**2.4.1 Foods judged to "probably" reduce the risk of colorectal cancer**

The 4 foods that affected the judgement that the evidence on the reduction of the risk of colorectal cancer was probable were food containing dietary fibre, garlic, milk and calcium.

#### **2.4.1.1 Dietary fibre**

210 Cancer Prevention – From Mechanisms to Translational Benefits

invasion and angiogenesis, and also to suppress immunity and apoptosis through inducing cyclin D1, Bcl-2 and vascular endothelial growth factor (VEGF) (Chan & Giovannucci, 2010). Figure 1 demonstrates the possible anti-tumor mechanisms of nutrients in the process of colorectal carcinogenesis (Janne & Mayer, 2000; Lamprecht & Lipkin, 2003; World Cancer

**2.3 Digestion, absorption, delivery and distribution, and the site of mechanisms of** 

For the clinical application of foods and nutrients for the prevention of colorectal cancer, we need to elucidate thoroughly how each food is digested, absorbed, delivered, and distributed to every organ or tissue, and determine what is the biologically active component, similar to the pharmacokinetics of drugs. Food constituents showed anti-tumor properties when they are distributed hematogenously to pre-cancer or cancer epithelial

We often find that there is a big gap in the effective concentration between *in vitro* and *in vivo* studies. It sometimes happens that *in vitro* studies need a much higher concentration to demonstrate significant anti-tumor effects, compared with the biological concentration. When the ingestion of a nutrient shows a cancer prevention effect in an *in vivo* study, this does not directly mean the nutrient affect will be imported into the cells, as it may change to another form after digestion and absorption. Each article of food includes a lot of constituents, so that various constituents may demonstrate additive action or synergetic effects. In addition, active constituents affect not only cancer epithelium cells, but also the cancer stromal environment, e.g. angiogenesis or the interaction between epithelial and stromal cells, since the paracrine interaction between epithelial and stroma cells affect each other for tumor progression (Ko et al., 2002; Adegboyega et al., 2004; Martinez-Outschoorn

For cancer prevention of the alimentary tract, active food components can have an effect not only hematogenously, but also from the gut lumen side. This indicates that indigestible constituents, as well as easily absorbed components, can function as potent anti-cancer agents against colorectal cancer. As mentioned above, resistant starches have cancer prevention properties as prebiotics that modify intestinal microorganism (Tuohy et al., 2005). Calcium may reduce the colorectal cancer risk associated with the combination to bile acid, the risk profile in intestinal lumen (Boursi & Arber, 2007). The effective site of food

Some of the blood levels of active components after the ingestion of foods have been reported, but those amounts in the gut or stool have been rarely reported. For colorectal cancer prevention in humans, we need to investigate the systemic function of food ingredients, how the food is digested, absorbed and remains in the gut, as well as the blood concentration and delivery in each organ. Further studies are necessary to illuminate the

The Food, Nutrition, Physical Activity and the Prevention of Cancer: a Global Perspective was produced by the World Cancer Research Fund and the AIRC, in order to generate a

components has been proposed in Figure 1 (Lamprecht & Lipkin, 2003).

mechanisms of food components on colorectal cancer prevention.

**2.4 Food, nutrition, physical activity and the prevention of cancer: a global** 

Research Fund, 2007a; Chan & Giovannucci, 2010; Vilar & Gruber, 2010).

**action** 

cells.

et al., 2011).

**perspective, 2007** 

Dietary fibre was associated with a reduced risk of colon cancer (Mastromarino et al., 1976). A meta-analysis of eight studies of dietary fibre estimated that the relative risk was 0.90 (95% confidence interval (CI) 0.84-0.97) per 10 g/day increment (World Cancer Research Fund, 2007c).

A few negative results have been demonstrated. There was no association shown between dietary fibre consumption and the onset of colorectal cancer or adenoma by a 16-year follow-up prospective study (Fuchs et al., 1999). In the paper, a higher consumption of vegetable fibre was even associated with an increased risk of colorectal cancer in women. There was another negative result shown for dietary fibre, i.e., a high-fibre cereal supplement did not reduce recurrent colorectal adenomas (Alberts et al., 2000).

The mechanisms of the action of dietary fibre are not clearly elucidated yet, but it has been suggested that it dilutes faecal contents, decrease transit time, and increase stool weight (World Cancer Research Fund, 2007c, as cited in Cummings, 1981). Short-chain fatty acids, like butyrate, are produced by the gut flora from dietary carbohydrates that reach the colon, induce apoptosis and cell cycle arrest, and promote differentiation (World Cancer Research Fund, 2007c). Dietary fibre intake is important for lipid and glucose metabolism or for acting as prebiotics on microflora health in preventing colonic cancer (Donini et al., 2009). The consumption of fibre is associated to the consumption of folate (World Cancer Research Fund, 2007c), which has also been reported to be associated with a reduced risk of colorectal cancer (Sanjoaquin et al., 2005).

#### **2.4.1.2 Garlic**

In the "Global Perspective", the World Cancer Research Fund and American Institute for Cancer Research judged that garlic probably protects against colorectal cancer (World Cancer Research Fund, 2007c). Ally sulphur, which is considered to be an effective component of garlic, inhibited colon tumors in animal studies. The biologically active compounds derived from garlic have been proposed as allicin, diallyl sulphide (DAS),

Colorectal Cancer and the Preventive Effects of Food Components 213

0.97 (0.92-1.03) per serving/day

0.81 (0.85-0.98) per serving/day

0.86 (0.75-1.00) for colorectal cancer 0.76 (0.63-0.91) for colon cancer

1.00 (0.90–1.11) per 2 servings/day

0.92 (0.79-1.06) van

0.88 (0.76-1.01) van

0.86 (0.78-0.95) per 10 μg/dl serum

0.96 (0.92-1.00) per serving/week

0.75 (0.64-0.89) Sanjoaquin et

0.95 (0.81-1.11) Sanjoaquin et

0.85 (0.55-1.32) vegetarians vs nonvegetarians

0.57 (0.34-0.97) Sanjoaquin et

World Cancer Research Fund, 2007c

World Cancer Research Fund, 2007c

Duijnhoven et al., 2009

World Cancer Research Fund, 2007c

Sanjoaquin et al., 2004

Duijnhoven et al., 2009

Duijnhoven et al., 2009

al., 2005

al., 2005

World Cancer Research Fund, 2007c

World Cancer Research Fund, 2007c

al., 2004

van

non-starchy vegetables and fruits

studies

studies

study

Conssumption of fruit was associated

Conssumption of fruit was associated

Consumption of fruit was associtated

cancer/cohort study

A high consumption of vegetable and

There is limited evidence suggesting that

colorectal cancer

Vegetarians diet was not significantly

cancer/cohort study

cancer/cohort study

the recuced risk of colorectal

recuced risk of colorectal

Selenium and foods containing selenium

with a reduced risk of colorecatl cancer/meta-analysis from 8 cohort

with a reduced risk of colorectal

with a reduced risk of colorecatl cancer in women/meta-analysis from 5 cohort

fruit was association with a reduced risk of colorectal and colon cancer/cohort

non-starchy vegetables protect against

associated with a reduced risk of colorectal cancer/cohort study

A high consumption of vegetable was not associated with recuded risk of rectal

A high consumption of fruit was not associated with recuded risk of colorectal

Dietary folate intake was associated with

cancer/meta-analysis of 7 cohort studies

Total folate intake was associated with a

cancer/metanalysis of 7 cohort studies

Dietary selenium was associated with a reduced risk of colorectal cancer/A meta-analysis from 5 case-control studies

Fish consumption was associated with a reduced risk of colorectal cancer/metaanalysis from 7 cohort studies

possitive

negative

Foods containing folate positive

positive

positive

negative

Table 1. (continued)

Fish


Table 1.

#### non-starchy vegetables and fruits

212 Cancer Prevention – From Mechanisms to Translational Benefits

**RR (95% CI) highest vs lowest exposure whcn it is not mentioned** 

0.90 (0.84-0.97) per 10g/day increment

0.77 (0.51-1.16) 0.68 (0.46-1.01)

0.94 (0.85-1.03) per serving/day

0.91 (0.85-0.94) per 200 g/day of milk

0.95 (0.92-0.98) per 200 mg/day

0.78 (0.69-0.88) for total calcium 0.86 (0.78-0.95) for calcium from food

sources

0.85 (0.78-0.94) Cho et al.,

0.95 (0.73-1.25) Fuchs et al.,

1.35 (1.05-1.72) Fuchs et al.,

0.88 (0.70-1.11) Alberts et al.,

**ref.** 

World Cancer Research Fund, 2007c

1999

1999

2000

World Cancer Research Fund, 2007c

World Cancer Research Fund, 2007c

2004

Aune et al., 2011

World Cancer Research Fund, 2007c

World Cancer Research Fund, 2007c, as cited in Samad et al., 2005

**Food and** 

positive

negative

garlic positive

milk positive

calcium positive

Table 1.

Foods containing dietary fibre

**nutrition Human studies** 

Dietary fibre was associated with a

from 8 studies

Dietary fibre was not associated with

follow-up cohort study

follow-up cohort study

adenomas/randomized trial

recurrent colorectal

Garlic intake was probably associated

Milk intake was associated with a

studies

cohort studies

reduced risk of recurrence of colorectal adenomas in woman /meta-analysis

colorectal cancer risk in women/16-year

Dietary supplement of wheat-bran fibre was not associated a reduced risk of

with a reduced risk of colon cancer/2 cohort studies and 6 case-control studies

reduced risk of colorectal cancer/metaanalysis from 4 cohort studies

Milk intake was associated with a reduced risk of colorectal cancer/metaanalysis from 10 cohort studies

Milk intake was associated with a reduced risk of colorectal cancer/metaanalysis from 19 cohort studies

Calcium supplementation was associtated with a reduced risk of adenomas/meta-analysis from 2 cohort

Total calcium intake and intake of calcium from food sources was was associtated with a reduced risk of colorectal cancer/meta-analysis from 10

Dietary fibre from vegetable was associated with an increased risk of colorectal cancer in women/16-year


Table 1. (continued)

Colorectal Cancer and the Preventive Effects of Food Components 215

Table 1. Positive and negative result of food and nutrition on colorectal cancer protection.

diallyl disulphide (DADS), diallyl trisulfide (DATS) and ajoene. DAS, DADS and S-allylcysteie (SAC) demonstrated the inhibitory effect on colon cancer in the rat (Shukla & Kalra, 2007).

In colon tumor cells, the induction of apoptosis, cell cycle modification and inhibition of tubulin polymerisation were suggested as the mechanism of the action of DATS, and the anti-proliferative effect, G2/M cell cycle arrest, decrease of polyamine biosynthesis, inhibition of histone deacetylase activity were suggested as the mechanisms of the actions of DADS (Filomeni et al., 2003; Shukla & Kalra, 2007). It also has been reported that garlic and its constituents inhibit DNA adduct formation, scavenge free radicals and modulate P-

A meta-analysis of "a global perspective" produced a summary effect estimate for relative risk of 0.94 (95% CI 0.850-1.03) per serving/day (World Cancer Research Fund, 2007c). An analysis of data obtained from 10 cohort studies demonstrated that higher milk intake (≧ 250 g/day) was related to a statistically significant reduced risk of colorectal cancer with relative risk 0.85 (95% CI 0.78-0.94) compared with the lowest intake (< 70 g/day) (Cho et al., 2004). According to the latest meta-analysis study, nineteen cohort studies concluded that the summary relative risk was 0.91 (95% CI 0.85-0.94) per 200 g/day of milk, and 0.83 (95% CI 0.78-0.88) per 400 g/day of total dairy products intake. There was no significant association between the consumption of cheese and a reduced risk (Aune et al., 2011).

Dietary milk fat globule membrane reduced the incidence of aberrant crypt foci in Fisher-

The cancer prevention effect of milk and dairy products is at least partly associated with the intake of calcium, which may bind to bile acids and ionized fatty acids to reduce cell

The main dietary sources of calcium in Europe and America are milk and dairy products. The meta-analysis estimate for the summary effect for colon cancer was 0.95 (95% CI 0.92- 0.98) per 200 mg/day of dietary calcium (World Cancer Research Fund, 2007c). Analysis from 10 cohort studies demonstrated that the total calcium had a greater correlation (relative risk 0.78; 95% CI 0.69-0.88) to colorectal cancer than calcium from food sources (relative risk 0.86; 95% CI 0.78-0.95) (World Cancer Research Fund, 2007c, as cited in Samad et al., 2005).

0.92 (0.81-1.05) for vitamin A 1.06 (0.95-1.18) for vitamin C 0.99 (0.89-1.11) for vitamin E

0.86 (0.71-1.04) for total carotenoids in men0.83 (0.67-1.04) for total carotenoids

in men

Park et al., 2010

Park et al., 2009

Vitamin A, vitamin C, and vitamin E

 A high consumption of carotenoid (except for β-carotene) was not associated with a reduced resk of colorecatl cancer/cohort study

Abbreviations: RR, relative risk; 95% CI, 95% confidence interval

glycoprotein-mediated multidrug resistance (Shukla & Kalra, 2007).

proliferation and promote cell differentiation (Aune et al., 2011).

**2.4.1.4 Calcium (supplemented at a dose of 1200 mg/day)** 

**2.4.1.3 Milk and other dairy products** 

344 rats (Snow et al., 2010).

intake from food only were not associated with colon cancer risk /pooled analysis of cohort studies


Table 1. (continued)

0.99 (0.97-1.00) per 100 IU/day

0.80 (0.71-0.90) for total vitamin C 0.82 (0.74-0.91) for total vitamin E

0.58 (0.42-0.80) for vitamin C 0.65 (0.48-0.89) for vitamin E 0.52 (0.38-0.71) for β-carotene 0.55 (0.39-0.77) for

0.50 (0.36-0.69) for

0.48 (0.35-0.67) for vitamin B6 0.59 (0.42-0.81) for vitamin B12

selenium

folate

0.88 (0.81-0.96) Park et al.,

0.55 (0.29-1.02) Williams et al.,

0.77 (0.763-0.95) Park et al.,

1.50 (1.04-2.16) Park et al.,

2010

2009

2009

Pot et al., 2009; Pot et al., 2010a; Pot et al., 2010b

World Cancer Research Fund, 2007c

Park et al., 2010

2010

2010

Williams et al.,

Consumption of salmon or cod was not

controlled study

Food containing vitamin D was

cohort studies

cohort studies

A high consumption of vitamin C and E

Multivitamin intake was associated with

analysis of cohort studies

A high intake of either dietary nutrients

A high intake of dietary selenium was

β-carotene intake was associated with a

lycopene intake was associated with an

men/cohort study

men/cohort study

coloredtal cancer in African Americans/case-control study

associated with a reduced risk of distal

reduced risk of colorectal cancer in

increased risk of rectal cancer in

Foods containing vitamin D

Vitamins (except vitamin D)

positive

positive

negative

Table 1. (continued)

associtated with local markers of inflammation, genotoxicity markers in colonocyte, and apoptotic and mitotic rate in colonic mucosa/randomized

associated with a reduced risk of colorectal cancer/meta-analysis from 9

from both food and supplements (total) was associated with a reduced risk of colon cancer risk/pooled analysis of

a reduced risk of colon cancer/pooled

(vitamin C, vitamin E, β-carotene, selenium, folate, vitamin B6, and vitamin B12) was associated a reduced the risk of

distal colorectal cancer in the caucasian/case-control study


Abbreviations: RR, relative risk; 95% CI, 95% confidence interval

Table 1. Positive and negative result of food and nutrition on colorectal cancer protection.

diallyl disulphide (DADS), diallyl trisulfide (DATS) and ajoene. DAS, DADS and S-allylcysteie (SAC) demonstrated the inhibitory effect on colon cancer in the rat (Shukla & Kalra, 2007).

In colon tumor cells, the induction of apoptosis, cell cycle modification and inhibition of tubulin polymerisation were suggested as the mechanism of the action of DATS, and the anti-proliferative effect, G2/M cell cycle arrest, decrease of polyamine biosynthesis, inhibition of histone deacetylase activity were suggested as the mechanisms of the actions of DADS (Filomeni et al., 2003; Shukla & Kalra, 2007). It also has been reported that garlic and its constituents inhibit DNA adduct formation, scavenge free radicals and modulate Pglycoprotein-mediated multidrug resistance (Shukla & Kalra, 2007).

#### **2.4.1.3 Milk and other dairy products**

A meta-analysis of "a global perspective" produced a summary effect estimate for relative risk of 0.94 (95% CI 0.850-1.03) per serving/day (World Cancer Research Fund, 2007c). An analysis of data obtained from 10 cohort studies demonstrated that higher milk intake (≧ 250 g/day) was related to a statistically significant reduced risk of colorectal cancer with relative risk 0.85 (95% CI 0.78-0.94) compared with the lowest intake (< 70 g/day) (Cho et al., 2004). According to the latest meta-analysis study, nineteen cohort studies concluded that the summary relative risk was 0.91 (95% CI 0.85-0.94) per 200 g/day of milk, and 0.83 (95% CI 0.78-0.88) per 400 g/day of total dairy products intake. There was no significant association between the consumption of cheese and a reduced risk (Aune et al., 2011).

Dietary milk fat globule membrane reduced the incidence of aberrant crypt foci in Fisher-344 rats (Snow et al., 2010).

The cancer prevention effect of milk and dairy products is at least partly associated with the intake of calcium, which may bind to bile acids and ionized fatty acids to reduce cell proliferation and promote cell differentiation (Aune et al., 2011).

#### **2.4.1.4 Calcium (supplemented at a dose of 1200 mg/day)**

The main dietary sources of calcium in Europe and America are milk and dairy products. The meta-analysis estimate for the summary effect for colon cancer was 0.95 (95% CI 0.92- 0.98) per 200 mg/day of dietary calcium (World Cancer Research Fund, 2007c). Analysis from 10 cohort studies demonstrated that the total calcium had a greater correlation (relative risk 0.78; 95% CI 0.69-0.88) to colorectal cancer than calcium from food sources (relative risk 0.86; 95% CI 0.78-0.95) (World Cancer Research Fund, 2007c, as cited in Samad et al., 2005).

Colorectal Cancer and the Preventive Effects of Food Components 217

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

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

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

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

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

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

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

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

gene-nutrient interactions (Prinz-Langenohl et al., 2001; Kim, 2003).

kinase C), and the activation of thioredoxin redactase (Combs, 2004).

consumption of meat (World Cancer Research Fund, 2007c).

**2.4.2.2 Foods containing folate and folate** 

in colon (Song et al., 2000).

(Ventrella-Lucente et al., 2010)

control diet.

**2.4.2.4 Fish** 

antioxidant properties (Ganther, 1999).

**2.4.2.3 Selenium and foods containing selenium** 

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

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