**2.4.2.2 Foods containing folate and folate**

216 Cancer Prevention – From Mechanisms to Translational Benefits

On the other hand, there was a negative report regarding the chemoprevention effects of calcium, 2.5 g/kg calcium reduced the number of small intestinal tumors, but increased the

Calcium binds bile acids in the bowel lumen to inhibit their proliferative and carcinogenic effects, since bile acids might promote hyper-proliferation of the colorectal epithelium and carcinogenesis. Calcium may also act directly on the colonic epithelial cells to inhibit *ras* mutation (Bautista et al., 1997; Janne & Mayer, 2000). Extracellular dietary calcium is associated with the activation of calcium-sensing receptors in intestinal epithelial cells, and then the activation of intracellular signalling pathways, including proliferation,

Since there was not sufficient evidence to judge, the factors below were concluded as limited-suggestive; non-starchy vegetables (not including salted and/or pickled products), fruits, foods containing folate, foods containing selenium, fish, foods containing vitamin D,

It is quite complicated to investigate which nutrient has the most effective properties for colorectal cancer prevention, since non-starchy vegetables are a source of dietary fibre, carotenoids, folate, selenium, glucosinolates, and so on, and fruits are sources of vitamin C, carotenoids, phenols, flavonoids and other anti-oxidants. The results of the anti-cancer

Dietary cruciferous vegetable intake was associated with a reduced colon risk of approximately 25% (Marshall, 2008), There was an inverse association between the consumption of fruits and the risk of colorectal cancer, although the vegetarians showed a moderate, but non-significant, decrease in the risk (Sanjoaquin et al., 2004). A high consumption of vegetable and fruit showed an inverse association with colorectal and colon cancer, but not rectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). There was no significant inverse association shown between vegetable consumption or fruit consumption and colorectal, colon, or rectal cancer (Key et al., 2009;

Vegetable-fruit mixture intake did not decrease the number of colon polyps both in low in fat (20% of energy) and high in fat (40% of energy) in the *Apc*Min mice which are genetically

It has been reported that several fruits have a specific potency for cancer prevention. Apple is rich in quercetin (World Cancer Research Fund, 2007c). Apple juice also showed the potency of preventing colon carcinogenesis in mice, but this effect was not found under the cancer promoting conditions associated with obesity (Koch et al., 2009). On the other hand, Nandir et al. showed apple pomace increased the number and diameter of colon polyps in *Apc*Min mice (Mandir et al., 2008). Citrus fruits are sources of antioxidants, such as vitamin C, phenols, flavonoid and bioactive phytochemicals. Vitamin C traps free radicals and reactive oxygen species, and protects DNA from mutagenic damage (World Cancer Research Fund, 2007c). Cruciferous vegetables, such as broccoli, cabbage and cauliflower, reduced the colorectal cancer risk (Marshall, 2008), although there was also a negative report (Graham et al., 1988).

number of colon tumors (Huerta et al., 2003).

differentiation, and apoptosis (Lamprecht & Lipkin, 2001).

and selenium (supplements at the dose of 1200 mg/day).

predisposed to intestinal polyps (van Kranen et al., 1998).

effects of fruit and vegetable are heterogeneous.

**2.4.2.1 Fruit and vegetable** 

van Duijnhoven et al., 2009).

**2.4.2 Food judged to be "limited-suggestively" reduced cancer risk** 

According to the meta-analysis study, there was strong association between folate consumption and colorectal cancer risk in 7 cohort studies. Dietary folate showed a stronger association (relative risk for high vs. low intake = 0.75; 95% CI 0.64-0.89) than total folate (relative risk for high vs. low =0.95; 95% CI 0.81-1.11) (Sanjoaquin et al., 2005). Folate intake was strongly correlated with dietary fibre intake (World Cancer Research Fund, 2007c).

Animal studies also supported the cancer prevention properties of folate, however, intervention with exceptionally high doses of folate (2.0-5.0 g of folic acid/kg diet) after the formation of microscopic neoplastic foci may have promoted colorectal carcinogenesis (Kim, 2003). Folate reduced the number of small intestinal tumors in mice, although the timing of folate intervention was critical in preventive properties. In contrast, this effect was not found in colon (Song et al., 2000).

Folate deficiency has the potential to modulate DNA synthesis, DNA methylation, DNA damage and impaired DNA repair, increase mutagenesis, hyperproliferation, abnormal apoptosis, and methylenetetrahydrofolate reductase (MTHFR) polymorphisms and related gene-nutrient interactions (Prinz-Langenohl et al., 2001; Kim, 2003).

Under certain conditions, folate potentialy has an inverse effect on cancer prevention. In DNA polymerase β deficiency mice, folate deficiency provided protection against tumorigenesis, the induction of apoptosis, and the suppression of cell proliferation (Ventrella-Lucente et al., 2010)

### **2.4.2.3 Selenium and foods containing selenium**

A meta-analysis of "a global perspective" produced a summary effect estimate of 0.86 (95% CI 0.78-0.95) per 10 μg/dl serum, with high heterogeneity (World Cancer Research Fund, 2007c). Dietary selenium deficiency has been reported to cause a lack of selenoprotein expression, and some of these selenoproteins play important roles in anti-inflammatory and antioxidant properties (Ganther, 1999).

Selenium-enriched broccoli reduced the number of small intestinal tumors in multiple intestinal neoplasia mice (Davis et al., 2002). In the study, selenium-enriched diet for 10 weeks significantly increased the plasma concentration of selenium, and reduced small intestinal (46.3 ± 3.7 vs 65.6 ± 6.1) and large intestin (0.43 ± 3.7 vs 1.93 ± 6.1) tumors than control diet.

Several mechanisms have been suggested for the cancer preventiion effect of selenium, including the induction of apoptosis, cell cycle modulation (inhibition of cdk2 and protein kinase C), and the activation of thioredoxin redactase (Combs, 2004).

#### **2.4.2.4 Fish**

A meta-analysis of "a global perspective" produced a summary effect estimate of 0.96 (95% CI 0.92-1.00) per serving/week. A high consumption of fish is associated with low consumption of meat (World Cancer Research Fund, 2007c).

Increasing salmon or cod consumption for 6 months resulted in a lower concentration of the systemic inflammation marker C-reactive protein (CRP), but showed no effect on the local

Colorectal Cancer and the Preventive Effects of Food Components 219

A pooled analysis of cohort studies concluded that a high consumption of vitamin C and E from both food and supplements showed an inverse association with colon cancer risk, although there were some interactions with folate intake. Multivitamin intake also significantly decreases the risk of colon cancer. On the other hand, vitamin A, vitamin C, and vitamin E intake from food only were not associated with colon cancer risk (Park et al.,

In the Caucasian race, a high intake of each anti-oxidant nutrient (vitamin C, vitamin E, βcarotene, selenium) and DNA methylation-related nutrients (folate, vitamin B6, vitamin B12) reduced the risk of distal colorectal cancer, and only selenium showed a lower risk in African Americans. In this study, both intake from food only and total intake (food and

In colorectal cancer patients, the level of vitamin A, vitamin C, and vitamin E were reduced, and urinary 8-oxo-dG, a biomarker of DNA oxidation, was elevated (Obtulowicz et al.,

A high consumption of carotenoid did not reduce the risk of colorectal cancer, except for βcarotene intake among men, which showed an inverse association (relative risk 0.77, 95% CI 0.763-0.95). On the other hand, lycopene intake was significantly associated with an increase in the risk of rectal cancer among men (relative risk 1.50, 95% CI 1.04-2.16) (Park et al., 2009).

Avenanthraide (Avns) polyphenols from oats showed anti-proliferative effects independent of Cox-2 expression in COX-2 positive HT29, Caco-2 and LS174T cells, and COX-2 negative HCT116 cells. Avns may also reduce the colon cancer risk inhibiting PGE2 production

In animal studies, the oral administration of flavone (400mg/kg over 4 weeks) increased apoptosis and reduced the rate of aberrant crypt formation in mice. The down-regulation of the tricarboxylic acid cycle may be a part of the action mechanism (Winkelmann et al., 2010). In a human study, a case-control study of dietary flavonoid showed that flavonoid, especially quercetin, was significantly associated with a reduction in the colorectal cancer

In an SD rat study, Coenzyme Q10 reduced the number of APFs, possibly by modulating COX-2 and iNOS gene expression in colonic mucosa, and DNA damage in leukocytes (Kim

It has been reported that an increased consumption of n-3 fatty acid, Sulforaphane, Chafuroside, Curcumin and Dibenzoylmethane decreased the number of small intestinal tumors in *Apc*Min mice. On the other hand, there are a few reports on colonic tumor that showed that 31 g/kg of steridonic acid or 600 ppm of sulforaphane demonstrated an inhibitory effect on colonic tumors in *Apc*Min mice (Petrik et al., 2000; Shen et al., 2007).

Various mechanisms, such as DNA repair, proapoptosis, cell cycle modification, immunity promotion, and the mediation of chemomediators, have been proposed as the effects of

supplements) demonstrated cancer prevention potency (Williams et al., 2010).

**2.4.3.1 Vitamins (except vitamin D)** 

2010).

2010).

**2.4.3.2 Other dietary factors** 

risk (Kyle et al., 2010).

& Park, 2010).

derived from macrophage (Guo et al., 2010).

**2.5 The latest proposed action mechanisms** 

markers of inflammation in the colonic biopsies or feces, the genotoxicity markers in colonocyte, and apoptotic and mitotic rate in colonic mucosa (Pot et al., 2009; Pot et al., 2010a; Pot et al., 2010b).

An animal study showed that fish oil significantly reduced colon tumors (Rao et al., 2001). A diet including fish oil and pectin protects against colon cancer, compared with that of corn oil and cellulose azoxymethane, which induced colon cancer in model rats (Cho et al., 2011).

The preventive mechanisms of fish have been proposed to include the effects on gene expression, decreasing adhesion genes such as *B44galt1* at the initiation stage, lowering the expression of both cell promoters and suppressors at the aberrant crypt foci (ACF) stage, and increasing apoptosis inducing genes at the tumor stage. These modifications may be associated to the induction of apoptosis and the suppression of proliferation (Cho et al., 2011). Fish n-3 polyunsaturated fatty acids (PUFAs) may reduce eicosanoid biosynthesis derived from n-6 PUFA to protect tissue from inflammation, and inhibit COX-2 (Rao et al., 2001).

On the other hand, it has been reported that dietary fish oil containing docosahexaenoic acid (DHA) promotes inflammation through the modification of CD4+ and CD8+ T-cell populations in SMAD-/- mice and that chronic inflammation is the risk factor for colorectal cancer (Woodworth et al., 2010).

#### **2.4.2.5 Foods containing vitamin D**

A meta-analysis of "a global perspective" produced a summary effect estimate of 0.99 (95% CI 0.97-1.00) per 100 IU/day (World Cancer Research Fund, 2007c). Higher vitamin D levels are associated with a lower risk of colon cancer and overall mortality. UV exposure stimulates vitamin D production, but it may increase the risk of skin cancer. Therefore it is recommended that high-risk populations with a low level of vitamin D intake increase the consumption of fish, or take vitamin D supplements (Zeeb & Greinert, 2010).

Vitamin D induces differentiation, apoptosis and induces G1 phase arrest in intestinal cells. It also increases the absorption of calcium in the small and large intestine. Most of the pleiotropic, long-term actions of [1,25 (OH)2D3] are mediated by binding to vitamin D receptors (VDR), which are high-affinity receptors in the nucleus of cells. Activated VDR induces gene transcription, and VDR density in colonic mucosa was higher in hyperplastic polyps and in early stages of carcinogenesis, compared with normal mucosa (Lamprecht & Lipkin, 2001; Lamprecht & Lipkin, 2003; World Cancer Research Fund, 2007c).

#### **2.4.3 Limited-non conclusive and others**

There was not enough evidence for cancer prevention at the time of when "a grovel Perspective" was drawn up in 2007, so the following foods and nutrition were judged limited-non conclusive: Cereals (grains) and their products, potatoes, poultry, shellfish and other seafood, other dairy products, total fat, fatty acid, cholesterol, sugar (sucrose), coffee, tea, caffeine, total carbohydrate, starch, vitamin A, retinol, vitamin C, vitamin E, multivitamins, non-dairy sources of calcium, methionine, beta-carotene, alpha-carotene, lycopene, meal frequency, and energy intake.

Some of the latest research has demonstrated new knowledge, or confirmed the previous results.
