Before the twentieth century, colorectal cancer was relatively uncommon however the incidence has risen dramatically especially in the last fifty years. Several risk factors have been proposed including the adoption of westernized diet, obesity and physical inactivity (1,2). The majority of colorectal cancer continues to occur in industrialized countries. It has been estimated that nutrition could account for more than one third of cancer deaths (3), and that dietary factors are responsible for 70% to 90% of all cases. Therefore, diet optimization could potentially help reduce the incidence of this type of malignancy (4,5). Here we review the key evidence for the role of different dietary components and their effect on colorectal cancer prevention and progression.
Bibliographical searches were performed in Pubmed for the terms “diet and colorectal cancer”, “diet and colon cancer”, “diet and rectal cancer”, “nutrition and colorectal cancer”, “probiotics and colorectal cancer”, “prebiotics and colorectal cancer”, “alcohol and cancer” and “colorectal cancer epidemiology”. The search was performed for the period 1980-2012. As expected, the search yielded an overwhelming abundance of evidence on the association between diet and colorectal cancer. For each type of nutrient/chemical compound we excluded most in vitro and animal studies and the remaining results were categorized into different levels of evidence (6) focusing on meta-analyses, systematic reviews and randomized controlled trials where available. Information on ongoing clinical trials was sourced from the URL: http://clinicaltrials.gov/.
Red meat might be directly linked to the incidence of colorectal cancer or indirectly because diets high in meat may be deficient of other dietary components such as fibre and polyphenols from fruit and vegetables. Cooking meat at high temperatures may lead to the formation of mutagenic and carcinogenic heterocyclic amines through the interaction of muscle creatinine with amino acids (7) as well as the formation of N-nitroso compounds (8). Frying, grilling, broiling or cooking on coal can potentially induce these changes. Haem in meat can act as a nitrosating agent promoting the formation of N-nitroso compounds. Darker meats are more abundant in haem than white meats and therefore, high consumption of red meat (beef, pork, or lamb) could increase the risk of colorectal cancer (9-13). Haem iron has been positively associated in the literature with the development of colonic polyps (14), adenomas (15) and colorectal cancer (16-18). Other studies including the Nurses’ Health Study did not show such association (19-21). Furthermore, colorectal carcinogenesis could involve the secretion of insulin as a response to red and processed meats and thus subsequent activation of insulin and insulin growth factor-1 receptors, may lead to increased cell proliferation and reduced apoptosis (22).
The association of total or red meat cooked at high temperatures and increased risk of colorectal cancer has been shown in some case-control studies (23-25) but not in others (26). High consumption of red meat such as beef, pork, or lamb was associated with increased risk of colorectal cancer in both men and women in cohort studies (27,28). Data from the Health Professionals Follow-up study (HPFS) cohort showed a three-fold increase risk of colon cancer in subjects who consumed red meat more than five times in a week (29). Furthermore, it showed an increased risk of developing distal colon adenoma.
A meta-analysis from 2002 by Norat et al. showed a 33% increased risk of colorectal cancer in people consuming higher levels of red and processed meat (30). A systematic review of prospective studies by Sandhu et al. determined that an increase of 100 g in daily consumption of all meat or red meat was associated with a 12-17% increase in risk of colorectal cancer (31). However contrary to this, a prospective cohort study of 45,496 women by the National Cancer Institute (32), showed no association between consumption of red meat, processed meat, or well-cooked meat and colorectal cancer risk. Other studies have also been unable to support a role of fresh meat and dietary fat in the etiology of colon cancer (28,33).
In 2007, the research ‘Expert Report’ of the second world cancer research fund/American research concluded that intake of red and processed meat increases the risk of colorectal cancer (34), however, more recent reviews of prospective epidemiological studies found that there is not enough epidemiological evidence to link red and processed meat with colorectal cancer (35,36). A recent meta-analysis of prospective studies by Chan et al. concluded that processed and red meat is associated with increased risk of colorectal cancer, and a linear increase in risk was reported for intake of red and processed meats up to 140 g/day.
Fish and poultry are alternative sources of protein and have been shown to reduce the risk of colon cancer and adenoma (27,28,37-45). Possible mechanisms may involve more efficient methylation due to high methionine content in these foods or the presence of n-3 polyunsaturated fatty acids (PUFA), especially from oily fish.
In summary, performing studies on diet is complex with so many variables and confounding factors. Overall, there is evidence from both case-control and cohort studies that consumption of processed or red meat, especially when cooked at high temperatures by methods such as frying, grilling or broiling, is associated with increased risk of colorectal cancer. The dose-response relationship as well as the gender differences need to be investigated further. A determined diet might suggest limitation or avoidance of red or processed meats and support the consumption of white meat and fish.
Several case- control studies have demonstrated an increase in the risk of colorectal cancer with increased total energy intake (46-48). Dietary lipids provide a rich source of energy and diets high in lipids, especially animal fat, may increase the risk of colorectal cancer (49,50). In contrast to this, there are large cohort studies that do not support an effect of dietary fat on colon cancer (51,52). Different types of fats may play different roles in colorectal carcinogenesis via different mechanisms such as upregulation of apoptosis, inhibition of interleukin 1 and tumour necrosis factor -α synthesis, COX-2 inhibition and modulation of the redox enviroment in the colonocytes (53,54).
Saturated fats are principally found in animal products including red meat and dairy products, such as cheese and butter. Coconut oil, coconut milk, palm oil, and cocoa butter are all sources of plant-derived saturated fats. Case-control (55) and prospective cohort (27) studies demonstrated an increase in risk of colorectal cancer in people with higher consumption of saturated fat but confounding factors in the food matrix such as red meat and reduced intake of dietary fibre always pose a challenge for researchers.
A prospective study of 88,751 women confirmed that high intake of animal fat increases the risk of colon cancer and supports substitution of red meat as a source of protein with fish or chicken (27). The results of the Dietary Approaches to Stop Hypertension Diet (DASH) study of 130,000 participants found a 20% relative risk reduction in patients who consumed lower levels of animal fat (56). In a meta-analysis, Alexander et al. found no independent association between animal fat intake and the risk for colorectal cancer (33). The Women’s Health Initiative Dietary Modification Trial was a randomized controlled trial, which showed that low-fat dietary pattern did not reduce the incidence of invasive colorectal cancer (57).
The advice to reduce intake of saturated fat in order to reduce the risk of colorectal cancer remains only suggestive due to the lack of consistency from clinical studies.
Omega-3 (n-3) PUFA
Epidemiological studies and populations consuming large numbers of polyunsaturated fish oils have been found to have lower rates of colon cancer (58). This has led to the hypothesis that diets high in n-3 fatty acids may reduce the risk of colorectal cancer. An inverse association between n-3 PUFA (omega-3) and colorectal cancer has been shown in case-control (45,59,60) and prospective studies (61,62). On the contrary, Daniel et al. reported that one of the major dietary sources of omega-3 fatty acids, alpha-linolenic acid, was associated with increased risk of colorectal cancer in women and that omega-6 intake was inversely related to colorectal cancer risk in men (63). In their cohort, Sasazuki et al. found no evidence that omega-6 acids increased the risk.
Fatty fish are an excellent source of omega-3 fatty acids and vitamin D. Butler et al. showed that dietary marine n-3 PUFAs were positively associated with advanced colorectal cancer (64) while other studies suggested the opposite (39-42,62,65). A Chinese meta-analysis of prospective studies of nearly half a million individuals did not show any protective properties effect of n-3 fatty acids on colorectal cancer risk (66). A recent meta-analysis of case-control and prospective cohort studies suggested that fish consumption decreased the risk of colorectal cancer by 12%. However, the results showed a less profound effect on colonic as opposed to rectal cancers and highlighted differences between case-control and cohort studies (67). Omega-3 fatty acids may be taken as food supplements however there is very limited data available in association to colorectal cancer. Skeie et al. showed that cod-liver oil consumption lowers risk of death in patients with solid tumours without significant results on colorectal cancer risk (68). In fact, a systematic review of 20 prospective cohort studies found that dietary supplementation with omega-3 fatty acids is unlikely to prevent cancer (69).
The evidence to suggest that consumption of diets high in omega-3 PUFAs may prevent colorectal cancer is limited and in many cases contradictory. This includes not only n-3 fatty acids derived from fish but also from other sources such as α-Linolenic acid from food sources including rapeseed, soybeans, walnuts, flaxseed and olive oil. The evidence to suggest supplementation of omega-3 PUFAs with cod-liver oil is non-conclusive.
Dietary fibre, fruit and vegetable
The hypothesis that high fibre consumption may be reducing the risk of colorectal cancer has been postulated following the observation of the low incidence of colorectal cancer in African populations that consume a high-fiber diet (70). Fibre is defined as heterogeneous plant material composed of cellulose, hemicellulose and pectin. It has been proposed to work by reducing faecal transit times, diluting and binding carcinogens, altering the proliferation of gastrointestinal epithelium, maintaining colorectal epithelial cell integrity (71), adsorbing heterocyclic amines (72) affecting bile acid metabolism, and stimulating bacterial anaerobic fermentation to increase the production of short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate. SCFAs have been shown to decrease colonic pH and inhibit carcinogenesis (73).
Colorectal adenomas are the precursors of most colorectal cancers. The effect of diet in relation to colorectal adenomas and adenoma recurrence was explored in several studies. Diets high in wheat bran (74), fruit and vegetables (49,75), citrus fruits (19), cruciferous vegetables (76), dark-green vegetables and onions garlic (77) and tomatoes (23) may confer protection against colorectal adenomas and subsequently colorectal carcinoma. Some prospective studies did not show this association (74,75).
Early meta-analyses of case-control studies have generally shown a protective association between fibre and colorectal cancer (78,79). In one study, high fibre diet was associated with decreased survival (80). Cohort studies yielded mixed results often showing none or a weak inverse association between dietary fiber and risk of colorectal cancer (19,28,37,38). Data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and the Swedish mammography cohort study showed reduced risk of colorectal cancer and colorectal adenomas among people who consumed the highest amounts of fibre particularly from grains fruits and vegetable (81-85). However, in a meta-analysis of prospective studies, Park et al. suggested that high dietary fiber intake was actually not associated with a reduced risk of colorectal cancer (86). In a recent meta-analysis of prospective cohort and nested case-control studies of dietary fibre the authors suggest a 10% reduction in risk of colorectal cancer for each 10 g/day intake of total dietary fibre and cereal fibre (87). Whole grain was also associated inversely (87). Other studies, did not suggest a protective association with specific subtypes of fibre such as fruit, vegetable or cereal (27,88,89).
One can conclude that the evidence for fibre is unclear in terms of benefit in reducing colonic adenoma pathway and colorectal cancer formation. There are discrepancices between case-control and prospective cohort studies for reasons such as recall bias, selection bias and sample size. The general health benefits of fibre which may pertain to a variety of cancers as well as the other benefits to the colon such as diverticulosis and constipation suggests that a high fibre diet including wheat bran, cereal, whole grain, citrus fruits, cruciferous vegetables, dark-green vegetables, onions, garlic and tomatoes may be recommended.
Folic acid/folate (vitamin B9)
These are water-soluble vitamins found in fruits, dark green vegetables and dried beans. Humans are not able to synthesize this vitamin, which has to come from dietary sources. The bioavailability of folic acid is higher than folate because it is non-conjugated and hence more stable. Several mechanisms have been suggested for its role as a preventer of carcinogenesis through molecular mechanisms such as DNA synthesis, repair and methylation (90,91).
The observation that folic acid supplementation was associated with a substantial decrease in colon cancer among patients with ulcerative colitis led researchers to examine the role of folic acid in the prevention of colorectal cancer (92). Observational studies highlighted that deficiency of dietary folate correlates with increased occurrence of colorectal neoplasia (93) but may protect against cancer risk or adenoma formation only in those patients with low folate baseline (94). Examination of the data from the Nurses’ Health Study (NHS) and the HPFS, showed that high intake of dietary folate was inversely associated with risk of colorectal adenomas (95). A few years later, using data from the NHS cohort, the same group were able to show a considerably lower risk of colon cancer among women who used multivitamins containing 400 µg of folate (96). This was also confirmed in other populations such as the Cancer Prevention Study II cohort (97). A large scale meta-analysis of prospective studies supported the hypothesis that folate has a small protective effect against colorectal cancer (98). Manson et al. showed dietary folate supplementation maybe responsible for reduction of incidence of colorectal cancer in the US and Canada (99), however, Giovanucci et al. showed how dietary folate reduced risk of colorectal cancer or adenoma but not when folate came from supplements (100). Giovanucci suggested that folate supplementation could be associated with higher risk of adenoma recurrence and may even be harmful to patients with a previous history of colon cancer (100). A randomized secondary prevention trial reported that folate supplements increased the risk of recurrent advanced adenomas or recurrent adenomas (93).
In conclusion, diets rich in folate may prevent colorectal carcinoma. Further studies are required in order to assess the role of supplemented folate and the reported risks of adenoma recurrence.
The mechanism by which alcohol might be linked to carcinogenesis is unknown but proposed pathways include its ability to reduce folate (101), promote abnormal DNA methylation (102), delay DNA repair, alter the composition of bile salts or induce Cytochrome p450 to activate carcinogens (103).
A large number studies have suggested an association between alcohol intake and colonic adenoma as well as colorectal cancer risk (104-106). Intake of 30 grams of alcohol per day is associated with increased risk of colorectal cancer compared to low intake. Giovannucci et al. showed that men in HPFS cohort who drank more than two drinks of alcohol per day had a 2-fold higher risk of colon cancer (107) compared to men who drank fewer than 0.25 drinks per day. Heavy drinkers were found to have a higher risk of colorectal adenoma. Data from the NHS and EPIC cohorts (95,104) showed similar findings. A meta-analysis of five large cohort studies showed similar results for both men and women (108). This risk may be directly related to alcohol or to the effects of alcohol on folate levels. In fact, women with low serum folate levels who consumed large amounts of alcohol, had a greater risk of colorectal cancer (109). Two other studies found no association of total alcohol consumption with all-cause mortality in colorectal (110) and colon cancer (111) and Zell et al. reported a lower risk of all-cause mortality when subjects consumed wine regularly as opposed to infrequently (112). Consumption of red wine can be beneficial but the protective role could be allocated to polyphenols rather than its alcohol content (113).
In conclusion, currently the literature would suggest minimizing alcohol intake as a means to reduce the risk of developing colorectal cancer or colorectal adenoma. A consumption of less than 30 g per day as well as folate supplementation is recommended in people who consume alcohol regularly.
Calcium and vitamin D
Vitamin D is one of the fat-soluble vitamins and more than 90% is synthesized endogenously from skin exposure to UV sunlight (114). The remaining comes from the diet as pro-vitamin cholecalciferol (D3), which is found naturally in oily saltwater fish, egg yolks and livers and from the plant-derived pro-vitamin ergocalciferol (D2) found in foods such as mushrooms. Food fortification may provide an extra source of vitamin D. The active form of vitamin D is 1,25-dihydroxyvitamin D3 (Calcitriol) which is formed by hydroxylating the pro-vitamins in the liver and kidneys. The use of Calcitriol in experimental studies has been shown to induce differentiation and inhibition of tumour cell proliferation of various types of cancer cells, however, its use is limited due to development of toxic hypercalcaemia. For this reasons, calcitriol analogues are usually used (115,116). Vitamin D and calcium are thought to exert their protective effects by decreasing cell proliferation, inhibiting angiogenesis, stimulating apoptosis and promoting cell differentiation (117). Other proposed mechanisms may involve binding of calcium to bile acids and ionized fatty acids to form insoluble soaps in the lumen of the colon (118,119).
Garland et al. proposed that lower levels of vitamin D could account for the increase in mortality from colon cancer in higher latitudes (120) and epidemiological studies showed that deaths from colorectal cancer have been found to be higher in areas with less sunlight (121). Populations consuming higher amounts of fresh fish, shellfish, calcium and vitamin D have lower incidence of colorectal cancer (122) and may even have the lowest incidence of both colon and rectal cancer in Europe and North America (123).
Data from case-control studies are inconsistent. The protective effects of calcium alone were demonstrated in some case-control studies (124) but not in others (125). Case-control studies involving only women showed reduced risk of colorectal cancer (126,127). This was not demonstrated in studies involving both men and women (128). No significant inverse association was observed between calcium and vitamin D levels and the risk of colorectal cancer (125,128). The Women’s health initiative study was a randomized controlled trial, which showed that daily supplementation of calcium with vitamin D for seven years, had no effect on the incidence of colorectal cancer among postmenopausal women (129). In terms of Vitamin D levels, a meta-analysis by Garland et al. found an inverse association between circulating levels of 25- hydroxyvitamin D3 and the risk of colorectal cancer (130).
Calcium was found to have protective effect on colorectal cancer risk in some prospective studies (131-133) but not in others (134,135). Data from the HPFS and NHS cohorts showed that total, dietary and supplemented calcium reduced the risk of distal colon but not proximal cancer. Most of the risk reduction was achieved by calcium intake of 700-800 mg/day. A meta analysis of 10 cohort studies showed 22% reduction in the risk of colorectal cancer in those with higher intake of calcium (136).
Regarding colorectal polyps, a three-year intervention study with calcium and antioxidants, found no effect on polyp growth but possibly a protective role against adenoma formation (137). Higher intake of calcium alone (138) or when combined with Vitamin D (139) was found to be protective against adenoma recurrence.
In conclusion, data from case-control studies are inconsistent but cohort studies and meta-analyses provide evidence on the benefits of circulating, diet-derived and supplemented vitamin D and calcium. Further studies are needed to ascertain whether there is any sex predilection. On the basis of current evidence one could suggest intake of vitamin D at a dose of 1,000 IU per day which is regarded as safe, and attaining calcium intakes of 700-800 mg per day. Modest duration of sunlight exposure should be sought to raise levels of 25-hydroxyvitamin D3. Diets rich in oily fish, shellfish, milk and dairy products contain high amounts of calcium and vitamin D.
Polyphenols are a class of chemicals known for their numerous benefits especially their antioxidant effects (113,140,141), inhibition of cellular proliferation (142), induction of cell cycle arrest (143), interaction with apoptotic pathways and antiangiogenic and antimetastatic properties (144). They are divided in five classes; flavonoids, phenolic acids, ligans, stillbenes and others. The most important dietary sources of polyphenols are fruits, vegetables, seeds, and beverages such as fruit juice, green tea, coffee, cocoa drinks, red wine, and beer. The chemoprotective role of polyphenols against cancer has been extensively studied. Evidence from case-control studies (145), cell culture and animal studies have shown a protective role against colorectal malignancy (145,146).
This polyphenol is a curcuminoid found in turmeric spice that has antioxidant, anti-inflammatory and anti-tumour properties (147,148). Curcumin has been shown to work by inhibiting cell invasion (149) and by having anti-inflammatory properties (150). It has been shown to reduce the number and size of ileal and rectal adenomas in patients with familial adenomatous polyposis (151).
Apigenin is a flavonoid found in parsley and celery and it has been shown to inhibit colonic carcinogenesis by inducing apoptosis in animal models (152). Cyanidin, a flavonoid in strawberries and cherries has been studied in vitro and in animal models and has also been shown to inhibit colonic carcninogenesis (153). Other flavonoids with similar properties include Delphinidin which is found in dark fruit (154) and Genistein which is abundant in Soy beans (155). Quercetin from onions, broccoli and apples has been shown to decrease cell growth by interacting with β-catenin (156) and by induction of apoptosis (157). Citrus fruits contain high levels 5-hydroxy-6,7,8,4'-tetramethoxyflavone and Naringenin which has been shown to induce apoptosis and cell-cycle arrest of luminal surface colonocytes (158,159).
Green tea is rich in a type of Flavonoids, the Flavonols. Examples include Catechin and Epicatechin. Epigallocatechin-3-gallate (EGCG) is the most abundant Catechin in green tea. The benefits have not only been shown in vitro and animal models (113,160-163) but also in large population studies. Consumption of green tea has been associated with a 40% reduction in colorectal cancer risk in a cohort of 69,710 Chinese women (163).
Coffee is a complex blend of hundred of chemicals including anti-oxidants, mutagenic, and anti-mutagenic compounds (164). Additionally, it has been shown to affect gastrointestinal physiology such as stimulating a motor response of the distal colon, reducing faecal transit times and reducing the gut’s exposure to potentially carcinogenic faecal load (165). Over the last few decades the relationship between coffee and colorectal cancer has been extensively explored (166,167). Outcomes from clinical studies have been inconsistent and no firm guidance has been suggested. Several meta-analyses of cohort and case-control studies found that substantial consumption of coffee is associated with lower risk of colorectal cancer (168-170). Other meta-analyses failed to reconfirm this inverse association (171). Li et al. examined the results of 25 case-control studies and 16 cohort studies in the most recent meta-analysis of the literature. Subgroup analysis of case-control results found a significant decrease in cancer risk, especially in Europe and for females. A subgroup analysis of cohort studies, showed a lower risk of colon cancer in Asian women only (172).
There are inconsistencies between case-control and prospective studies as well as noted differences between sex and race. Consumption of coffee maybe protective against colorectal cancer but further studies are required to establish a dose-risk relationship and further clarify whether there is any sex predilection in the risk.
These molecules are smaller in size than polyphenols. Examples include Resveratol which is found in the skin of grapes and red wine and has been shown to inhibit metastasis by reducing hypoxia inducible factor-1α and MMP-9 expression in colonocytes (173) as well as inhibiting Wnt signalling and β-catenin localisation (174).
Carotenoids are naturally occuring pigments some of which can be converted by the body into vitamin A. Examples include β-carotene which is found in carrots, red palm oil and pumkin. Lycopene is another example of pigmented phytochemical found in tomatoes, watermelons, papaya, apricots and citrus fruit. They have been found to exhibit anti-oxidant, anti-proliferative and anti-inflammatory properties (175-177).
These are Sulphur-containing phytochemicals found in abundance in cabbage, turnips, broccoli, kale, cauliflower, watercress, brussel sprouts, mustard seeds and horseradish. They have been found to possess chemopreventative activity (178-180) against colonic cancer.
Overall, diets high in polyphenols and other phytochemicals such as carotenoids, isothiocyanates and natural phenols have been shown to be protective against colorectal cancer. Foods rich in these compounds includes spices such as mustard seeds and tumeric, fruits including strawberries, cherries, apples, citrus fruit, grapes, watermelons, papaya, apricot and vegetables such as onions, brocolli, carrots, red palm oil, pumkin, leafy green vegetables and tomatoes. Consumption of green tea may also be beneficial.
Animal models have shown that low zinc levels may be associated with preneoplastic lesions and colonic carcinogenesis (181). In vitro studies suggested that Zinc supplementation may positively influence tumour cell response to anticancer drugs by altering colonic cancer cell gene expression (182). In the Iowa Women’s Health Study, intake of dietary zinc was associated with a decreased risk of both proximal and distal colon cancer (18). A more recent prospective study by Zhang et al. did not find a role for Zinc intake with colorectal cancer risk but the authors highlighted a possible inverse association between dietary zinc and rectal cancer in women (183). Therefore, no substantive evidence is available for dietary Zinc intake however the putative inverse association in women needs to be explored further.
An inverse association between Selenium supplementation and the risk of colorectal cancer was observed in several studies (184-189). Selenium supplementation by way of brewer’s yeast supplementation was associated with up to 50% reduction in the incidence of colorectal cancer (188,190). Other studies contradict these findings and show no significant associations (191-192). Therefore, studies do not currently provide evidence for Selenium supplementation.
The colon contains more bioactive cells than the rest of the body (193). Inulin-type fructants are oligosaccharides obtained through diet and 90% of them are effectively metabolized by endogenous colonic microbiota into gases and organic acids including short chain fatty acids (SCFAs) (194). Animal-model experiments showed that these oligofructants can reduce the numbers of aberrant crypt foci (195) and influence the activity of natural killer cells and production of IL-10 (196). Naturally-occurring oligofructants can be found in foods such as onions, Jerusalem artichokes, garlic, asparagus and chicory. Examples of SCFAs include acetic and butyric acid. SCFAs have been shown to reduce tumourgenesis (197) and proposed mechanisms include promotion of the growth of probiotic Lactobacilli species which maintain epithelial health and downregulate the inflammatory response (198). As Bifidobacteria and Lactobacilli are selectively stimulated to grow, this may happen at the expense of pathogenic bacteria (199). Other benefits of microbiota include synthesis of vitamins such as folate (200). In human trials synbiotics were found to decrease DNA damage in colonic mucosa and lower the level of colonic proliferation (201). Low proliferation is a recognized marker of low colonic cancer risk (202).
Other components in our diet may affect the gut microbiota and influence colorectal oncogenesis. Gut microbiota hydrolyse polyphenols to a great extend affecting the amount of these chemicals being absorbed, thus, ameliorating their protective properties. Excess fat in the diet means that more bile will be produced and more bile acids will escape the enterohepatic circulation. In the colon, these can be metabolized to mutagenic components (203). High butyrate levels are known to protect against the mutagenic effects of bile acids (204). Moreover, Lactobacilli have been shown to directly reduce the mutagenic properties in bile acids (205). As mentioned above, meat cooked at high temperatures contains high levels of heterocyclic amines which have been found to be fermented by gut microbiota. The byproducts of this process can damage DNA and increase the risk of colorectal cancer (206).
There is a completed Phase 2 trial assessing the role of probiotics on gut microbiotca and colorectal cancer but the results have not been published yet (207). The role of VSL#3 probiotics in rectal cancer is investigated in a phase 3 clinical trial but results are also awaited (208). Currently there is no strong evidence regarding prebiotics and colorectal cancer risk.
Overall, the role of probiotics and prebiotics is not completely clear but in vitro and in vivo studies have highlighted a possible protective role of gut microbiota in colorectal carcinogenesis. There appears to be benefit from a diet high in oligofructant-containing foods including onions, jerusalem artichokes, garlic, asparagus and chicory.
Apart from alcohol and smoking (38), other lifestyle factors have also been associated with the risk of developing colorectal cancer. Higher levels of physical activity have been reported to reduce risk by up to 40% and several studies have reported adverse outcomes in patients who are obese (209-211), suffer from diabetes (209,212) or use the oral contraceptive pill (213). Non-modifiable factors which may increase the risk include higher body height (38,214), post-menopausal status (213,215) and endogenous oestrogen exposure (215).
There is an abundance of evidence in the literature on the role of nutrition on colorectal carcinogenesis. Often the evidence may be inconclusive due to the lack of randomized trials and because many studies have been overwhelmed by confounding factors such as smoking status, physical activity, obesity and diabetes. Many studies were influenced by possible recall and selection biases, which make it difficult to draw solid conclusions. In this review, we set out to identify nutritional factors that could play a role in the development of colorectal cancer. Red or processed meats especially when cooked at high temperatures should be limited and can be replaced by the consumption of white meat and fish. Diets high in n-3 fatty acids, dietary fibre, folate, vitamin D, calcium and polyphenols may protect against colorectal cancer and colorectal adenoma formation. The consumption of alcohol is not advocated. The role of probiotics and prebiotics is not completely clear but in vitro and in vivo studies have highlighted a possible protective role of gut microbiota in colorectal carcinogenesis.
Disclosure: The authors declare no conflict of interest.
- Wiseman M. The second World Cancer Research Fund/American Institute for Cancer Research expert report. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Proc Nutr Soc 2008;67:253-6. [PubMed]
- Center MM, Jemal A, Ward E. International trends in colorectal cancer incidence rates. Cancer Epidemiol Biomarkers Prev 2009;18:1688-94. [PubMed]
- Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst 1981;66:1191-308. [PubMed]
- Ahmed FE. Effect of diet, life style, and other environmental/chemopreventive factors on colorectal cancer development, and assessment of the risks. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 2004;22:91-147. [PubMed]
- Shannon J, White E, Shattuck AL, et al. Relationship of food groups and water intake to colon cancer risk. Cancer Epidemiol Biomarkers Prev 1996;5:495-502. [PubMed]
- Phillips B, Ball C, Sackett D, et al. since November 1998. Updated by Jeremy Howick March 2009. Available online: http://www.cebm.net/index.aspx?o=1025
- Sugimura T, Wakabayashi K, Nakagama H, et al. Heterocyclic amines: Mutagens/carcinogens produced during cooking of meat and fish. Cancer Sci 2004;95:290-9. [PubMed]
- Cross AJ, Sinha R. Meat-related mutagens/carcinogens in the etiology of colorectal cancer. Environ Mol Mutagen 2004;44:44-55. [PubMed]
- Bonnett R, Holleyhead R, Johnson BL, et al. Reaction of acidified nitrite solutions with peptide derivatives: evidence for nitrosamine and thionitrite formation from 15N N.m.r. studies. J Chem Soc Perkin 1 1975;(22):2261-41.
- Wade RS, Castro CE. Redox reactivity of iron(III) porphyrins and heme proteins with nitric oxide. Nitrosyl transfer to carbon, oxygen, nitrogen, and sulfur. Chem Res Toxicol 1990;3:289-91. [PubMed]
- Lakshmi VM, Nauseef WM, Zenser TV. Myeloperoxidase potentiates nitric oxide-mediated nitrosation. J Biol Chem 2005;280:1746-53. [PubMed]
- Rao CV. Nitric oxide signaling in colon cancer chemoprevention. Mutat Res 2004;555:107-19. [PubMed]
- Kuhnle GG, Bingham SA. Dietary meat, endogenous nitrosation and colorectal cancer. Biochem Soc Trans 2007;35:1355-7. [PubMed]
- Bird CL, Witte JS, Swendseid ME, et al. Plasma ferritin, iron intake, and the risk of colorectal polyps. Am J Epidemiol 1996;144:34-41. [PubMed]
- Nelson RL, Davis FG, Sutter E, et al. Body iron stores and risk of colonic neoplasia. J Natl Cancer Inst 1994;86:455-60. [PubMed]
- Shaheen NJ, Silverman LM, Keku T, et al. Association between hemochromatosis (HFE) gene mutation carrier status and the risk of colon cancer. J Natl Cancer Inst 2003;95:154-9. [PubMed]
- Wurzelmann JI, Silver A, Schreinemachers DM, et al. Iron intake and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev 1996;5:503-7. [PubMed]
- Lee DH, Anderson KE, Harnack LJ, et al. Heme iron, zinc, alcohol consumption, and colon cancer: Iowa Women’s Health Study. J Natl Cancer Inst 2004;96:403-7. [PubMed]
- Michels KB, Giovannucci E, Chan AT, et al. Fruit and vegetable consumption and colorectal adenomas in the Nurses’ Health Study. Cancer Res 2006;66:3942-53. [PubMed]
- Tseng M, Greenberg ER, Sandler RS, et al. Serum ferritin concentration and recurrence of colorectal adenoma. Cancer Epidemiol Biomarkers Prev 2000;9:625-30. [PubMed]
- Tseng M, Sandler RS, Greenberg ER, et al. Dietary iron and recurrence of colorectal adenomas. Cancer Epidemiol Biomarkers Prev 1997;6:1029-32. [PubMed]
- Giovannucci E. Insulin and colon cancer. Cancer Causes Control 1995;6:164-79. [PubMed]
- Bidoli E, Franceschi S, Talamini R, et al. Food consumption and cancer of the colon and rectum in north-eastern Italy. Int J Cancer 1992;50:223-9. [PubMed]
- Probst-Hensch NM, Sinha R, Longnecker MP, et al. Meat preparation and colorectal adenomas in a large sigmoidoscopy-based case-control study in California (United States). Cancer Causes Control 1997;8:175-83. [PubMed]
- Sinha R, Chow WH, Kulldorff M, et al. Well-done, grilled red meat increases the risk of colorectal adenomas. Cancer Res 1999;59:4320-4. [PubMed]
- Navarro A, Díaz MP, Muñoz SE, et al. Characterization of meat consumption and risk of colorectal cancer in Cordoba, Argentina. Nutrition 2003;19:7-10. [PubMed]
- Willett WC, Stampfer MJ, Colditz GA, et al. Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N Engl J Med 1990;323:1664-72. [PubMed]
- Goldbohm RA, van den Brandt PA, van’t Veer P, et al. A prospective cohort study on the relation between meat consumption and the risk of colon cancer. Cancer Res 1994;54:718-23. [PubMed]
- Young TB, Wolf DA. Case-control study of proximal and distal colon cancer and diet in Wisconsin. Int J Cancer 1988;42:167-75. [PubMed]
- Norat T, Lukanova A, Ferrari P, et al. Meat consumption and colorectal cancer risk: dose-response meta-analysis of epidemiological studies. Int J Cancer 2002;98:241-56. [PubMed]
- Sandhu MS, White IR, McPherson K. Systematic review of the prospective cohort studies on meat consumption and colorectal cancer risk: a meta-analytical approach. Cancer Epidemiol Biomarkers Prev 2001;10:439-46. [PubMed]
- Flood A, Velie EM, Sinha R, et al. Meat, fat, and their subtypes as risk factors for colorectal cancer in a prospective cohort of women. Am J Epidemiol 2003;158:59-68. [PubMed]
- Alexander DD, Cushing CA, Lowe KA, et al. Meta-analysis of animal fat or animal protein intake and colorectal cancer. Am J Clin Nutr 2009;89:1402-9. [PubMed]
- Wiseman M. The second World Cancer Research Fund/American Institute for Cancer Research expert report. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Proc Nutr Soc 2008;67:253-6. [PubMed]
- Alexander DD, Miller AJ, Cushing CA, et al. Processed meat and colorectal cancer: a quantitative review of prospective epidemiologic studies. Eur J Cancer Prev 2010;19:328-41. [PubMed]
- Alexander DD, Cushing CA. Red meat and colorectal cancer: a critical summary of prospective epidemiologic studies. Obes Rev 2011;12:e472-93. [PubMed]
- Giovannucci E, Willett WC. Dietary factors and risk of colon cancer. Annals of medicine 1994;26:443-52. [PubMed]
- Bostick RM, Potter JD, Kushi LH, et al. Sugar, meat, and fat intake, and non-dietary risk factors for colon cancer incidence in Iowa women (United States). Cancer Causes Control 1994;5:38-52. [PubMed]
- Norat T, Bingham S, Ferrari P, et al. Meat, fish, and colorectal cancer risk: the European Prospective Investigation into cancer and nutrition. J Natl Cancer Inst 2005;97:906-16. [PubMed]
- Geelen A, Schouten JM, Kamphuis C, et al. Fish consumption, n-3 fatty acids, and colorectal cancer: a meta-analysis of prospective cohort studies. Am J Epidemiol 2007;166:1116-25. [PubMed]
- Hall MN, Campos H, Li H, et al. Blood levels of long-chain polyunsaturated fatty acids, aspirin, and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev 2007;16:314-21. [PubMed]
- Hall MN, Chavarro JE, Lee IM, et al. A 22-year prospective study of fish, n-3 fatty acid intake, and colorectal cancer risk in men. Cancer Epidemiol Biomarkers Prev 2008;17:1136-43. [PubMed]
- Larsson SC, Kumlin M, Ingelman-Sundberg M, et al. Dietary long-chain n-3 fatty acids for the prevention of cancer: a review of potential mechanisms. Am J Clin Nutr 2004;79:935-45. [PubMed]
- Oh K, Willett WC, Fuchs CS, et al. Dietary marine n-3 fatty acids in relation to risk of distal colorectal adenoma in women. Cancer Epidemiol Biomarkers Prev 2005;14:835-41. [PubMed]
- Kimura Y, Kono S, Toyomura K, et al. Meat, fish and fat intake in relation to subsite-specific risk of colorectal cancer: The Fukuoka Colorectal Cancer Study. Cancer Sci 2007;98:590-7. [PubMed]
- Satia-Abouta J, Galanko JA, Potter JD, et al. Associations of total energy and macronutrients with colon cancer risk in African Americans and Whites: results from the North Carolina colon cancer study. Am J Epidemiol 2003;158:951-62. [PubMed]
- Magalhães B, Bastos J, Lunet N. Dietary patterns and colorectal cancer: a case-control study from Portugal. Eur J Cancer Prev 2011;20:389-95. [PubMed]
- Lo AC, Soliman AS, Khaled HM, et al. Lifestyle, occupational, and reproductive factors and risk of colorectal cancer. Dis Colon Rectum 2010;53:830-7. [PubMed]
- Hamer HM, Jonkers D, Venema K, et al. Review article: the role of butyrate on colonic function. Aliment Pharmacol Ther 2008;27:104-19. [PubMed]
- Burnstein MJ. Dietary factors related to colorectal neoplasms. Surg Clin North Am 1993;73:13-29. [PubMed]
- Giovannucci E, Rimm EB, Stampfer MJ, et al. Intake of fat, meat, and fiber in relation to risk of colon cancer in men. Cancer Res 1994;54:2390-7. [PubMed]
- Pietinen P, Malila N, Virtanen M, et al. Diet and risk of colorectal cancer in a cohort of Finnish men. Cancer Causes Control 1999;10:387-96. [PubMed]
- Vanamala J, Glagolenko A, Yang P, et al. Dietary fish oil and pectin enhance colonocyte apoptosis in part through suppression of PPARdelta/PGE2 and elevation of PGE3. Carcinogenesis 2008;29:790-6. [PubMed]
- Sanders LM, Henderson CE, Hong MY, et al. An increase in reactive oxygen species by dietary fish oil coupled with the attenuation of antioxidant defenses by dietary pectin enhances rat colonocyte apoptosis. J Nutr 2004;134:3233-8. [PubMed]
- Franceschi S, La Vecchia C, Russo A, et al. Macronutrient intake and risk of colorectal cancer in Italy. Int J Cancer 1998;76:321-4. [PubMed]
- Fung TT, Hu FB, Wu K, et al. The Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diets and colorectal cancer. Am J Clin Nutr 2010;92:1429-35. [PubMed]
- Beresford SA, Johnson KC, Ritenbaugh C, et al. Low-fat dietary pattern and risk of colorectal cancer: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 2006;295:643-54. [PubMed]
- Blot WJ, Lanier A, Fraumeni JF Jr, et al. Cancer mortality among Alaskan natives, 1960-69. J Natl Cancer Inst 1975;55:547-54. [PubMed]
- Theodoratou E, McNeill G, Cetnarskyj R, et al. Dietary fatty acids and colorectal cancer: a case-control study. Am J Epidemiol 2007;166:181-95. [PubMed]
- Kim S, Sandler DP, Galanko J, et al. Intake of polyunsaturated fatty acids and distal large bowel cancer risk in whites and African Americans. Am J Epidemiol 2010;171:969-79. [PubMed]
- Weijenberg MP, Luchtenborg M, de Goeij AF, et al. Dietary fat and risk of colon and rectal cancer with aberrant MLH1 expression, APC or KRAS genes. Cancer Causes Control 2007;18:865-79. [PubMed]
- Sasazuki S, Inoue M, Iwasaki M, et al. Intake of n-3 and n-6 polyunsaturated fatty acids and development of colorectal cancer by subsite: Japan Public Health Center-based prospective study. Int J Cancer 2011;129:1718-29. [PubMed]
- Daniel CR, McCullough ML, Patel RC, et al. Dietary intake of omega-6 and omega-3 fatty acids and risk of colorectal cancer in a prospective cohort of U.S. men and women. Cancer Epidemiol Biomarkers Prev 2009;18:516-25. [PubMed]
- Butler LM, Wang R, Koh WP, et al. Marine n-3 and saturated fatty acids in relation to risk of colorectal cancer in Singapore Chinese: a prospective study. Int J Cancer 2009;124:678-86. [PubMed]
- Kim YS, Milner JA. Dietary modulation of colon cancer risk. J Nutr 2007;137:2576S-9S. [PubMed]
- Shen XJ, Zhou JD, Dong JY, et al. Dietary intake of n-3 fatty acids and colorectal cancer risk: a meta-analysis of data from 489 000 individuals. Br J Nutr 2012;108:1550-6. [PubMed]
- Wu S, Feng B, Li K, et al. Fish consumption and colorectal cancer risk in humans: a systematic review and meta-analysis. Am J Med 2012;125:551-9.e5.
- Skeie G, Braaten T, Hjartaker A, et al. Cod liver oil, other dietary supplements and survival among cancer patients with solid tumours. Int J Cancer 2009;125:1155-60. [PubMed]
- MacLean CH, Newberry SJ, Mojica WA, et al. Effects of omega-3 fatty acids on cancer risk: a systematic review. JAMA 2006;295:403-15. [PubMed]
- Burkitt DP. Related disease--related cause? Lancet 1969;2:1229-31. [PubMed]
- Rieger MA, Parlesak A, Pool-Zobel BL, et al. A diet high in fat and meat but low in dietary fibre increases the genotoxic potential of ‘faecal water’. Carcinogenesis 1999;20:2311-6. [PubMed]
- Harris PJ, Triggs CM, Roberton AM, et al. The adsorption of heterocyclic aromatic amines by model dietary fibres with contrasting compositions. Chem Biol Interact 1996;100:13-25. [PubMed]
- Scharlau D, Borowicki A, Habermann N, et al. Mechanisms of primary cancer prevention by butyrate and other products formed during gut flora-mediated fermentation of dietary fibre. Mutat Res 2009;682:39-53. [PubMed]
- Alberts DS, Martinez ME, Roe DJ, et al. Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal adenomas. Phoenix Colon Cancer Prevention Physicians’ Network. N Engl J Med 2000;342:1156-62. [PubMed]
- Schatzkin A, Lanza E, Corle D, et al. Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal adenomas. Polyp Prevention Trial Study Group. N Engl J Med 2000;342:1149-55. [PubMed]
- Millen AE, Subar AF, Graubard BI, et al. Fruit and vegetable intake and prevalence of colorectal adenoma in a cancer screening trial. Am J Clin Nutr 2007;86:1754-64. [PubMed]
- Witte JS, Longnecker MP, Bird CL, et al. Relation of vegetable, fruit, and grain consumption to colorectal adenomatous polyps. Am J Epidemiol 1996;144:1015-25. [PubMed]
- Trock B, Lanza E, Greenwald P. Dietary fiber, vegetables, and colon cancer: critical review and meta-analyses of the epidemiologic evidence. J Natl Cancer Inst 1990;82:650-61. [PubMed]
- Howe GR, Benito E, Castelleto R, et al. Dietary intake of fiber and decreased risk of cancers of the colon and rectum: evidence from the combined analysis of 13 case-control studies. J Natl Cancer Inst 1992;84:1887-96. [PubMed]
- Slattery ML, French TK, Egger MJ, et al. Diet and survival of patients with colon cancer in Utah: is there an association? Int J Epidemiol 1989;18:792-7. [PubMed]
- Peters U, Sinha R, Chatterjee N, et al. Dietary fibre and colorectal adenoma in a colorectal cancer early detection programme. Lancet 2003;361:1491-5. [PubMed]
- Bingham SA, Day NE, Luben R, et al. Dietary fibre in food and protection against colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC): an observational study. Lancet 2003;361:1496-501. [PubMed]
- van Duijnhoven FJ, Bueno-De-Mesquita HB, Ferrari P, et al. Fruit, vegetables, and colorectal cancer risk: the European Prospective Investigation into Cancer and Nutrition. Am J Clin Nutr 2009;89:1441-52. [PubMed]
- Bingham SA, Norat T, Moskal A, et al. Is the association with fiber from foods in colorectal cancer confounded by folate intake? Cancer Epidemiol Biomarkers Prev 2005;14:1552-6. [PubMed]
- Terry P, Giovannucci E, Michels KB, et al. Fruit, vegetables, dietary fiber, and risk of colorectal cancer. J Natl Cancer Inst 2001;93:525-33. [PubMed]
- Park Y, Hunter DJ, Spiegelman D, et al. Dietary fiber intake and risk of colorectal cancer: a pooled analysis of prospective cohort studies. JAMA 2005;294:2849-57. [PubMed]
- Aune D, Chan DS, Lau R, et al. Dietary fibre, whole grains, and risk of colorectal cancer: systematic review and dose-response meta-analysis of prospective studies. BMJ 2011;343:d6617. [PubMed]
- Fuchs CS, Giovannucci EL, Colditz GA, et al. Dietary fiber and the risk of colorectal cancer and adenoma in women. N Engl J Med 1999;340:169-76. [PubMed]
- Michels KB, Edward G, Joshipura KJ, et al. Prospective study of fruit and vegetable consumption and incidence of colon and rectal cancers. J Natl Cancer Inst 2000;92:1740-52. [PubMed]
- Lamprecht SA, Lipkin M. Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms. Nat Rev Cancer 2003;3:601-14. [PubMed]
- Duthie SJ. Folate and cancer: how DNA damage, repair and methylation impact on colon carcinogenesis. J Inherit Metab Dis 2011;34:101-9. [PubMed]
- Lashner BA, Heidenreich PA, Su GL, et al. Effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis. A case-control study. Gastroenterology 1989;97:255-9. [PubMed]
- Cole BF, Baron JA, Sandler RS, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007;297:2351-9. [PubMed]
- Martínez ME, Giovannucci E, Jiang R, et al. Folate fortification, plasma folate, homocysteine and colorectal adenoma recurrence. Int J Cancer 2006;119:1440-6. [PubMed]
- Giovannucci E, Stampfer MJ, Colditz GA, et al. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst 1993;85:875-84. [PubMed]
- Giovannucci E, Stampfer MJ, Colditz GA, et al. Multivitamin use, folate, and colon cancer in women in the Nurses’ Health Study. Ann Intern Med 1998;129:517-24. [PubMed]
- Jacobs EJ, Connell CJ, Patel AV, et al. Multivitamin use and colon cancer mortality in the Cancer Prevention Study II cohort (United States). Cancer Causes Control 2001;12:927-34. [PubMed]
- Sanjoaquin MA, Allen N, Couto E, et al. Folate intake and colorectal cancer risk: a meta-analytical approach. Int J Cancer 2005;113:825-8. [PubMed]
- Mason JB, Dickstein A, Jacques PF, et al. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol Biomarkers Prev 2007;16:1325-9. [PubMed]
- Giovannucci E. Epidemiologic studies of folate and colorectal neoplasia: a review. J Nutr 2002;132:2350S-5S. [PubMed]
- Seitz HK, Simanowski UA, Garzon FT, et al. Possible role of acetaldehyde in ethanol-related rectal cocarcinogenesis in the rat. Gastroenterology 1990;98:406-13. [PubMed]
- Choi SW, Stickel F, Baik HW, et al. Chronic alcohol consumption induces genomic but not p53-specific DNA hypomethylation in rat colon. J Nutr 1999;129:1945-50. [PubMed]
- Kune GA, Vitetta L. Alcohol consumption and the etiology of colorectal cancer: a review of the scientific evidence from 1957 to 1991. Nutr Cancer 1992;18:97-111. [PubMed]
- Cho E, Smith-Warner SA, Ritz J, et al. Alcohol intake and colorectal cancer: a pooled analysis of 8 cohort studies. Ann Intern Med 2004;140:603-13. [PubMed]
- Chan AT, Giovannucci EL. Primary prevention of colorectal cancer. Gastroenterology 2010;138:2029-2043.e10.
- Ferrari P, Jenab M, Norat T, et al. Lifetime and baseline alcohol intake and risk of colon and rectal cancers in the European prospective investigation into cancer and nutrition (EPIC). Int J Cancer 2007;121:2065-72. [PubMed]
- Giovannucci E, Rimm EB, Ascherio A, et al. Alcohol, low-methionine--low-folate diets, and risk of colon cancer in men. J Natl Cancer Inst 1995;87:265-73. [PubMed]
- Mizoue T, Inoue M, Wakai K, et al. Alcohol drinking and colorectal cancer in Japanese: a pooled analysis of results from five cohort studies. Am J Epidemiol 2008;167:1397-406. [PubMed]
- Kato I, Dnistrian AM, Schwartz M, et al. Serum folate, homocysteine and colorectal cancer risk in women: a nested case-control study. Br J Cancer 1999;79:1917-22. [PubMed]
- Park SM, Lim MK, Shin SA, et al. Impact of prediagnosis smoking, alcohol, obesity, and insulin resistance on survival in male cancer patients: National Health Insurance Corporation Study. J Clin Oncol 2006;24:5017-24. [PubMed]
- Asghari-Jafarabadi M, Hajizadeh E, Kazemnejad A, et al. Site-specific evaluation of prognostic factors on survival in Iranian colorectal cancer patients: a competing risks survival analysis. Asian Pac J Cancer Prev 2009;10:815-21. [PubMed]
- Zell JA, McEligot AJ, Ziogas A, et al. Differential effects of wine consumption on colorectal cancer outcomes based on family history of the disease. Nutr Cancer 2007;59:36-45. [PubMed]
- Scalbert A, Manach C, Morand C, et al. Dietary polyphenols and the prevention of diseases. Crit Rev Food Sci Nutr 2005;45:287-306. [PubMed]
- Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr 2004;79:362-71. [PubMed]
- Abe-Hashimoto J, Kikuchi T, Matsumoto T, et al. Antitumor effect of 22-oxa-calcitriol, a noncalcemic analogue of calcitriol, in athymic mice implanted with human breast carcinoma and its synergism with tamoxifen. Cancer Res 1993;53:2534-7. [PubMed]
- Akhter J, Chen X, Bowrey P, et al. Vitamin D3 analog, EB1089, inhibits growth of subcutaneous xenografts of the human colon cancer cell line, LoVo, in a nude mouse model. Dis Colon Rectum 1997;40:317-21. [PubMed]
- Peters U, McGlynn KA, Chatterjee N, et al. Vitamin D, calcium, and vitamin D receptor polymorphism in colorectal adenomas. Cancer Epidemiol Biomarkers Prev 2001;10:1267-74. [PubMed]
- Newmark HL, Wargovich MJ, Bruce WR. Colon cancer and dietary fat, phosphate, and calcium: a hypothesis. J Natl Cancer Inst 1984;72:1323-5. [PubMed]
- Van der Meer R, De Vries HT. Differential binding of glycine- and taurine-conjugated bile acids to insoluble calcium phosphate. Biochem J 1985;229:265-8. [PubMed]
- Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol 1980;9:227-31. [PubMed]
- Tangpricha V, Flanagan JN, Whitlatch LW, et al. 25-hydroxyvitamin D-1alpha-hydroxylase in normal and malignant colon tissue. Lancet 2001;357:1673-4. [PubMed]
- Kato I, Akhmedkhanov A, Koenig K, et al. Prospective study of diet and female colorectal cancer: the New York University Women’s Health Study. Nutr Cancer 1997;28:276-81. [PubMed]
- Dalberg J, Jacobsen O, Nielsen NH, et al. Colorectal cancer in the Faroe Islands--a setting for the study of the role of diet. J Epidemiol Biostat 1999;4:31-6. [PubMed]
- De Stefani E, Mendilaharsu M, Deneo-Pellegrini H, et al. Influence of dietary levels of fat, cholesterol, and calcium on colorectal cancer. Nutr Cancer 1997;29:83-9. [PubMed]
- Boutron MC, Faivre J, Marteau P, et al. Calcium, phosphorus, vitamin D, dairy products and colorectal carcinogenesis: a French case--control study. Br J Cancer 1996;74:145-51. [PubMed]
- Marcus PM, Newcomb PA. The association of calcium and vitamin D, and colon and rectal cancer in Wisconsin women. Int J Epidemiol 1998;27:788-93. [PubMed]
- Franceschi S, Favero A. The role of energy and fat in cancers of the breast and colon-rectum in a southern European population. Ann Oncol 1999;10:61-3. [PubMed]
- Levi F, Pasche C, Lucchini F, et al. Selected micronutrients and colorectal cancer. a case-control study from the canton of Vaud, Switzerland. Eur J Cancer 2000;36:2115-9. [PubMed]
- Wactawski-Wende J, Kotchen JM, Anderson GL, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684-96. [PubMed]
- Gorham ED, Garland CF, Garland FC, et al. Vitamin D and prevention of colorectal cancer. J Steroid Biochem Mol Biol 2005;97:179-94. [PubMed]
- Pietinen P, Malila N, Virtanen M, et al. Diet and risk of colorectal cancer in a cohort of Finnish men. Cancer Causes Control 1999;10:387-96. [PubMed]
- Terry P, Baron JA, Bergkvist L, et al. Dietary calcium and vitamin D intake and risk of colorectal cancer: a prospective cohort study in women. Nutr Cancer 2002;43:39-46. [PubMed]
- McCullough ML, Robertson AS, Rodriguez C, et al. Calcium, vitamin D, dairy products, and risk of colorectal cancer in the Cancer Prevention Study II Nutrition Cohort (United States). Cancer Causes Control 2003;14:1-12. [PubMed]
- Kampman E, Goldbohm RA, van den Brandt PA, et al. Fermented dairy products, calcium, and colorectal cancer in The Netherlands Cohort Study. Cancer Res 1994;54:3186-90. [PubMed]
- Martínez ME, Giovannucci EL, Colditz GA, et al. Calcium, vitamin D, and the occurrence of colorectal cancer among women. J Natl Cancer Inst 1996;88:1375-82. [PubMed]
- Cho E, Smith-Warner SA, Spiegelman D, et al. Dairy foods, calcium, and colorectal cancer: a pooled analysis of 10 cohort studies. J Natl Cancer Inst 2004;96:1015-22. [PubMed]
- Hofstad B, Almendingen K, Vatn M, et al. Growth and recurrence of colorectal polyps: a double-blind 3-year intervention with calcium and antioxidants. Digestion 1998;59:148-56. [PubMed]
- Baron JA, Beach M, Mandel JS, et al. Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group. N Engl J Med 1999;340:101-7. [PubMed]
- Grau MV, Baron JA, Sandler RS, et al. Vitamin D, calcium supplementation, and colorectal adenomas: results of a randomized trial. J Natl Cancer Inst 2003;95:1765-71. [PubMed]
- Ramos S. Cancer chemoprevention and chemotherapy: dietary polyphenols and signalling pathways. Mol Nutr Food Res 2008;52:507-26. [PubMed]
- Nijveldt RJ, van Nood E, van Hoorn DE, et al. Flavonoids: a review of probable mechanisms of action and potential applications. Am J Clin Nutr 2001;74:418-25. [PubMed]
- Kuntz S, Wenzel U, Daniel H. Comparative analysis of the effects of flavonoids on proliferation, cytotoxicity, and apoptosis in human colon cancer cell lines. Eur J Nutr 1999;38:133-42. [PubMed]
- Ramos S. Effects of dietary flavonoids on apoptotic pathways related to cancer chemoprevention. J Nutr Biochem 2007;18:427-42. [PubMed]
- Araújo JR, Gonçalves P, Martel F. Chemopreventive effect of dietary polyphenols in colorectal cancer cell lines. Nutr Res 2011;31:77-87. [PubMed]
- Johnson IT. Phytochemicals and cancer. Proc Nutr Soc 2007;66:207-15. [PubMed]
- Manson MM. Cancer prevention -- the potential for diet to modulate molecular signalling. Trends Mol Med 2003;9:11-8. [PubMed]
- Mohanty C, Acharya S, Mohanty AK, et al. Curcumin-encapsulated MePEG/PCL diblock copolymeric micelles: a novel controlled delivery vehicle for cancer therapy. Nanomedicine (Lond) 2010;5:433-49. [PubMed]
- Sarkar FH, Banerjee S, Li Y. Pancreatic cancer: pathogenesis, prevention and treatment. Toxicol Appl Pharmacol 2007;224:326-36. [PubMed]
- Chen A, Xu J, Johnson AC. Curcumin inhibits human colon cancer cell growth by suppressing gene expression of epidermal growth factor receptor through reducing the activity of the transcription factor Egr-1. Oncogene 2006;25:278-87. [PubMed]
- Su CC, Chen GW, Lin JG, et al. Curcumin inhibits cell migration of human colon cancer colo 205 cells through the inhibition of nuclear factor kappa B /p65 and down-regulates cyclooxygenase-2 and matrix metalloproteinase-2 expressions. Anticancer Res 2006;26:1281-8. [PubMed]
- Cruz-Correa M, Shoskes DA, Sanchez P, et al. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clin Gastroenterol Hepatol 2006;4:1035-8. [PubMed]
- Chung CS, Jiang Y, Cheng D, et al. Impact of adenomatous polyposis coli (APC) tumor supressor gene in human colon cancer cell lines on cell cycle arrest by apigenin. Mol Carcinog 2007;46:773-82. [PubMed]
- Kim JM, Kim JS, Yoo H, et al. Effects of black soybean [Glycine max (L.) Merr.] seed coats and its anthocyanidins on colonic inflammation and cell proliferation in vitro and in vivo. J Agric Food Chem 2008;56:8427-33. [PubMed]
- Yun JM, Afaq F, Khan N, et al. Delphinidin, an anthocyanidin in pigmented fruits and vegetables, induces apoptosis and cell cycle arrest in human colon cancer HCT116 cells. Mol Carcinog 2009;48:260-70. [PubMed]
- Seibel J, Molzberger AF, Hertrampf T, et al. Oral treatment with genistein reduces the expression of molecular and biochemical markers of inflammation in a rat model of chronic TNBS-induced colitis. Eur J Nutr 2009;48:213-20. [PubMed]
- Park CH, Chang JY, Hahm ER, et al. Quercetin, a potent inhibitor against beta-catenin/Tcf signaling in SW480 colon cancer cells. Biochem Biophys Res Commun 2005;328:227-34. [PubMed]
- Kim HJ, Kim SK, Kim BS, et al. Apoptotic effect of quercetin on HT-29 colon cancer cells via the AMPK signaling pathway. J Agric Food Chem 2010;58:8643-50. [PubMed]
- Qiu P, Dong P, Guan H, et al. Inhibitory effects of 5-hydroxy polymethoxyflavones on colon cancer cells. Mol Nutr Food Res 2010;54:S244-52. [PubMed]
- Leonardi T, Vanamala J, Taddeo SS, et al. Apigenin and naringenin suppress colon carcinogenesis through the aberrant crypt stage in azoxymethane-treated rats. Exp Biol Med (Maywood) 2010;235:710-7. [PubMed]
- Yang CS. Inhibition of carcinogenesis by tea. Nature 1997;389:134-5. [PubMed]
- Yang CS, Chung JY, Yang GY, et al. Mechanisms of inhibition of carcinogenesis by tea. Biofactors 2000;13:73-9. [PubMed]
- Demeule M, Michaud-Levesque J, Annabi B, et al. Green tea catechins as novel antitumor and antiangiogenic compounds. Curr Med Chem Anticancer Agents 2002;2:441-63. [PubMed]
- Yang G, Shu XO, Li H, et al. Prospective cohort study of green tea consumption and colorectal cancer risk in women. Cancer Epidemiol Biomarkers Prev 2007;16:1219-23. [PubMed]
- Nehlig A, Debry G. Potential genotoxic, mutagenic and antimutagenic effects of coffee: a review. Mutat Res 1994;317:145-62. [PubMed]
- Brown SR, Cann PA, Read NW. Effect of coffee on distal colon function. Gut 1990;31:450-3. [PubMed]
- Coffee, tea, mate, methylxanthines and methylglyoxal. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon, 27 February to 6 March 1990. IARC Monogr Eval Carcinog Risks Hum 1991;51:1-513. [PubMed]
- Tavani A, La Vecchia C. Coffee, decaffeinated coffee, tea and cancer of the colon and rectum: a review of epidemiological studies, 1990-2003. Cancer Causes Control 2004;15:743-57. [PubMed]
- Giovannucci E. Meta-analysis of coffee consumption and risk of colorectal cancer. Am J Epidemiol 1998;147:1043-52. [PubMed]
- Yu X, Bao Z, Zou J, et al. Coffee consumption and risk of cancers: a meta-analysis of cohort studies. BMC Cancer 2011;11:96. [PubMed]
- Galeone C, Turati F, La Vecchia C, et al. Coffee consumption and risk of colorectal cancer: a meta-analysis of case-control studies. Cancer Causes Control 2010;21:1949-59. [PubMed]
- Je Y, Liu W, Giovannucci E. Coffee consumption and risk of colorectal cancer: a systematic review and meta-analysis of prospective cohort studies. Int J Cancer 2009;124:1662-8. [PubMed]
- Li G, Ma D, Zhang Y, et al. Coffee consumption and risk of colorectal cancer: a meta-analysis of observational studies. Public Health Nutr 2013;16:346-57. [PubMed]
- Wu H, Liang X, Fang Y, et al. Resveratrol inhibits hypoxia-induced metastasis potential enhancement by restricting hypoxia-induced factor-1 alpha expression in colon carcinoma cells. Biomed Pharmacother 2008;62:613-21. [PubMed]
- Hope C, Planutis K, Planutiene M, et al. Low concentrations of resveratrol inhibit Wnt signal throughput in colon-derived cells: implications for colon cancer prevention. Mol Nutr Food Res 2008;52:S52-61. [PubMed]
- Tang FY, Shih CJ, Cheng LH, et al. Lycopene inhibits growth of human colon cancer cells via suppression of the Akt signaling pathway. Mol Nutr Food Res 2008;52:646-54. [PubMed]
- Joo YE, Karrasch T, Muhlbauer M, et al. Tomato lycopene extract prevents lipopolysaccharide-induced NF-kappaB signaling but worsens dextran sulfate sodium-induced colitis in NF-kappaBEGFP mice. PLoS One 2009;4:e4562. [PubMed]
- Choi SY, Park JH, Kim JS, et al. Effects of quercetin and beta-carotene supplementation on azoxymethane-induced colon carcinogenesis and inflammatory responses in rats fed with high-fat diet rich in omega-6 fatty acids. Biofactors 2006;27:137-46. [PubMed]
- Lai KC, Huang AC, Hsu SC, et al. Benzyl isothiocyanate (BITC) inhibits migration and invasion of human colon cancer HT29 cells by inhibiting matrix metalloproteinase-2/-9 and urokinase plasminogen (uPA) through PKC and MAPK signaling pathway. J Agric Food Chem 2010;58:2935-42. [PubMed]
- Kim YH, Kwon HS, Kim DH, et al. 3,3'-diindolylmethane attenuates colonic inflammation and tumorigenesis in mice. Inflamm Bowel Dis 2009;15:1164-73. [PubMed]
- Choi HJ. Lim do Y, Park JH. Induction of G1 and G2/M cell cycle arrests by the dietary compound 3,3'-diindolylmethane in HT-29 human colon cancer cells. BMC Gastroenterol 2009;9:39. [PubMed]
- Christudoss P, Selvakumar R, Pulimood AB, et al. Zinc and zinc related enzymes in precancerous and cancerous tissue in the colon of dimethyl hydrazine treated rats. Asian Pac J Cancer Prev 2012;13:487-92. [PubMed]
- Sheffer M, Simon AJ, Jacob-Hirsch J, et al. Genome-wide analysis discloses reversal of the hypoxia-induced changes of gene expression in colon cancer cells by zinc supplementation. Oncotarget 2011;2:1191-202. [PubMed]
- Zhang X, Giovannucci EL, Smith-Warner SA, et al. A prospective study of intakes of zinc and heme iron and colorectal cancer risk in men and women. Cancer Causes Control 2011;22:1627-37. [PubMed]
- Athar M, Back JH, Tang X, et al. Resveratrol: a review of preclinical studies for human cancer prevention. Toxicol Appl Pharmacol 2007;224:274-83. [PubMed]
- Bjelakovic G, Nikolova D, Simonetti RG, et al. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet 2004;364:1219-28. [PubMed]
- Clark LC, Hixson LJ, Combs GF Jr, et al. Plasma selenium concentration predicts the prevalence of colorectal adenomatous polyps. Cancer Epidemiol Biomarkers Prev 1993;2:41-6. [PubMed]
- Jacobs ET, Jiang R, Alberts DS, et al. Selenium and colorectal adenoma: results of a pooled analysis. J Natl Cancer Inst 2004;96:1669-75. [PubMed]
- Reid ME, Duffield-Lillico AJ, Sunga A, et al. Selenium supplementation and colorectal adenomas: an analysis of the nutritional prevention of cancer trial. Int J Cancer 2006;118:1777-81. [PubMed]
- Kune G, Watson L. Colorectal cancer protective effects and the dietary micronutrients folate, methionine, vitamins B6, B12, C, E, selenium, and lycopene. Nutr Cancer 2006;56:11-21. [PubMed]
- Clark LC, Combs GF Jr, Turnbull BW, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 1996;276:1957-63. [PubMed]
- van den Brandt PA, Goldbohm RA, van’t Veer P, et al. A prospective cohort study on toenail selenium levels and risk of gastrointestinal cancer. J Natl Cancer Inst 1993;85:224-9. [PubMed]
- Wallace K, Byers T, Morris JS, et al. Prediagnostic serum selenium concentration and the risk of recurrent colorectal adenoma: a nested case-control study. Cancer Epidemiol Biomarkers Prev 2003;12:464-7. [PubMed]
- O’Keefe SJ. The colon as a metabolic organ. S Afr Med J 1994;84:376-7. [PubMed]
- Ellegård L, Andersson H, Bosaeus I. Inulin and oligofructose do not influence the absorption of cholesterol, or the excretion of cholesterol, Ca, Mg, Zn, Fe, or bile acids but increases energy excretion in ileostomy subjects. Eur J Clin Nutr 1997;51:1-5. [PubMed]
- Verghese M, Rao DR, Chawan CB, et al. Dietary inulin suppresses azoxymethane-induced preneoplastic aberrant crypt foci in mature Fisher 344 rats. J Nutr 2002;132:2804-8. [PubMed]
- Roller M, Pietro Femia A, Caderni G, et al. Intestinal immunity of rats with colon cancer is modulated by oligofructose-enriched inulin combined with Lactobacillus rhamnosus and Bifidobacterium lactis. Br J Nutr 2004;92:931-8. [PubMed]
- Roy CC, Kien CL, Bouthillier L, et al. Short-chain fatty acids: ready for prime time? Nutr Clin Pract 2006;21:351-66. [PubMed]
- McGarr SE, Ridlon JM, Hylemon PB. Diet, anaerobic bacterial metabolism, and colon cancer: a review of the literature. J Clin Gastroenterol 2005;39:98-109. [PubMed]
- Bosscher D, Breynaert A, Pieters L, et al. Food-based strategies to modulate the composition of the intestinal microbiota and their associated health effects. J Physiol Pharmacol 2009;60:5-11. [PubMed]
- Rossi M, Amaretti A, Raimondi S. Folate production by probiotic bacteria. Nutrients 2011;3:118-34. [PubMed]
- Rafter J, Bennett M, Caderni G, et al. Dietary synbiotics reduce cancer risk factors in polypectomized and colon cancer patients. Am J Clin Nutr 2007;85:488-96. [PubMed]
- Yu CC, Filipe MI. Update on proliferation-associated antibodies applicable to formalin-fixed paraffin-embedded tissue and their clinical applications. Histochem J 1993;25:843-53. [PubMed]
- Nagengast FM, Grubben MJ, van Munster IP. Role of bile acids in colorectal carcinogenesis. Eur J Cancer 1995;31A:1067-70. [PubMed]
- McMillan L, Butcher S, Wallis Y, et al. Bile acids reduce the apoptosis-inducing effects of sodium butyrate on human colon adenoma (AA/C1) cells: implications for colon carcinogenesis. Biochem Biophys Res Commun 2000;273:45-9. [PubMed]
- De Boever P, Wouters R, Verschaeve L, et al. Protective effect of the bile salt hydrolase-active Lactobacillus reuteri against bile salt cytotoxicity. Appl Microbiol Biotechnol 2000;53:709-14. [PubMed]
- Huycke MM, Gaskins HR. Commensal bacteria, redox stress, and colorectal cancer: mechanisms and models. Exp Biol Med (Maywood) 2004;229:586-97. [PubMed]
- Vittorio GL. University of Milano Bicocca Clinical, Trials.gov Identifier: NCT00936572.
- Valentini V. ClinicalTrials.gov Identifier: NCT01579591. Catholic University of the Sacred Heart.
- Payne JE. Colorectal carcinogenesis. Aust N Z J Surg 1990;60:11-8. [PubMed]
- Ning Y, Wang L, Giovannucci EL. A quantitative analysis of body mass index and colorectal cancer: findings from 56 observational studies. Obes Rev 2010;11:19-30. [PubMed]
- Renehan AG, Tyson M, Egger M, et al. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008;371:569-78. [PubMed]
- Khaw KT, Wareham N, Bingham S, et al. Preliminary communication: glycated hemoglobin, diabetes, and incident colorectal cancer in men and women: a prospective analysis from the European prospective investigation into cancer-Norfolk study. Cancer Epidemiol Biomarkers Prev 2004;13:915-9. [PubMed]
- Tsilidis KK, Allen NE, Key TJ, et al. Oral contraceptives, reproductive history and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition. Br J Cancer 2010;103:1755-9. [PubMed]
- Hughes LA, Williamson EJ, van Engeland M, et al. Body size and risk for colorectal cancers showing BRAF mutations or microsatellite instability: a pooled analysis. Int J Epidemiol 2012;41:1060-72. [PubMed]
- Zervoudakis A, Strickler HD, Park Y, et al. Reproductive history and risk of colorectal cancer in postmenopausal women. J Natl Cancer Inst 2011;103:826-34. [PubMed]