Diet and gastrointestinal carcinogenesis

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In 1981, Doll and Peto estimated that 35% of all cancer deaths may be attributable to diet and lifestyle factors (including exercise) [2]. More recently, Willett arrived at a similar estimate with narrower upper and

Table 7.1

Estimated New Cases of Gastrointestinal Cancers and Cancer Deaths in the US in 2005 [1]

Table 7.1

Estimated New Cases of Gastrointestinal Cancers and Cancer Deaths in the US in 2005 [1]

Cancer

New cases

Cancer deaths

Esophagus

14,520

13,570

Stomach

21,860

11,550

Small intestine

5,420

1,070

Colon

104,950

56, 290*

Rectum

40,340

*

Anal

3,990

620

Pancreas

32,180

31,800

Liver and intrahepatic Duct

17,550

15,420

Gallbladder and biliary

7,480

3,340

Other

5,210

2,400

Total

253,500

136,060

* Colon and rectal deaths combined Adapted from: American Cancer Society. Cancer Facts and Figures 2005. Atlanta; American Cancer Society:2005.

* Colon and rectal deaths combined Adapted from: American Cancer Society. Cancer Facts and Figures 2005. Atlanta; American Cancer Society:2005.

lower boundaries (20-42%) [3]. It is important to consider the mechanisms by which dietary factors may influence GI cancer risk. First, the process of cancer development usually occurs over decades and may occur in response to the synergistic effects of multiple factors. This makes it difficult to identify specific dietary causes of cancer, and also obscures the relevant mechanisms. Furthermore, it is rarely possible to determine a dietary cause for an individual cancer. Tables 7.2 and 7.3 summarize some of the dietary components implicated in GI carcinogenesis. Both in-vitro and in-vivo studies have been helpful in elucidating the mechanisms of dietary carcinogenesis.

In-vitro investigations are very important for understanding the biochemical and molecular interactions between diet and carcinogenesis. Mutations in oncogenes are crucial for the development of cancer, and in-vitro studies have shown how dietary components may play a role in the generation of such mutations; food-based substances may also protect against such alterations [4]. Animal models help to generate hypotheses concerning biological effects of foods and food-based substances on GI carcinogenesis. Furthermore, animal models may be used to test mechanisms of carcinogenesis and of cancer prevention. Animal systems allow the design of experiments that require strictly defined dietary interventions under tightly controlled circumstances. Species differences, however, make it impossible to directly extrapolate these data to humans.

Epidemiologic studies are the primary source of information regarding the effects of foods and dietary substances on cancer risk [5]. However, these studies cannot control for all confounding factors. Exposures to exogenous and endogenous carcinogens including radiation, physical agents, bacteria and viruses impact carcinogenesis and may further complicate analysis of epidemiologically derived data [6]. Although case-control and human dietary intervention studies provide more specific information, these studies are expensive and difficult to carry out. Interventional dietary trials require years to test narrow sets of nutritional hypotheses. It is also unknown if the effectiveness of individual nutrients relies on a critical exposure period or are tumor specific [7]. Because of methodological difficulties with all of the methods for assessing the impact of diet on cancer risk, results need to be approached with caution [5].

Observations regarding diet types are more reliable than those regarding specific foods or nutrients. This is highlighted by several unsuccessful intervention studies. Individual nutrients (i.e., beta-carotene, vitamin E and vitamin A) previously identified as protective through epidemiologic studies have been found to be ineffective or

Table 7.2

Dietary Components Implicated in the Development of Gastrointestinal

Cancer

Component

Relationship

Proposed mechanism

Alcohol Low "doses" (equivalent of 1-2 ounces of hard liquor): protective [12, 22]

Higher doses: increased risk [12]

Carbohydrate Overall: decreased [28];

Simple carbohydrates: increase risk [12, 19, 137, 138]

Red meat

Dietary fat

Fruits and vegetables

Solvent for tobacco carcinogens; acetaldehyde (principal metabolite of alcohol) is likely carcinogenic [25, 135]; related micronutrient deficiencies [14]; direct hepatocyte toxicity [136]; reaction with MTHFR and subsequent antagonization of DNA methylation pathways [41] Overall: association with lower fat intake [28]; Simple: leads to increases in IGF-1; association with high overall caloric intake [26]; associated with excess energy intake and decreased fruit and vegetable intake [12]; conversion of nitrate to nitrite [18, 19]; high glycemic load [32] Formation of carcinogenic heterocyclic amines and nitrosamines [20, 139]; excess salt used in cooking damages the gastric mucosa and causes gastritis [27, 28] Formation of carcinogenic heterocyclic amines [21] and oxidative stress; high dietary fat intake associated with high meat intake [12]; alteration of cell membranes and enzymes [41] Antioxidant, antiproliferative and anti-inflammatory constituents [12, 13, 142, 143]; bind bile acids; reduction of intestinal transit; increase in stool bulk [141]

Micronutrients Antioxidants: decreased [12]

Zinc: decreased [12, 16] Calcium: decreased [36-39]

Folate: conflicted [40, 142] Lycopene: decreased [144]

Selenium: decreased [41]

Green tea Decreased [12, 15, 34]

Antioxidants: modulation of endogenous antioxidant systems [8]; decreases the ability of H-pylori to cause inflammatory damage [23, 24];

Zinc: COX 2 overexpression [16];

Calcium: binds secondary bile acids and ionized fatty acids [36-38]; decreased colon epithelial hyperproliferation induced by bile and fatty acids [41];

Folate: modulation of DNA methylation [142];

Lycopene: inhibition of gap junction communication; activation of phase II enzymes; suppression of COX-2 synthesis; repression of IGF-1 GF activation [144];

Selenium: inhibition of prostaglandin E2 levels; enhancement of the peroxidation-inhibiting enzyme glutathione peroxidase; induction of apoptosis

Intracellular antioxidant; inhibition of procarcinogen formation; suppression of angiogenesis and cancer cell proliferation [15, 30]

even harmful when supplemented in human dietary trials [5, 8]. This may be due to the isolation of the nutrients from the whole food source, specific population characteristics or many other variables. Many healthful compounds are found in vegetables and fruits, and it is likely that these compounds work synergistically to exert a beneficial effect. There may be important, but unidentified components of whole foods that are not included in individual supplements. There is little

Table 7.3

Nutrients Implicated in Carcinogenesis by Site

Site

Protective

Carcinogenic

Esophagus Fruits and vegetables [12-14]

Gastric

Pancreatic Colorectal

Hepatic

Fruits and vegetables [12, 14, 27, 29]

Fruits and vegetables [12, 142, 143]

Fruits and vegetables [137, 141]

Calcium [36-39]

Folate [40]

Green tea [15]

Unknown

Alcohol [12, 14, 25, 135] Red meat [12, 20] Dietary fat [21] Alcohol [12, 22, 25] Red meat [27, 28] Red meat [139] Alcohol [41]

Alcohol [136]

evidence that dietary supplements can reproduce the benefits of a well-conceived, nutrient-rich diet.

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