139] M.I. Buescher, D.D. Gallaher, Wheat color (class), not refining, influences colon cancer risk in rats, Nutr. Cancer 66 (2014) 849
856. [140] A. Islam, D.D. Gallaher, Wheat type (class) influences development and regression of colon cancer risk markers in rats, Nutr. Cancer 67 (2015) 1283
1292. [141] Z. Yu, M. Xu, G. Santana-Rios, et al., A comparison of whole wheat, refined wheat and wheat bran as inhibitors of heterocyclic amines in the Salmonella mutagenicity assay and in the rat colonic aberrant crypt focus assay, Food Chem. Toxicol. 39 (2001) 655
665. [142] D.S. Barnes, N.K. Clapp, D.A. Scott, et al., Effects of wheat, rice, corn, and soybean bran on 1,2-dimethylhydrazine-induced large bowel tumorigenesis in F344 rats, Nutr. Cancer 5 (1983) 1
9. [143] G.H. McIntosh, R.K. Le Leu, P.J. Royle, et al., A comparative study of the influence of differing barley brans on DMH-induced intestinal tumours in male Sprague-Dawley rats, J. Gastroenterol. Hepatol. 11 (1996) 113
119.

Nutrition and Colon Cancer Chapter | 36

[144] B.S. Reddy, H. Mori, M. Nicolais, Effect of dietary wheat bran and dehydrated citrus fiber on azoxymethane-induced intestinal carcinogenesis in Fischer 344 rats, J. Natl Cancer Inst. 66 (1981) 553
557. [145] O. Alabaster, Z. Tang, A. Frost, et al., Effect of beta-carotene and wheat bran fiber on colonic aberrant crypt and tumor formation in rats exposed to azoxymethane and high dietary fat, Carcinogenesis 16 (1995) 127
132. [146] K. Watanabe, B.S. Reddy, J.H. Weisburger, et al., Effect of dietary alfalfa, pectin, and wheat bran on azoxymethane-or methylnitrosourea-induced colon carcinogenesis in F344 rats, J. Natl. Cancer Inst. 63 (1979) 141
145. [147] R.B. Wilson, D.P. Hutcheson, L. Wideman, Dimethylhydrazineinduced colon tumors in rats fed diets containing beef fat or corn oil with and without wheat bran, Am. J. Clin. Nutr. 30 (1977) 176
181. [148] G.P. Young, A. McIntyre, V. Albert, et al., Wheat bran suppresses potato starch
potentiated colorectal tumorigenesis at the aberrant crypt stage in a rat model, Gastroenterology 110 (1996) 508
514. [149] O. Alabaster, Z.C. Tang, A. Frost, et al., Potential synergism between wheat bran and psyllium: enhanced inhibition of colon cancer, Cancer Lett. 75 (1993) 53
58. [150] R.J. Calvert, D.M. Klurfeld, S. Subramaniam, et al., Reduction of colonic carcinogenesis by wheat bran independent of fecal bile acid concentration, J. Natl Cancer Inst. 79 (1987) 875
880. [151] K. Drankhan, J. Carter, R. Madl, et al., Antitumor activity of wheats with high orthophenolic content, Nutr. Cancer 47 (2003) 188
194. [152] C.W. Compher, W.L. Frankel, J. Tazelaar, et al., Wheat bran decreases aberrant crypt foci, preserves normal proliferation, and increases intraluminal butyrate levels in experimental colon cancer, JPEN J. Parenter. Enteral Nutr. 23 (1999) 269
277, discussion 277
278. [153] T. Takahashi, M. Satou, N. Watanabe, et al., Inhibitory effect of microfibril wheat bran on azoxymethane-induced colon carcinogenesis in CF1 mice, Cancer Lett. 141 (1999) 139
146. [154] N.K. Clapp, M.A. Henke, J.F. London, et al., Enhancement of 1,2-dimethylhydrazine-induced large bowel tumorigenesis in Balb/c mice by corn, soybean, and wheat brans, Nutr. Cancer 6 (1984) 77
85. [155] L.R. Jacobs, Enhancement of rat colon carcinogenesis by wheat bran consumption during the stage of 1,2-dimethylhydrazine administration, Cancer Res. 43 (1983) 4057
4061. [156] L.R. Jacobs, J.R. Lupton, Relationship between colonic luminal pH, cell proliferation, and colon carcinogenesis in 1,2-dimethylhydrazine treated rats fed high fiber diets, Cancer Res. 46 (1986) 1727
1734. [157] M. Mutanen, A.M. Pajari, S.I. Oikarinen, Beef induces and rye bran prevents the formation of intestinal polyps in Apc(Min) mice: relation to beta-catenin and PKC isozymes, Carcinogenesis 21 (2000) 1167
1173. [158] M.J. Davies, E.A. Bowey, H. Adlercreutz, et al., Effects of soy or rye supplementation of high-fat diets on colon tumour development in azoxymethane-treated rats, Carcinogenesis 20 (1999) 927
931. [159] S. Oikarinen, S. Heinonen, S. Karppinen, et al., Plasma enterolactone or intestinal bifidobacterium levels do not explain

[160]

[161]

[162]

[163]

[164]

[165]

[166]

[167]

[168] [169]

[170]

[171]

[172]

[173]

[174]

[175]

805

adenoma formation in multiple intestinal neoplasia (Min) mice fed with two different types of rye-bran fractions, Br. J. Nutr. 90 (2003) 119
125. H.J. van Kranen, A. Mortensen, I.K. Sorensen, et al., Lignan precursors from flaxseed or rye bran do not protect against the development of intestinal neoplasia in ApcMin mice, Nutr. Cancer 45 (2003) 203
210. B.S. Reddy, Y. Maeura, M. Wayman, Effect of dietary corn bran and autohydrolyzed lignin on 3,2’-dimethyl-4-aminobiphenylinduced intestinal carcinogenesis in male F344 rats, J. Natl Cancer Inst. 71 (1983) 419
423. R.D. Verschoyle, P. Greaves, H. Cai, et al., Evaluation of the cancer chemopreventive efficacy of rice bran in genetic mouse models of breast, prostate and intestinal carcinogenesis, Br. J. Cancer 96 (2007) 248
254. C. Kyro, G. Skeie, S. Loft, et al., Intake of whole grains from different cereal and food sources and incidence of colorectal cancer in the Scandinavian HELGA cohort, Cancer Causes Control 24 (2013) 1363
1374. T. Bakken, T. Braaten, A. Olsen, et al., Consumption of wholegrain bread and risk of colorectal cancer among Norwegian women (the NOWAC study), Nutrients 8 (2016) 40. M.D. Knudsen, C. Kyro, A. Olsen, et al., Self-reported wholegrain intake and plasma alkylresorcinol concentrations in combination in relation to the incidence of colorectal cancer, Am. J. Epidemiol. 179 (2014) 1188
1196. C. Kyro, A. Olsen, R. Landberg, et al., Plasma alkylresorcinols, biomarkers of whole-grain wheat and rye intake, and incidence of colorectal cancer, J. Natl Cancer Inst 106 (2014) djt352. C. Kyro, A. Olsen, H.B. Bueno-de-Mesquita, et al., Plasma alkylresorcinol concentrations, biomarkers of whole-grain wheat and rye intake, in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, Br. J. Nutr. 111 (2014) 1881
1890. F. Levi, C. Pasche, C. La Vecchia, et al., Food groups and colorectal cancer risk, Br. J. Cancer 79 (1999) 1283
1287. M.C. Boutron-Ruault, P. Senesse, J. Faivre, et al., Foods as risk factors for colorectal cancer: a case-control study in Burgundy (France), Eur. J. Cancer Prev. 8 (1999) 229
235. L. Chatenoud, C. La Vecchia, S. Franceschi, et al., Refinedcereal intake and risk of selected cancers in Italy, Am. J. Clin. Nutr. 70 (1999) 1107
1110. C. Kyro, G. Skeie, L.O. Dragsted, et al., Intake of whole grains in Scandinavia is associated with healthy lifestyle, socio-economic and dietary factors, Public Health Nutr. 14 (2011) 1787
1795. J.W. Lampe, J.L. Slavin, E.A. Melcher, et al., Effects of cereal and vegetable fiber feeding on potential risk factors for colon cancer, Cancer Epidemiol. Biomarkers Prev. 1 (1992) 207
211. F. Macrae, Wheat bran fiber and development of adenomatous polyps: evidence from randomized, controlled clinical trials, Am. J. Med. 106 (1999) 38S
42S. S.A. Beresford, K.C. Johnson, C. Ritenbaugh, et al., Low-fat dietary pattern and risk of colorectal cancer: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial, JAMA 295 (2006) 643
654. D.S. Alberts, M.E. Martinez, D.J. Roe, et al., Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal adenomas. Phoenix Colon Cancer Prevention Physicians’ Network, N. Engl. J. Med. 342 (2000) 1156
1162.

806 PART | F Cancer

[176] B.J. Majer, E. Hofer, C. Cavin, et al., Coffee diterpenes prevent the genotoxic effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and N-nitrosodimethylamine in a human derived liver cell line (HepG2), Food Chem. Toxicol. 43 (2005) 433
441. [177] R. Edenharder, J.W. Sager, H. Glatt, et al., Protection by beverages, fruits, vegetables, herbs, and flavonoids against genotoxicity of 2-acetylaminofluorene and 2-amino-1-methyl-6phenylimidazo[4,5-b]pyridine (PhIP) in metabolically competent V79 cells, Mutat. Res. 521 (2002) 57
72. [178] W.W. Huber, L.P. McDaniel, K.R. Kaderlik, et al., Chemoprotection against the formation of colon DNA adducts from the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the rat, Mutat. Res. 376 (1997) 115
122. [179] R.J. Turesky, J. Richoz, A. Constable, et al., The effects of coffee on enzymes involved in metabolism of the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in rats, Chem. Biol. Interact. 145 (2003) 251
265. [180] W.W. Huber, S. Prustomersky, E. Delbanco, et al., Enhancement of the chemoprotective enzymes glucuronosyl transferase and glutathione transferase in specific organs of the rat by the coffee components kahweol and cafestol, Arch. Toxicol. 76 (2002) 209
217. [181] W.W. Huber, C.H. Teitel, B.F. Coles, et al., Potential chemoprotective effects of the coffee components kahweol and cafestol palmitates via modification of hepatic N-acetyltransferase and glutathione S-transferase activities, Environ. Mol. Mutagen. 44 (2004) 265
276. [182] K.J. Lee, H.G. Jeong, Protective effects of kahweol and cafestol against hydrogen peroxide-induced oxidative stress and DNA damage, Toxicol. Lett. 173 (2007) 80
87. [183] W.W. Huber, G. Scharf, W. Rossmanith, et al., The coffee components kahweol and cafestol induce gamma-glutamylcysteine synthetase, the rate limiting enzyme of chemoprotective glutathione synthesis, in several organs of the rat, Arch. Toxicol. 75 (2002) 685
694. [184] F. Esposito, F. Morisco, V. Verde, et al., Moderate coffee consumption increases plasma glutathione but not homocysteine in healthy subjects, Aliment. Pharmacol. Ther. 17 (2003) 595
601. [185] M.J. Grubben, C.C. Van Den Braak, R. Broekhuizen, et al., The effect of unfiltered coffee on potential biomarkers for colonic cancer risk in healthy volunteers: a randomized trial, Aliment. Pharmacol. Ther. 14 (2000) 1181
1190. [186] K. Yanagimoto, H. Ochi, K.G. Lee, et al., Antioxidative activities of fractions obtained from brewed coffee, J. Agric. Food Chem. 52 (2004) 592
596. [187] R.C. Borrelli, A. Visconti, C. Mennella, et al., Chemical characterization and antioxidant properties of coffee melanoidins, J. Agric. Food Chem. 50 (2002) 6527
6533. [188] M.D. del Castillo, J.M. Ames, M.H. Gordon, Effect of roasting on the antioxidant activity of coffee brews, J. Agric. Food Chem. 50 (2002) 3698
3703. [189] J.E. Jung, H.S. Kim, C.S. Lee, et al., Caffeic acid and its synthetic derivative CADPE suppress tumor angiogenesis by blocking STAT3-mediated VEGF expression in human renal carcinoma cells, Carcinogenesis 28 (2007) 1780
1787. [190] N.J. Kang, K.W. Lee, B.H. Kim, et al., Coffee phenolic phytochemicals suppress colon cancer metastasis by targeting MEK and TOPK, Carcinogenesis 32 (2011) 921
928.

[191] A. Belkaid, J.C. Currie, J. Desgagnes, et al., The chemopreventive properties of chlorogenic acid reveal a potential new role for the microsomal glucose-6-phosphate translocase in brain tumor progression, Cancer Cell Int. 6 (2006) 7. [192] H. Mori, K. Kawabata, K. Matsunaga, et al., Chemopreventive effects of coffee bean and rice constituents on colorectal carcinogenesis, Biofactors 12 (2000) 101
105. [193] U.H. Jin, J.Y. Lee, S.K. Kang, et al., A phenolic compound, 5-caffeoylquinic acid (chlorogenic acid), is a new type and strong matrix metalloproteinase-9 inhibitor: isolation and identification from methanol extract of Euonymus alatus, Life Sci. 77 (2005) 2760
2769. [194] A. Gosslau, D.L. En Jao, M.T. Huang, et al., Effects of the black tea polyphenol theaflavin-2 on apoptotic and inflammatory pathways in vitro and in vivo, Mol. Nutr. Food Res. 55 (2011) 198
208. [195] C.A. Larsen, R.H. Dashwood, (-)-Epigallocatechin-3-gallate inhibits Met signaling, proliferation, and invasiveness in human colon cancer cells, Arch. Biochem. Biophys. 501 (2010) 52
57. [196] A.C. Tan, I. Konczak, D.M. Sze, et al., Molecular pathways for cancer chemoprevention by dietary phytochemicals, Nutr. Cancer 63 (2011) 495
505. [197] P. Boffetta, M. Hashibe, Alcohol and cancer, Lancet Oncol. 7 (2006) 149
156. [198] A. Hamid, N.A. Wani, J. Kaur, New perspectives on folate transport in relation to alcoholism-induced folate malabsorption— association with epigenome stability and cancer development, FEBS J. 276 (2009) 2175
2191. [199] H. Mori, I. Hirono, Effect of coffee on carcinogenicity of cycasin, Br. J. Cancer 35 (1977) 369
371. [200] C. Carvalho Ddo, M.R. Brigagao, M.H. dos Santos, et al., Organic and conventional Coffea arabica L.: a comparative study of the chemical composition and physiological, biochemical and toxicological effects in Wistar rats, Plant Foods Hum. Nutr. 66 (2011) 114
121. [201] C.V. Rao, D. Chou, B. Simi, et al., Prevention of colonic aberrant crypt foci and modulation of large bowel microbial activity by dietary coffee fiber, inulin and pectin, Carcinogenesis 19 (1998) 1815
1819. [202] R. Wang, W.M. Dashwood, C.V. Lohr, et al., Protective versus promotional effects of white tea and caffeine on PhIP-induced tumorigenesis and beta-catenin expression in the rat, Carcinogenesis 29 (2008) 834
839. [203] M. Xu, A.C. Bailey, J.F. Hernaez, et al., Protection by green tea, black tea, and indole-3-carbinol against 2-amino-3-methylimidazo[4,5-f]quinoline-induced DNA adducts and colonic aberrant crypts in the F344 rat, Carcinogenesis 17 (1996) 1429
1434. [204] G. Caderni, C. De Filippo, C. Luceri, et al., Effects of black tea, green tea and wine extracts on intestinal carcinogenesis induced by azoxymethane in F344 rats, Carcinogenesis 21 (2000) 1965
1969. [205] A. Challa, D.R. Rao, B.S. Reddy, Interactive suppression of aberrant crypt foci induced by azoxymethane in rat colon by phytic acid and green tea, Carcinogenesis 18 (1997) 2023
2026. [206] J.H. Weisburger, A. Rivenson, C. Aliaga, et al., Effect of tea extracts, polyphenols, and epigallocatechin gallate on azoxymethane-induced colon cancer, Proc. Soc. Exp. Biol. Med. 217 (1998) 104
108. [207] J. Ju, Y. Liu, J. Hong, et al., Effects of green tea and high-fat diet on arachidonic acid metabolism and aberrant crypt foci formation in an azoxymethane-induced colon carcinogenesis mouse model, Nutr. Cancer 46 (2003) 172
178.

Nutrition and Colon Cancer Chapter | 36

[208] G. Santana-Rios, G.A. Orner, M. Xu, et al., Inhibition by white tea of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced colonic aberrant crypts in the F344 rat, Nutr. Cancer 41 (2001) 98
103. [209] R.L. Nelson, S.L. Samelson, Neither dietary ethanol nor beer augments experimental colon carcinogenesis in rats, Dis. Colon Rectum 28 (1985) 460
462. [210] S.R. Hamilton, J. Hyland, D. McAvinchey, et al., Effects of chronic dietary beer and ethanol consumption on experimental colonic carcinogenesis by azoxymethane in rats, Cancer Res. 47 (1987) 1551
1559. [211] A.E. Howarth, E. Pihl, High-fat diet promotes and causes distal shift of experimental rat colonic cancer—beer and alcohol do not, Nutr. Cancer 6 (1984) 229
235. [212] H. Nozawa, A. Yoshida, O. Tajima, et al., Intake of beer inhibits azoxymethane-induced colonic carcinogenesis in male Fischer 344 rats, Int. J. Cancer 108 (2004) 404
411. [213] G. Caderni, S. Remy, V. Cheynier, et al., Effect of complex polyphenols on colon carcinogenesis, Eur. J. Nutr. 38 (1999) 126
132. [214] P. Dolara, C. Luceri, C. De Filippo, et al., Red wine polyphenols influence carcinogenesis, intestinal microflora, oxidative damage and gene expression profiles of colonic mucosa in F344 rats, Mutat. Res. 591 (2005) 237
246. [215] A.P. Femia, G. Caderni, F. Vignali, et al., Effect of polyphenolic extracts from red wine and 4-OH-coumaric acid on 1,2-dimethylhydrazine-induced colon carcinogenesis in rats, Eur. J. Nutr. 44 (2005) 79
84. [216] G. Li, D. Ma, Y. Zhang, et al., Coffee consumption and risk of colorectal cancer: a meta-analysis of observational studies, Public Health Nutr. 16 (2013) 346
357. [217] C. Galeone, F. Turati, C. La Vecchia, et al., Coffee consumption and risk of colorectal cancer: a meta-analysis of case-control studies, Cancer Causes Control. 21 (2010) 1949
1959. [218] Y. Gan, J. Wu, S. Zhang, et al., Association of coffee consumption with risk of colorectal cancer: a meta-analysis of prospective cohort studies, Oncotarget (2016). Available from: http://dx.doi. org/10.18632/oncotarget.8627. [219] Y. Je, W. Liu, E. Giovannucci, Coffee consumption and risk of colorectal cancer: a systematic review and meta-analysis of prospective cohort studies, Int. J. Cancer 124 (2009) 1662
1668. [220] C. Tian, W. Wang, Z. Hong, et al., Coffee consumption and risk of colorectal cancer: a dose-response analysis of observational studies, Cancer Causes Control. 24 (2013) 1265
1268. [221] W.M. Ratnayake, R. Hollywood, E. O’Grady, et al., Lipid content and composition of coffee brews prepared by different methods, Food Chem. Toxicol. 31 (1993) 263
269. [222] G. Gross, E. Jaccaud, A.C. Huggett, Analysis of the content of the diterpenes cafestol and kahweol in coffee brews, Food Chem. Toxicol. 35 (1997) 547
554. [223] R. Urgert, G. Van der Weg, T.G. Kosmeiher-Schuil, et al., Levels of the cholesterol-elevating diterpenes cafestol and kahweol in various coffee brews, J. Agric. Food Chem. 43 (1995) 2167
2172.

807

[224] G. Yang, X.O. Shu, H. Li, et al., Prospective cohort study of green tea consumption and colorectal cancer risk in women, Cancer Epidemiol. Biomarkers Prev. 16 (2007) 1219
1223. [225] M. Shimizu, Y. Fukutomi, M. Ninomiya, et al., Green tea extracts for the prevention of metachronous colorectal adenomas: a pilot study, Cancer Epidemiol. Biomarkers Prev. 17 (2008) 3020
3025. [226] C.L. Sun, J.M. Yuan, W.P. Koh, et al., Green tea and black tea consumption in relation to colorectal cancer risk: the Singapore Chinese Health Study, Carcinogenesis 28 (2007) 2143
2148. [227] J.M. Yuan, Y.T. Gao, C.S. Yang, et al., Urinary biomarkers of tea polyphenols and risk of colorectal cancer in the Shanghai Cohort Study, Int. J. Cancer 120 (2007) 1344
1350. [228] G. Yang, W. Zheng, Y.B. Xiang, et al., Green tea consumption and colorectal cancer risk: a report from the Shanghai Men’s Health Study, Carcinogenesis 32 (2011) 1684
1688. [229] Z.H. Wang, Q.Y. Gao, J.Y. Fang, Green tea and incidence of colorectal cancer: evidence from prospective cohort studies, Nutr. Cancer 64 (2012) 1143
1152. [230] Y.F. Zhang, Q. Xu, J. Lu, et al., Tea consumption and the incidence of cancer: a systematic review and meta-analysis of prospective observational studies, Eur. J. Cancer Prev. 24 (2015) 353
362. [231] A. Moskal, T. Norat, P. Ferrari, et al., Alcohol intake and colorectal cancer risk: a dose-response meta-analysis of published cohort studies, Int. J. Cancer 120 (2007) 664
671. [232] V. Fedirko, I. Tramacere, V. Bagnardi, et al., Alcohol drinking and colorectal cancer risk: an overall and dose-response metaanalysis of published studies, Ann. Oncol. 22 (2011) 1958
1972. [233] C. Zhang, M. Zhong, Consumption of beer and colorectal cancer incidence: a meta-analysis of observational studies, Cancer Causes Control. 26 (2015) 549
560. [234] J.A. Satia, M. Tseng, J.A. Galanko, et al., Dietary patterns and colon cancer risk in Whites and African Americans in the North Carolina Colon Cancer Study, Nutr. Cancer 61 (2009) 179
193. [235] Z. Chen, P.P. Wang, J. Woodrow, et al., Dietary patterns and colorectal cancer: results from a Canadian population-based study, Nutr. J. 14 (2015) 8. [236] T.T. Fung, F.B. Hu, M. Schulze, et al., A dietary pattern that is associated with C-peptide and risk of colorectal cancer in women, Cancer Causes Control 23 (2012) 959
965. [237] Y. Kumagai, W.T. Chou, Y. Tomata, et al., Dietary patterns and colorectal cancer risk in Japan: the Ohsaki Cohort Study, Cancer Causes Control 25 (2014) 727
736. [238] B. Magalhaes, B. Peleteiro, N. Lunet, Dietary patterns and colorectal cancer: systematic review and meta-analysis, Eur. J. Cancer Prev. 21 (2012) 15
23. [239] J.W. Lampe, Nutrition and cancer prevention: small-scale human studies for the 21st century, Cancer Epidemiol. Biomarkers Prev. 13 (2004) 1987
1988. [240] J.W. Lampe, Interindividual differences in response to plantbased diets: implications for cancer risk, Am. J. Clin. Nutr. 89 (2009) 1553S
1557S.