**2.1 Epidemiology**

Colorectal cancer is the third most commonly diagnosed cancer in males and the second in females, and it is the fourth common cause of death in males and third in females, according to a survey conducted in 2008 (Jemal et al., 2011) . The increasing rate of colorectal cancer is considered to be due to the combination of changes in dietary patterns, obesity and smoking (Jemal et al., 2011). Approximately only 5-10% of all colorectal cancers are a consequence of recognized hereditary conditions (Lynch & de la Chapelle, 2003). Since dietary habits play an important role in the incidence of colorectal cancer, this subject must be employed as one of the main strategies to investigate components derived from foods with cancer prevention properties.

It has been reported that dietary patterns are associated with the onset of colorectal cancer. The Mediterranean diet was associated with a reduced risk of recurrence of colorectal adenomas in woman. The Mediterranean diet is characterized by a high consumption of breads, vegetables, fruit, fish and olive oil (World Cancer Research Fund, 2007c, as cited in Cottet et al., 2005). The Japanese traditional diet is characterized by a high consumption of fish and seafood with a high salt content. Japanese cohort studies demonstrated that both the Japanese traditional diet and western diet were associated with an increased risk of colon cancer in women, but not in men (Kim et al., 2005). The 'Pork, processed meats and potatoes' diet was associated with an increased risk of colon cancer in women and also with rectal cancer in men. 'Pork, processed meats and potatoes' diet pattern was characterized as intakes of energy, protein carbohydrate, fat, saturated and monounsaturated fatty acids, cholesterol, B vitamins, and minerals (Dixon et al., 2004). Vegetarian diets might moderately reduce the risk of colon cancer, which is due to not only to no or low consumption of meat, but also to a high consumption of plant foods (Sanjoaquin et al., 2004; World Cancer Research Fund, 2007c), although there is a negative result of colorectal cancer prevention (Key et al., 1996).

#### **2.2 Adenoma-to-carcinoma sequence and pathology**

A genetic model for colorectal tumorigenesis has been proposed in the following procedures (Fearon & Vogelstein, 1990). 1) The mutation of APCTS gene transform normal colonic epithelia tissue to multiple polyps, 2) DNA hypomethylation is related to the onset and development of and early adenoma, 3) The K-*ras* oncogene play an important role in the progression from early to intermediate adenomas, 4) A mutation of the Thymidylate synthase gene plays an important role in the development from intermediate to late adenoma, 5) A mutation of TP53 gene is highly found in late adenomas and colorectal cancers (Tammariello & Milner, 2010) (Figure 1).

Oxidative stress, which provided by both exogenous (irradiation, chemicals, and drugs) and endogenous (O2 metabolism, immune response, and inflammation) origin, plays a critical

proven method of prevention. Avoiding body fatness, especially abdominal fatness, and the consumption of an excessive amount of alcohol are also important for colorectal cancer prevention (World Cancer Research Fund, 2007b). Despite the confirmation of cancer inducing foods, foods or nutritional elements that have protective qualities against

Colorectal cancer is the third most commonly diagnosed cancer in males and the second in females, and it is the fourth common cause of death in males and third in females, according to a survey conducted in 2008 (Jemal et al., 2011) . The increasing rate of colorectal cancer is considered to be due to the combination of changes in dietary patterns, obesity and smoking (Jemal et al., 2011). Approximately only 5-10% of all colorectal cancers are a consequence of recognized hereditary conditions (Lynch & de la Chapelle, 2003). Since dietary habits play an important role in the incidence of colorectal cancer, this subject must be employed as one of the main strategies to investigate components derived from foods with cancer prevention

It has been reported that dietary patterns are associated with the onset of colorectal cancer. The Mediterranean diet was associated with a reduced risk of recurrence of colorectal adenomas in woman. The Mediterranean diet is characterized by a high consumption of breads, vegetables, fruit, fish and olive oil (World Cancer Research Fund, 2007c, as cited in Cottet et al., 2005). The Japanese traditional diet is characterized by a high consumption of fish and seafood with a high salt content. Japanese cohort studies demonstrated that both the Japanese traditional diet and western diet were associated with an increased risk of colon cancer in women, but not in men (Kim et al., 2005). The 'Pork, processed meats and potatoes' diet was associated with an increased risk of colon cancer in women and also with rectal cancer in men. 'Pork, processed meats and potatoes' diet pattern was characterized as intakes of energy, protein carbohydrate, fat, saturated and monounsaturated fatty acids, cholesterol, B vitamins, and minerals (Dixon et al., 2004). Vegetarian diets might moderately reduce the risk of colon cancer, which is due to not only to no or low consumption of meat, but also to a high consumption of plant foods (Sanjoaquin et al., 2004; World Cancer Research Fund, 2007c), although there is a negative result of colorectal cancer prevention

A genetic model for colorectal tumorigenesis has been proposed in the following procedures (Fearon & Vogelstein, 1990). 1) The mutation of APCTS gene transform normal colonic epithelia tissue to multiple polyps, 2) DNA hypomethylation is related to the onset and development of and early adenoma, 3) The K-*ras* oncogene play an important role in the progression from early to intermediate adenomas, 4) A mutation of the Thymidylate synthase gene plays an important role in the development from intermediate to late adenoma, 5) A mutation of TP53 gene is highly found in late adenomas and colorectal

Oxidative stress, which provided by both exogenous (irradiation, chemicals, and drugs) and endogenous (O2 metabolism, immune response, and inflammation) origin, plays a critical

colorectal cancer have not yet been fully confirmed.

**2.2 Adenoma-to-carcinoma sequence and pathology** 

cancers (Tammariello & Milner, 2010) (Figure 1).

**2.1 Epidemiology** 

properties.

(Key et al., 1996).

Abbreviations: COX, cyclooxygenase; AA, arachidonic acid; VEGF vascular endothelial growth factor; Ca, calcium; CoQ10, coenzyme Q10

Fig. 1. Proposed anticarcinogenetic effects of nutrients on colorectal cancer. Selenium, folate, vitamin A and CoQ10 have been reported to repair damaged DNA. Vitamin D and n-3 fatty acid may suppress the COX-2 mediated carcinogenesis. Ca plays a diverse role, including the inhibition of *APC* mutation, suppression of β-catenin and binding to bile acid. Probiotics and/or prebiotics reduce colorectal cancer to modify the proportion of gut microflora.

role in DNA damage (Kryston et al., 2011). Reactive oxygen spices (ROS) and DNA interactions induce DNA damage, which causes mutation via either double-strand break (DSB) or non-DSB lesions (Sedelnikova et al., 2010). Carcinogenesis of oxidative stress also involve immune cell activation via CCL2/MCP-1, pro-inflammatory factor (Martin et al., 2011).

The methods of accurate measurement of oxidative stress have been brought by HPLC, tandem mass spectrometry (MS/MS) electrochemical detector (Cadet et al., 2010). There are also biomarkers to assess the level of oxidative stress, such as 8-oxo-2'deoxyguanosine (8 oxo-dG) (Ziech et al., 2010). These can allow us precise studies of anti-oxidative property by food.

Cyclooxygenase (COX) also plays an important role in carcinogenesis, e.g. to induce prostaglandin E2 (PGE2). PGE2 has diverse functions to promote cell proliferation, migration,

Colorectal Cancer and the Preventive Effects of Food Components 211

comprehensive series of recommendations on food, nutrition, and physical activity, for reducing cancer risk for all populations worldwide (World Cancer Research Fund, 2007b). The World Cancer Research Fund and the American Institute for Cancer Research judged that the evidence that physical activity protects against colorectal cancer was convincing, and the evidence that foods containing dietary fibre, garlic, milk and calcium protect against colorectal cancer was probable. On the other hand, the evidence that red meat, processed meat, alcoholic drinks for men, body fatness, abdominal fatness and adult attained height caused colorectal cancer was convincing, and the evidence that alcoholic drinks in women

Table 1 shows the positive and negative results on colorectal cancer protection of foods and

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.

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

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

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

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),

supplement did not reduce recurrent colorectal adenomas (Alberts et al., 2000).

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

caused this cancer was probable.

nutrition.

**2.4.1.1 Dietary fibre** 

cancer (Sanjoaquin et al., 2005).

**2.4.1.2 Garlic** 

Fund, 2007c).

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

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

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 cells.

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 et al., 2011).

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

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 mechanisms of food components on colorectal cancer prevention.

#### **2.4 Food, nutrition, physical activity and the prevention of cancer: a global perspective, 2007**

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 comprehensive series of recommendations on food, nutrition, and physical activity, for reducing cancer risk for all populations worldwide (World Cancer Research Fund, 2007b).

The World Cancer Research Fund and the American Institute for Cancer Research judged that the evidence that physical activity protects against colorectal cancer was convincing, and the evidence that foods containing dietary fibre, garlic, milk and calcium protect against colorectal cancer was probable. On the other hand, the evidence that red meat, processed meat, alcoholic drinks for men, body fatness, abdominal fatness and adult attained height caused colorectal cancer was convincing, and the evidence that alcoholic drinks in women caused this cancer was probable.

Table 1 shows the positive and negative results on colorectal cancer protection of foods and nutrition.
