Nutrition and Colon Cancer

C H A P T E R

37 Nutrition and Colon Cancer Daniel D. Gallaher, Sabrina P. Trudo University of Minnesota, St. Paul, Minnesota

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]. Affecting approximately 141,000 people each year, 72% of new cases arise in the colon and 28% 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 focuses 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 can only demonstrate associations between a particular dietary component or dietary pattern and colon cancer risk and thus are most useful to generate hypotheses or provide support to findings from intervention or animal studies. However, because they directly examine humans consuming their normal diets, epidemiologic studies are invaluable in identifying potentially beneficial or harmful foods or dietary patterns. 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

Nutrition in the Prevention and Treatment of Disease, Third Edition. DOI: http://dx.doi.org/10.1016/B978-0-12-391884-0.00037-8

there is no question about applicability to humans. However, this approach requires an outcome measure other than the development of cancer because 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. Furthermore, even polyps are not completely validated as a marker of colon cancer risk. However, there is reason for optimism because 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 influences initiation events such as biotransformation of carcinogens, DNA adduct formation, DNA repair, and apoptosis, as well as post-initiation events such as changes in signaling pathways and eventual tumor formation. Cell culture studies are frequently employed for the study of how isolated compounds influence cancer cell growth and signaling pathways, in addition to 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 focus on only animal, case
control, prospective

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cohort, and intervention studies related to nutrition and cancer. In discussion of the animal studies, we focus on studies using whole foods and their effect on morphological end points of colon cancer: adenomas (benign tumors that may progress to cancer), adenocarcinomas (cancerous tumors), or aberrant crypt foci (ACF), believed to be precancerous lesions. For discussion of human studies, we similarly focus on studies using colon cancer as the end point, with the exception of intervention trials. Emphasis is likewise 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 summarize the proposed impact on colon cancer risk, including putative biological mechanisms for influencing cancer risk, and review the relevant animal and human data.

II FRUITS, VEGETABLES, AND LEGUMES A Proposed Mechanisms for Influencing Cancer Risk It has been hypothesized that plant foods protect against cancers such as colon cancer [8]. 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 [9,10]. Other phytochemicals that induce apoptosis include proanthocyanidins (apples, chocolate, grapes, berries, and other fruits), resveratrol (grape skins and peanuts), isothiocyanates (derived from cruciferous vegetables such as broccoli and cabbage), and limonene (citrus fruits and cherries) (reviewed in [10,11]). 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 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]). 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 and, second, conjugating the metabolite with another molecule. The net effect is usually a more safe and water-soluble product that can be safely 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), 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, isothiocyanates, furanocoumarins, and phenolic compounds influence CYP activity [13,14]; isothiocyanates and cruciferous vegetables modulate GST activity [14
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; pro-inflammatory cytokines can also regulate epithelial
mesenchymal transition and thus influence invasion and metastasis [19]. Flavonoids, proanthocyanidins, isothiocyanates, and resveratrol have demonstrated anti-inflammatory activity [11,19]. In addition, 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]. However, whereas 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 [8,21
25]. Accordingly, the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) reported in 1997 that the evidence for protection against colon cancer by diets rich in vegetables “is convincing” [26]. Subsequent

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studies, however, were less supportive; thus, in the second report released in 2007 by WCRF/AICR, the reassessment indicated limited suggestive evidence for risk reduction by fruits and nonstarchy vegetables. 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. In addition, 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 and treatment with the intact food source (see review [27]).

B 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 [28]. A similar finding was reported with freeze-dried black raspberries [29] and with whole apples [30]. In contrast, feeding dried plum powder, produced by air drying, did not result in a reduction of ACF [31]. 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. 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 [32]. Furthermore, a tendency for reduction in ACF has been found with juices of garden cress [33] and Brussels sprouts [34] but not red cabbage [34]. Finally, carcinogen-treated mice that were fed cabbage had fewer adenomas, a benign tumor that can progress to a cancerous tumor [35]. 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 given garlic have shown a reduction in either ACF [36] or

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mucin-depleted foci [37] (subset of ACF that are thought to more likely progress to tumors), as well as a reduction in tumor incidence [38]. Dried onions also reduced ACF in carcinogen-treated rats [39]. 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 [40] and ACF number [41,42]. Soy flour has also reduced ACF number [43]. Interestingly, miso had no effect on ACF number or tumor incidence [44]. Few other legumes have been examined. In carcinogentreated rats, garbanzo bean flour [43] and lentils [42] reduced ACF number, whereas cooked navy beans had no effect on tumor incidence [45]. 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.

C Human Studies Case
control studies have taken differing approaches but generally suggest a protective association between fruit and vegetable intake or specific groups of phytochemicals and colon cancer. Utilizing the expansion of dietary databases to include flavonoid data, the association was investigated between six groups of flavonoids and colorectal cancer in Scotland [46]. The six groups were flavonols, flavones, flavan-3-ols or catechins, procyanidins, flavanones, and phytoestrogens. For colon cancer, individual inverse relationships were observed between increasing intake of quercetin, catechin, and epicatechin (p-trends ,0.05) across quartiles of intake. Also in Scotland, four different subclasses of flavonoids (flavonols, procyanidins, flavan-3-ols, and flavanones) were investigated with regard to colorectal cancer [47]. A weak negative trend was observed for flavanones (ptrend 5 0.07), whereas quercetin specifically was associated with a reduced colon cancer risk with increasing intake (odds ratio and 95% confidence interval (OR (95% CI)) 5 0.50 (0.3, 0.8) for highest vs. lowest intake quartile; p-trend 5 0.01). Proanthocyanidins were the focus of an Italian study of colorectal cancer; whereas decreased

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risk for colorectal cancer was observed with increased proanthocyanidin intakes, the inverse associations were apparently stronger for rectal cancer than for colon cancer [48]. 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 [49]. The three dietary patterns were “Western
Southern” (high loadings for red meats, fried foods, cheese dishes, and sweets), “fruit
vegetable” (high loadings for fruits, vegetables, and legumes), and “metropolitan” (salad, seafood, pastas, Mexican foods, turkey, chicken, veal, lamb, cruciferous vegetables, and alfalfa sprouts). The “fruit
vegetable” pattern was significantly inversely associated with colon cancer risk in whites (OR (95% CI) 5 0.40 (0.30, 0.60)) but not in African Americans. In the population-based Western Australian Bowel Health Study, the association of fruit and vegetable intake with colorectal cancer was assessed by subsite (proximal colon, distal colon, and rectum) [50]. Cruciferous vegetable intake was inversely associated with proximal colon cancer (OR (95% CI) 5 0.62 (0.41, 0.93) for highest vs. lowest intake quartile), whereas for distal colon cancer there were significant negative trends for total fruit and vegetable intake and total vegetable intake. Furthermore, risk for distal colon cancer significantly decreased with increased intake specifically of dark yellow vegetables and apples; however, no associations were found with legumes at any of the subsites. Case
control studies, in general, have fairly consistently found an inverse association between cruciferous vegetable intake and colon cancer (reviewed in [51]). Prospective cohort studies are typically considered stronger than case
control studies due to less susceptibility to recall and selection bias. Cohort studies have been less consistent with regard to fruit, vegetable, and legumes decreasing colon cancer risk. In the Multiethnic Cohort Study, inverse associations were seen only in men and mostly for vegetables: relative risk and 95% confidence interval (RR (95% CI)) 5 0.72 (0.55, 0.94), p-trend 5 0.037 for vegetables and fruit combined; RR (95% CI) 5 0.80 (0.63, 1.03), p-trend 5 0.039 for vegetables only; and RR (95% CI) 5 0.75 (0.58, 0.97), p-trend 5 0.108 for fruit only [52]. The European Prospective Investigation into Cancer and Nutrition study observed an inverse association for usual combined fruit and vegetable intake; however, with adjustment for total fiber, the risk estimate for colon cancer lost significance when comparing the highest with the lowest quintile of intake [53]. Dietary flavonol, flavones, and catechin were assessed in the Netherlands Cohort Study, and no association was observed with colon cancer [54]. In one meta-analysis, the data from 14 cohort studies were pooled and no associations were found for total fruit and vegetable intake, total fruit intake, or

total vegetable intake with colon cancer [55]. However, when analyzed by colon subsite and comparing total fruit and vegetable intake of 800 g/day or more versus less than 200 g/day, an inverse association was observed for distal colon cancer (RR (95% CI) 5 0.74 (0.57, 0.95), p-trend 5 0.02) but not for proximal colon cancer. For total fruits and total vegetables, similar sitespecific associations were observed [55]. The data were further examined for associations by intake of botanically defined food groups. There was a modest risk reduction associated with intake of Umbelliferae (i.e., Apiaceae, carrot or parsley family) but no additional associations for any other botanically defined food group such as cruciferous vegetables [55]. In another meta-analysis, assessments were made for high versus low, dose
response, and nonlinear reduction in colon cancer risk [56]. Inverse associations were observed when comparing high versus low intake of combined fruit and vegetables, high and low intake of fruit, and high and low intake of vegetables. However, none of the risk estimates were less than 0.90, suggesting a weak effect. Lastly, a meta-analysis of case
control and cohort studies was conducted to determine the relationship between soy intake and colorectal, colon, and rectal cancers [57]. There was no association for colorectal, colon, or rectal cancers when men and women were combined. When analyzing by gender, there was a 21% reduction in risk of colorectal cancer in women only; the authors did not indicate if this varied by subsite. In a 12-month randomized intervention trial, 50- to 80-year-old men diagnosed with adenomatous polyps supplemented their diets with soy protein containing isoflavones to assess the effect on colorectal epithelial proliferation, an intermediate end point biomarker for neoplasia [58]. There was no reduction in epithelial cell proliferation or the average height of proliferating cells in the cecum or sigmoid colon. In summary, the human data on fruit, vegetable, and legume intake reducing colon cancer risk are inconsistent. Plant foods contain thousands of bioactive constituents that may interact or counteract each other as normally consumed in whole foods and complex diet patterns. 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.

III MEAT A 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

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causes formation of heterocyclic aromatic amines (HAAs), which are known carcinogens in rodents [59]. However, the failure to detect differences in colon cancer risk between populations consuming well-done meat versus normal meat [60] has caused some to question the role of HAAs in human colon carcinogenesis. A second meat component is heme—present in myoglobin, hemoglobin, and various heme proteins—which is suggested to act as a colon cancer promoter by an uncertain mechanism [61]. Nitrite and N-nitroso compounds represent yet another class of compounds that are present in primarily certain processed meats (e.g., grilled bacon) and smoked fish and have been shown to be carcinogenic in animal studies [62]. Finally, animal sources of dietary fat, primarily saturated fat, are implicated as a risk factor in epidemiologic studies [63,64]. Why saturated fat may promote colon carcinogenesis remains uncertain. 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 [65], 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.

B Animal Studies A large number of animal studies on the effect of red meat on colon carcinogenesis have been conducted. These include studies in which the end points were either colonic tumors [66
68] or ACF [69] and in which either carcinogen-treated animals or genetic models [70] 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 [67,68,70]. For example, diets containing either 30 or 60% of freeze-dried beef, chicken, or bacon were fed to carcinogen-treated rats and ACF number was 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 [69]. Pence et al. [67] 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. After 27 weeks of feeding, total incidence and the number of tumors were lower in the beef-fed rats than in the casein-fed rats. To explain why animal studies do not support a promotional effect of red meat, whereas epidemiologic studies largely do (discussed later), Pierre et al. [71]

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proposed that high-calcium diets may protect against the promotional effect of red meat. This was based on observations that most rodent diets are relatively high in calcium, that heme added to the diets of rats promoted colonic epithelial proliferation [72], and that this heme-induced proliferation was inhibited by high calcium [73]. This hypothesis was examined in carcinogen-treated rats fed diets containing 60% beef in the context of either a low- or a high-calcium diet. A casein-based diet served as the control. Both ACF and mucin-depleted foci (MDF) were increased in the low-calcium 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 those of 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. Furthermore, a diet of 60% beef represents a concentration of beef in the diet well beyond what would be consumed by humans. However, this work suggests an important interaction between dietary red meat and calcium in terms of colon cancer risk that warrants further study.

C Human Studies In the 2007 WCRF/AICR report, 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 [20]. Additional studies have been published since the report; a meta-analysis of only prospective studies, including the additional studies published since the 2007 report, similarly concluded that red meat and processed meat (assessed separately) were both associated with increased risk of colon cancer [74]. However, some investigators critically reviewing the prospective epidemiologic data contradictorily conclude that the data show weak associations; lack a clear dose
response trend; vary by gender; and are susceptible to the colinearity of meat intake with other dietary and behavioral factors, which limits isolation of the independent effects of meat [75]. They also suggest that the lack of an established mechanism by which meat causes colon cancer underscores the insufficiency of the evidence for a positive association between meat intake and colon cancer risk. The 2007 WCRF/AICR report also concluded that there was insufficient evidence for the mechanism by

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which meats cause cancer. One group investigated potential mechanisms in a large prospective cohort [76]. Whereas heme iron was positively associated with colorectal and rectal cancer, it was not associated with colon cancer. For the highest quintile of intake of nitrate from processed meat compared to the lowest quintile, the hazard ratio (HR) and 95% CI were 1.13 (0.97, 1.32), p-trend 5 0.009 for colon cancer. An even higher elevated risk was observed for two HAAs: HR (95% CI) 5 1.26 (1.09, 1.45), p-trend , 0.001 for MeIQx, and HR (95% CI) 5 1.23 (1.10, 1.39), p-trend , 0.001 for DiMeIQx. In a meta-analysis that included five prospective cohort studies, a positive association was found for heme iron with colon cancer (summary RR (95% CI) 5 1.18 (1.06, 1.32)) [77]. 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). In addition, genetic polymorphisms, such as in genes involved in metabolism of HAA or DNA repair, could modify the risk related to a putative mechanism [78
80].

IV MILK AND DAIRY FOODS A Proposed Mechanisms for Influencing Cancer Risk A number of constituents in dairy foods have been investigated for their chemopreventive potential. Calcium and vitamin D have received the most attention. However, lipid components found in dairy fat, such as conjugated linoleic acid 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. [81], 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 [82] and thereby reduced the cytotoxicity of the fecal water [83]. Another potential mechanism involves the calcium sensing receptor, which is involved in controlling differentiation of colonic epithelial cells. 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)D3, the active form of vitamin D [84].

Because the active form of vitamin D functions as a steroid hormone, it is understandable that the proposed mechanisms of action of vitamin D would involve effects on gene expression, functioning as a transcription factor bound to the vitamin D receptor (VDR). Because many sporadic colon cancers show mutations in the adenomatous polyposis coli gene (Apc) [85], 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 that, through a complex series of events [86], leads to constitutive activation of target genes promoting proliferation of 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 [87], suggesting that 1,25(OH)D3 acts to modulate the WNT pathway. Conjugated linoleic acid (CLA) is a term for a group of isomers of linoleic acid that contain a conjugated double-bond system. Dairy products represent a major dietary source of CLA, with the two major forms being cis-9,trans-11 CLA and trans-10,cis-12 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 evidence that cis-9,trans-11 CLA decreases cyclooxygenase-2 expression in breast cancer cell lines [88]—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 [89,90]. 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 and, 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 [91]; supplementing the diet with sphingolipid increases apoptosis in the colonic epithelium in carcinogen-treated mice [92]. Thus, sphingolipidinduced changes in differentiation and apoptosis 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 [93], which are known carcinogens. A casein hydrolysate

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was shown to inhibit β-glucuronidase activity [94]. Decreased β-glucuronidase activity has the potential to reduce colon cancer risk because 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 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 cysteine. Feeding whey proteins to rats increases tissue levels of the cysteine-containing tripeptide glutathione [95]. This is significant for two reasons. First, glutathione is a potent intracellular antioxidant and can participate in the elimination of reactive oxygen species (ROS), either directly or as a co-substrate 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 co-substrate 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 [66], suggesting that increasing tissue glutathione may be chemopreventive.

B Animal Studies Tavan et al. [96] 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 [97], and partially hydrolyzed whey proteins reduce ACF number compared to casein-fed animals [98]. 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, the milk fat globule membrane, but not the anhydrous milk fat, reduced ACF number [99], pointing to the potential of sphingolipids as an important chemopreventive compound in milk. This is plausible because a number of animal studies have demonstrated that sphingolipids show chemopreventive effects [100]. A large number of animal studies have examined the potential for calcium to reduce tumorigenesis.

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A meta-analysis of studies through 2005 concluded that high-calcium diets reduced tumor incidence in carcinogen-treated animals (RR 5 0.91, p 5 0.03) [100]. 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) [101]. A relatively new animal model of colon carcinogenesis is the so-called “new Western diet,” 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 new Western diet resulted in intestinal tumor formation, primarily in the large intestine [102]. Using this model, 2 years of feeding the new Western diet with added calcium and vitamin D resulted in no colon tumors compared to 27% of mice fed the new Western diet [103]. Because 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 reported the influence of vitamin D, independent of calcium (i.e., when dietary calcium was adequate), on tumorigenesis or precancerous lesion. In rats given the directacting 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 [104]. 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 that of the control group, which was not administered 1,25-(OH)2-D3 [105]. In carcinogen-treated rats, administration of 1,25-(OH)2-D3 prior to administration of the carcinogen reduced tumor formation by 50% [106]. 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 animals fed 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 [107]. 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 dietary calcium. However, in a 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

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multiplicity compared to those of animals of the same species given a normal amount of vitamin D [108]. Thus, the results from animal studies are inconsistent and do not provide strong support for a chemopreventive effect of supplemental vitamin D.

C Human Studies Unlike animal studies, there have been several investigations of the effects of actual milk and other dairy items on colon cancer in humans, in addition to the effects of milk components. The most recent meta-analysis pooled data from 26 cohort studies and 34 case
control studies to examine the relationship between milk and dairy, calcium, and vitamin D intakes with colon cancer [109]. The summary RR (95% CI) for high milk intake was 0.78 (0.67, 0.92), and for high dairy intake it was 0.84 (0.75, 0.95). The same meta-analysis also showed that high intake of dietary/total calcium had a stronger protective effect on distal colon cancer versus proximal colon cancer. The association of dietary vitamin D with reduced risk was not statistically significant, but the authors speculated that this might be due to the relatively low levels of intake across the studies [109]. Other meta-analyses examining only vitamin D have been published since but with inconsistent results. A marginal nonsignificant risk reduction was reported with increased serum 25-hydroxyvitamin D (integrated measure of vitamin D from diet, supplements, and skin production) [110]. However, a meta-analysis showed an inverse association with 25hydroxyvitamin D status as well as supplemental vitamin D and total vitamin D [111]. Although Lee et al. [112] reported an inverse association between 25-hydroxyvitamin D and colorectal cancer, their meta-analysis also indicated that the association was stronger for rectal, not colon, cancer (OR for top vs. bottom quantile (95% CI) 5 0.50 (0.28, 0.88) for rectal and 0.77 (0.56, 1.07) for colon). In recent cohort studies on milk, an inverse association was observed in the Shanghai Women’s Health Study [113] and an inverse association was observed for adolescent and midlife intake in the NIH-AARP Diet and Health Study [114], but no association was observed in the Netherlands Cohort Study [115]. Although not conclusive, the evidence is somewhat consistent for a protective effect from milk and dairy and possibly calcium intake. The human data on vitamin D are not as consistent, and the relationship to colon cancer warrants further investigation.

V WHOLE GRAINS A Proposed Mechanisms for Influencing Cancer Risk Whole grains include a heterogeneous collection of cereals, 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 it 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 [116]. Another potential dietary fiber mechanism is the promotion of the growth of probiotic bacteria (e.g., bifidobacteria) by fructans (e.g., inulin). Although increasing probiotic bacteria in the colon by feeding prebiotics reduces colon cancer risk in animal models [117,118], it appears unlikely that humans consuming a normal cerealcontaining diet could consume a sufficient quantity of fructans to significantly increase the colonic bifidobacteria population [119]. 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

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in supplements, although a mixture of tocopherols shows some promise [120]. 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 [121] but is almost entirely bound within the cereal matrix [122] and therefore poorly available for absorption. Consistent with this is the finding in diabetic rats, which exhibit elevated levels of oxidative stress, that feeding cereal-based diets had no effect on markers of oxidative stress [123]. A number of other compounds found in cereals have been shown, in purified form, to reduce colon cancer risk, including phytic acid [124,125], sphingolipids [92], and lignans [126] (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.

B 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. [127] fed red and white flour, in both whole and refined forms, to mice given a chemical carcinogen. After 40 weeks, mice fed the wheat-containing diets did not differ from those fed the wheat-free control diet with regard to tumor incidence. Interestingly, however, mice fed the red wheat diets, regardless of refining state, had significantly lower tumor incidence than mice fed white flour, again regardless of refining state. In other words, it was wheat color, not the state of refinement, that influenced tumor incidence. 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 [128], although the number of ACF per animal was extremely small. 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 because whole grains differ from refined grains by the

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inclusion of both bran and germ in the whole grain. However, because germ represents only approximately 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 [129
137]. 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 [138]. 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 [136,139]. 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 [140]. 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 [141]. 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 [142]. 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 the bran of cereals other than wheat. Oat bran fed to carcinogentreated rats resulted in a greater number of colonic tumors in the proximal colon, but not the distal colon, compared to a fiber-free control [143]. In Min mice, however, oat bran feeding had no effect on the development of intestinal tumors [144]. Feeding rye bran to carcinogen-treated rats resulted in fewer colon tumors and fewer ACF compared to those in the cellulose-fed control group [145]. However, rye bran fed to Min mice resulted in either no effect [144,146] or an increase in intestinal tumors [147]. Barley bran was shown to reduce tumor incidence in carcinogen-treated rats compared to cellulose-fed control group [137], whereas corn bran increased colon tumor incidence in carcinogen-treated rats [132,148]. 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 [149], but it had no effect in carcinogen-treated rats [132].

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Thus, animal studies provide considerable support for protection against colon cancer by whole wheat, primarily based on studies of wheat bran. For other cereals, studies are highly inconsistent and are too few to ascertain whether the cereals have a chemopreventive effect or may even promote colon cancer.

C Human Studies According the 2007 WCRF/AICR report, the evidence for an association between whole grains and colon cancer is limited [20]. However, several encouraging studies showed that whole grain products reduce the risk of colon cancer [22,150
153], but in some instances the protective association was only observed in men [52,154]. Further evidence that grains may influence risk of colon cancer includes studies in which an increased risk was observed with intake of refined grains [155
157]. Using putative intermediary biomarkers of colorectal cancer, a few intervention trials have been conducted [158
161]. However, they typically used an isolated grain fraction such as the bran or fiber instead of actual whole grain foods, or they combined high intake of whole grain foods with other practices that may have an independent effect (e.g., low fat and high vegetable intakes) and thus make it difficult to assess effects attributable to whole grain intake.

VI BEVERAGES A Proposed Mechanisms for Influencing Cancer Risk Three types of non-nutritive 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 diterpenes (cafestol and kahweol) mitigate the genotoxicity of HAA [162
164], increase the activities of enzymes that generally detoxify carcinogens (UGTs and GSTs ), decrease the activity of some carcinogenactivating enzymes (N-acetyltransferase and SULTs), and decrease HAA-mediated genotoxicity [162
167]. In addition, cafestol and kahweol have antioxidant properties and induce γ-glutamylcysteine synthetase (the rate-limiting enzyme in glutathione synthesis) [168,169]. Human consumption of Italian-style coffee (or espresso) increases plasma glutathione and unfiltered French press coffee increases glutathione content in colorectal mucosa [170,171]. Moreover, coffee is rich in phenolic acids, flavonoids, and melanoidins, many of which have demonstrated antioxidant properties

that can depend on degree of roasting [172
174]. 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 [175
179]. Both green tea and black tea have also interested cancer prevention researchers. Theaflavin-2 (black tea polyphenol) exhibits anti-inflammatory and proapoptotic activities [180]. Green tea polyphenols inhibit proliferation and invasiveness of colon cancer cells [181], induce apoptosis and demonstrate antioxidant activity [11,16], modulate GST activity [16], and are anti-inflammatory [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 [20,182,183].

B Animal Studies Very few studies have examined the effect of coffee on colon cancer in animal models. Mori and Hirono [184] 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. In another study, 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 total) was examined in carcinogen-treated rats [185]. The authors reported no significant effect of the coffee on ACF number. However, 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 [186]. Because caffeine alone has been shown to increase tumor number and decrease longterm survival in rats treated with an HAA [187], 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

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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 [188]. However, in rats treated with azoxymethane as a carcinogen, the group fed black tea, but not green tea, had fewer adenomas [189]. There were also fewer cancers in the black tea group, but this reduction was not statistically significant. A second study using azoxymethane reported that green tea did not reduce the number of ACF [190]. Furthermore, Weisburger et al. [191] reported that extracts of black or green tea given to azoxymethane-treated rats had no influence on tumor development. 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 [192]. However, in a second study by the same investigators, white tea was found to promote the formation of colon tumors in rats administered an HAA [187]. 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. Few animal studies examining the effect of fermented beverages such as beer and wine have been performed. Feeding beer to carcinogen-treated rats led to a significant reduction in gastrointestinal tumor incidence but not colon tumor incidence [193]. This finding is consistent with those of two studies in 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 [194,195]. However, in another study, feeding freeze-dried beer, which contains no ethanol or the volatile components of beer, reduced ACF formation when fed in both initiation and promotion phases of carcinogenesis [196]. 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 [197]. Interestingly, in two subsequent studies by the same investigators, a polyphenolic extract of red wine reduced adenoma incidence in carcinogen-treated rats [198,199]. Given that the polyphenolic extract differs from wine, 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.

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C Human Studies Lee et al. [200] reported a protective association for coffee intake, particularly for invasive disease and in women (RR (95% CI) 5 0.44 (0.19, 1.04), p-trend 5 0.04), but not men, in the Japanese Public Health-based Prospective Study. A meta-analysis of 12 prospective studies resulted in somewhat similar assessments of the risk association: A “slight suggestion of an inverse association” was indicated for women (RR (95% CI) 5 0.79 (0.60, 1.04) when comparing the highest to the lowest intake group [201]. This is in contrast to a subsequent meta-analysis of prospective cohort studies that indicated no association [202]. For the highest coffee drinkers in a meta-analysis of 24 case
control studies, the OR (95% CI) 5 0.75 (0.64, 0.88), but the authors noted the association could reflect actual protection or be largely due to reverse causation [203]. Published the same year as the latter two meta-analyses, the findings of three cohort studies were inconsistent. No association was found for colorectal cancer in a Swedish cohort [204] and no association was found for colon cancer in a Dutch cohort [115], but in analysis by subsite and stage restricted to ever smokers, a statistically significant coffee
colon cancer association was observed for advanced disease in Singapore Chinese (p-trend 5 0.01) [205]. In the Singapore cohort, the HR (95% CI) was 0.56 (0.35, 0.90) for advanced colon cancer in drinkers of two or more cups per day compared with those who drank no coffee or less than one cup per day [205]. Perhaps subgroups of populations are more responsive to the effects of coffee, or perhaps another issue in clearly assessing the relationship between coffee and colon cancer is insufficient measurement of the method of coffee preparation or type of coffee. Instant, filtered, and percolated coffees have negligible amounts of cafestol and kahweol (paper filters significantly trap cafestal and kahweol) [206,207]; espresso has intermediate amounts; and Turkish, cafetie`re, and Scandinavian-type boiled coffees have large amounts [208]. The majority of studies on tea have primarily focused on green tea and have frequently indicated a protective effect, but an assessment of the evidence was deemed limited and inconclusive in the 2007 WCRF/AICR report [20]. For example, results of a meta-analysis published in 2006 indicated reduced risk of colon cancer with green tea intake based on case
control studies (OR (95% CI) 5 0.74 (0.60, 0.93)); however, results from cohort studies were compatible with the null hypothesis (OR (95% CI) 5 0.99 (0.79, 1.24)), leading the authors to conclude that there was insufficient data to indicate a protective effect from green tea [209]. In addition, they also found no association between black tea intake and colon cancer, regardless of

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study design. Studies since 2007 have more consistently reported a protective association. Examples include an inverse relationship reported between green tea intake and colon cancer (RR (95% CI) 5 0.66 (0.43, 1.01)) in a cohort of Chinese women [210]. 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) [211]. However, 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 [212]. Using urinary biomarkers of tea polyphenols, Yuan et al. [213] observed that in comparing the highest tertile of urinary epigallocatechin to undetected epigallocatechin, the OR (95% CI) 5 0.40 (0.19, 0.83), p-trend 5 0.002; 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. Lastly, in a cohort of Chinese men, green tea intake was associated with reduced risk of colon cancer in male non-smokers (HR (95% CI) 5 0.51 (0.28,0.93)) [214]. Alcohol is one of a few dietary exposures with some of the most convincing human evidence for increasing risk of colon cancer [20]. For instance, results of a metaanalysis of 16 cohort studies indicated that high intake of alcohol increased risk of colon cancer (RR (95% CI) 5 1.50 (1.25, 1.79)) when the highest intake group was compared to the lowest; this was equivalent to a 15% increased risk of colon cancer for an increase of 100 g of alcohol per week [215]. A subsequent metaanalysis sought to clarify the dose
risk relation of alcohol to colorectal cancer and found a positive association with more than one drink per day, and the association of alcohol drinking with colorectal cancer did not differ by colon and rectal subsites [216].

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, but effects from isolated wheat bran are supportive of a chemopreventive potential. Evidence in humans is limited with regard to whole grains but is generally encouraging of potential protection. Finally, with regard to non-nutritive 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. 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 [27]. A greater use of foods in animal and human studies is needed to move us closer to developing appropriate dietary recommendations regarding cancer prevention. In addition, there are relatively few feeding intervention trials in humans. Although of necessity they rely on intermediary markers of colon cancer, they could prove valuable in testing or confirming hypotheses and findings from population-based studies and animal studies [217]. Furthermore, future human studies may need to better account for genetic variation among individuals that can not only impact metabolism of carcinogens (as briefly mentioned previously) but also may impact tolerance, absorption, and metabolism of the putative chemopreventive constituents in the diet [218].

References VII SUMMARY With regard to fruit, vegetable, and legume intake, there is some indication 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. Whereas animal data are not supportive of meat increasing colon cancer risk, human studies are more consistent, although confirmation of the exact mechanism is lacking. Strong data from animal studies are supportive of a protective effect from calcium, but the animal data are

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