Omega‐3 fatty acids in colorectal cancer prevention

Colon cancer, which is the fourth most common cancer in the world, is one of the leading causes of cancer death in both men and women in the United States, Canada, Northern and Western Europe, Australia and New Zealand.1, 2 It is markedly less frequent in Asia, Africa and South America.1, 2 Therefore, it is a major public health problem. Migrant and temporal trend studies suggest that colon cancer is determined largely by environmental exposures, especially nutritional habits.1 Marked international differences in the incidence and mortality of colon cancer and increase of risk in populations migrating from low- to high-risk areas such as from Japan, China and the Philippines to the United States within 1 or 2 generations suggest that environmental factors, specifically dietary habits, rather than the genetic factors play an important role in the etiology of this cancer. This upward trend in incidences of colon cancer among Japanese immigrants in Hawaii and California compared to Japanese in Japan stimulated epidemiologists to investigate the reasons for this increase. Although the relationship between nutrition and cancer is complex and sometimes perplexing to nutritionists and to those who visualize carcinogenesis in terms of a specific carcinogen, it should be recognized that nutritional factors and diet may relate to cancer risk in several ways; first, food additives, contaminants, a particular dietary component, or products formed during food preparation may act as carcinogens, cocarcinogens and/or promoters; second, nutrient deficiencies and excesses may lead to biochemical/molecular alterations that may promote neoplastic processes; third, changes in the intake of selected macronutrients may induce metabolic, biochemical and molecular abnormalities that enhance cancer risk; and fourth, certain dietary constituents act as anticarcinogens or chemopreventives. During the last 3 decades, substantial progress has been made in understanding the relationship between dietary constituents and colon cancer risk. Fish oils are unique because they contain high levels of polyunsaturated omega-3 fatty acids (n-3 PUFAs) that are not present in vegetable oils or in saturated fats. Omega-3 fatty acids that are present in fish oil include docosahexaenoic acid (DHA; C22:6), eicosapentaenoic acid (EPA; C20:5) and docosapentaenoic acid (DPA; C22:5). Vegetable oils including corn oil and safflower oil contain high levels of linoleic acid (LA; C18:2). LA has the terminal double-bond 6 carbon atoms from the terminal (omega) methyl group of fatty acid, whereas DHA has the terminal double-bond 3 carbon atoms from the terminal (omega) methyl group of fatty acid (Fig. 1). Chemical structures of omega-3 and omega-6 fatty acids. Nutritional epidemiologic studies have provided evidence that dietary factors are important determinants of colorectal cancer in different populations worldwide. Cancer statistics in Japan for 2001 published by the Foundation for Promotion of Cancer Research indicate that there is an upward trend in age-adjusted mortality rates for colon cancer from 1955 to 1999.3 According to this report, the death rates due to colon cancer in Japanese men and women in 1955 were 2.9 and 3.0, respectively, whereas they increased to 14.7 and 9.8 in 1999. This upward trend in death rates due to colon cancer is mainly attributable to Westernization of Japanese food habits.3, 4 In addition, the report by the Foundation for Promotion of Cancer Research provided the data on the time trends in food consumption, which show increased dietary intakes of animal fat and meat and decreased consumption of whole grains from 1960 to 1999. For example, animal fat consumption in 1960 was about 25 g/day (per capita), whereas in 1999 it increased to about 58 g/day. Meat intake was increased from 19 to 78 g/day (per capita), whereas grain consumption decreased from 453 to 245 g/day during these years.3 The importance of types of dietary fat differing in fatty acid composition rather than total fat cannot be discounted because several preclinical studies using well-established colon cancer models strongly supported the notion that the colon tumor-promoting effect of dietary fat or lack of such effect depends on its fatty acid composition.5 A recent report by an expert panel assembled by the American Institute for Cancer Research/World Cancer Research Fund came to the scientific consensus that evidence for an association between the intake of saturated fat and/or animal fat and colon cancer risk is very strong.6 Continuing population studies revealed that diets particularly high in total fat, especially animal fat, are generally associated with increased risk of developing colon cancer, whereas high dietary fish oil or fish reduces this risk.7, 8 A recent ecologic study suggests that mortality data for colorectal cancer in 22 European countries, the United States and Canada correlate with the consumption of animal fat.7 That eating a diet rich in n-3 PUFAs may decrease the risk of colorectal cancer has been hypothesized in relation to fish and fish oil.7 Caygill and Hill et al.8 reported an inverse correlation between fish and fish oil consumption and colorectal cancer when expressed as a proportion of total or animal fat. This inverse relationship was significant for both male and female colorectal cancer, whether the intakes were in the current period or 10 years or 23 years before cancer mortality, It is noteworthy that these effects were only observed in countries with a high (> 85 g/caput/day) animal fat intake.8 Also, Mediterranean diet rich in olive oil and fish is associated with a low risk of colorectal cancer.9 On the basis of epidemiologic evidence, it is reasonable to suggest that diets high in saturated fats increase the risk of colorectal cancer, whereas diets high in fish and fish oil rich in n-3 PUFAs reduce the risk. Animal models have contributed significantly to understanding of the carcinogenesis process and to study the multiple environmental factors against the pathogenesis of colon cancer.10 Several studies have utilized these relevant animal models to investigate the modulation of colon carcinogenesis by nutritional and chemopreventive agents. These animal models include induction of colon tumors in rats by administration of aromatic amines such as 3,2′-dimethyl-4-aminobi-phenyl (DMBA); derivatives and analogs of cycacin, such as methylazoxymethanol (MAM), 1,2-dimethyl-hydrazine (DMH) and azoxymethane (AOM) in rats and mice of selected strains; direct-acting carcinogens of the type of alkylureas, such as methylnitrosourea (MNU) or N-methyl-N′-nitro-N-nitrosoguanidine (MNNG); and heterocyclic amines such as 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). The spectrum of epithelial lesions induced in the colon by these agents is similar to various types of neoplastic lesions observed in the colorectum of humans. Azoxymethane (AOM), which is a potent inducer of carcinomas of the large intestine in various strains of male and female rats, has been used extensively by many investigators to induce colon tumors and to study the effects of nutritional factors and chemopreventive agents in colon carcinogenesis.10, 11, 12, 13, 14, 15, 16, 17 Colons of Fischer (F344) rats treated with AOM seem to have light and electron microscopic morphology as well as histochemical properties that are quite similar to that of humans and the biologic behavior of AOM-induced rat colon carcinomas is similar to that of human colon carcinomas.10, 18 Other characteristics of the human disease process reflected in the AOM rat model are the occurrence of both adenomas and adenocarcinomas.18 Also, aberrant crypt foci (ACF), which are recognized as early appearing preneoplastic lesions, develop in experimentally induced colon carcinogenesis in laboratory rodents as well as in the colonic mucosa of patients with colon cancer.19, 20 Recently, β-catenin-accumulated crypts were identified in the colonic mucosa at the early stages of AOM-induced colon carcinogenesis and are considered as early-appearing preneoplastic lesions.21 Therefore, ACF are now regarded as putative preneoplastic lesions for colon cancers and are used as biomarkers to evaluate potential chemopreventive agents against colon carcinogenesis.22 AOM treatment also induces oncogene mutations at codon 12 of K- and H-ras and increases in the expression of the ras family of protooncogenes have been causally associated with colon tumor development.23, 24 Enhanced ras oncogene expression has been observed in a variety of human colon tumors.25 AOM-induced colon tumors also demonstrate enhanced cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression similar to human colon tumors.13, 26 Mutations in the tumor suppressor gene, APC, are known to be early events in the colon cancer process in humans and have been identified in patients with familial adenomatous polyposis, who have germline mutation in one of the APC alleles, and in sporadic colorectal cancer.27, 28 Evidence in humans thus implicates the APC suppressor gene as causal in large bowel carcinogenesis. Recent studies indicating the presence of APC mutation in AOM-induced colon tumors in rats strengthens the concept that these models are appropriate for human colon cancer studies.29 It has been increasingly apparent that β-catenin signaling pathway is closely associated with the development of colon cancer.30 Also, frequent mutations in the β-catenin gene are confirmed in AOM-induced colon tumors in rodent models.30 Furthermore, it has recently been indicated that the expression of nuclear β-catenin is correlated with the size of colon neoplasms.31 Because of similarities of histopathology of adenomas and adenocarcinomas, ACF and several molecular parameters between human colon tumors and AOM-induced colon tumors, it is indicated that the AOM model system and other chemically induced colon models appear to be appropriate colon cancer models. Recent progress in the area of molecular carcinogenesis has identified multiple molecular targets for the chemoprevention and nutritional modulation of colon cancer. The multiple intestinal neoplasia (Min) mouse, which carries a fully penetrant dominant mutation converting codon 850 of the murine APC gene from a lucine to a stop codon, is markedly different from that of patients with familial adenomatous polyposis (FAP) in which adenomas are found exclusively in the colon and duodenum, whereas in Min mouse adenomas are detectable in the small intestine and rarely in the colon. APCΔ716 knockout mice also develop numerous intestinal polyps at an early age.32 These are potential limitations of APCMin mouse and knockout models for testing agents for their potential chemopreventive properties against colon carcinogenesis. The development of strategies for prevention of colorectal cancer by dietary modification has been markedly facilitated by the use of relevant laboratory animal models, including carcinogen-induced colon cancer mimicking the neoplastic process that occurs in humans. Ample and consistent experimental evidence from preclinical efficacy studies conducted earlier have provided convincing evidence that not only the amount but also types of dietary fat differing in fatty acid composition are important factors in determining modulating effect of this nutrient in colon tumor development.33, 34, 35, 36 Studies conducted in our laboratory and those of others have consistently demonstrated that diets high in beef tallow, lard and corn oil (20–23% in the diet) significantly increased chemically induced colon carcinogenesis in F344 and Sprague-Dawley rats as compared to diets low (5%) in these fats.11, 33, 34, 35, 36, 37, 38 Additional studies conducted in our laboratory also demonstrate that male F344 rats fed diets containing 20% lard or 20% corn oil rich in n-6 PUFAs were more susceptible to 1,2-dimethylhydrazine-induced colon carcinogenesis compared with those fed diets containing 5% lard or 5% corn oil.38 Deschner et al.39 demonstrated that dietary n-3 PUFAs (fish oil) inhibits methylazoxymethanol (metabolite of azoxymethane)-induced focal areas of dysplasia and colon tumors, whereas n-6 PUFAs (corn oil) enhance colon tumorigenesis in rats. In a recent study, Chang et al.11 reported a protective effect of dietary fish oil against AOM-induced colon carcinogenesis in male Sprague-Dawley rats. High dietary fish oil significantly inhibited colon tumors as compared to high corn oil diet. In addition, colon tumor inhibition by fish oil diet was associated with lower levels of DNA damage in the distal colon compared with corn oil diet.11, 40 These studies provided evidence in preclinical models that diets containing high amount of saturated fat of animal origin or n-6 PUFAs had a greater colon tumor-enhancing effect than diets low in such fatty acids, whereas diets high in n-3 PUFAs had no such enhancing effect Further studies in our laboratory have evaluated the modulating effects of high dietary corn oil and safflower oil rich in n-6 PUFAs, olive oil high in monounsaturated fatty acid oleic acid, coconut oil high in medium-chain fatty acids such as lauric acid and fish oil during the postinitiation stage of AOM-induced colon carcinogenesis in male F344 rats.14, 37, 38, 41 Animals fed diets containing high corn oil or safflower oil (23.5%) had a higher incidence of colon tumors than did those fed diets low in fat (5%). By contrast, diets high in coconut oil, olive oil or menhaden fish oil had no such colon tumor-enhancing effect. The varied effects of different types of fat on colon carcinogenesis during postinitiation stage suggest that fatty acid composition is one of the determining factors in colon tumor promotion by a dietary fat and that the influence of types and amount of dietary fat is exerted mostly during the postinitiation phase of carcinogenesis.34, 41, 42 In this connection, it is interesting to note that in a phase 2 clinical trial of patients with colonic polyps, dietary fish oil supplements have in fact inhibited cell proliferation in the colonic mucosa.43 Thus far, progress has been made with regard to the relationship between dietary fat intake and colon cancer risk in that we know of the tumor-promoting effects of diets rich in n-6 PUFAs and saturated fatty acids and lack of such effects by n-3 PUFAs. However, it should be recognized that among the sources of dietary fat, animal fat with its high-saturated fatty acid content is by far the most important contributor, amounting to about 60%, to the Western diet. dietary fat intake in the United States and Canada and other Western countries, colon cancer rates are of a of monounsaturated and polyunsaturated A recent in mice demonstrated that high dietary fat composition of the diet lesions in the colon of In of the of in colon cancer and because of potential properties of n-3 PUFAs, we have conducted a study to the effects of diets that contain rich in saturated fatty acids and to with the effects of fish oil during the different stages of colon carcinogenesis in male F344 preneoplastic lesions, were in fed the experimental diets for 23 and 38 which are putative preneoplastic lesions in the were observed at high in the colonic mucosa of patients with colon and of rats and mice treated with colon ACF and their are to be biomarkers of the effects of agents carcinogenesis in the colon. ACF were observed in the distal of rats. fed the diet a significantly greater of compared with those fed the corn oil or fish oil diet at time The incidence of aberrant foci was also higher in the diet group than in the or diet that administration of the diet significantly inhibits the and of preneoplastic lesions in the whereas the diet the of such Also, dietary significantly increased colon tumor incidence and when compared with the or rats fed the diet incidence of colonic compared with incidences of and in rats fed the and Also, the of was significantly higher in fed the diet as compared to those fed the diet. the diet containing 20% fat in the of fish oil) induced tumors than diet containing the amount of total fat from This that both the type and the amount of fatty acids in the diet play a role in colon carcinogenesis. In evidence from preclinical studies is consistent with the epidemiologic The efficacy of dietary n-3 PUFAs including DHA and against colon carcinogenesis has also been in rodent models. et reported that administration of of DHA a for 4 and 12 significantly AOM-induced ACF in the colon. et also reported that administration of 1 of DHA a for 36 significantly AOM-induced colon tumor specifically in the and distal colon in male F344 rats. et compared dietary at LA at or LA at 5% against AOM-induced colon carcinogenesis in male rats. The indicate that the rats fed had a significantly lower colon tumor incidence and than those fed the LA diet. of tumors that the rats on diet had and more than those on the LA diet. Also, the content of in the colon tumors of LA diet group was higher than that in the colon tumors of the diet These suggest that its effect the modulation of in colon Several potential have been for colon cancer of types of dietary fat. Several studies indicate that diets high in saturated fatty acids and and n-6 PUFAs (corn oil or safflower oil) increase the of colonic acids, including acid and acid, whereas dietary fish oil high in n-3 PUFAs had no such enhancing epidemiologic studies demonstrated that populations who are on Western diet and at high risk for colon cancer high levels of acids have been to in a similar to induce cell proliferation and a in and act as in colon these suggest that acids that are by types of dietary fat may be important for in relation to colon tumor in by et dietary PUFAs may DNA and n-3 PUFAs may against colon carcinogenesis by DNA and/or enhancing DNA levels of AOM-induced DNA were in fish rats as compared to those fed corn oil rich in n-6 PUFAs. et and Chang et have also demonstrated that fish oil an increase in in the colon compared with corn rats. It is reasonable to that one of the by which n-3 PUFAs against colon carcinogenesis is in by the of DNA and by enhancing the of colonic Also, of fish oil or n-3 fatty acid increased and DHA levels in the of at the of n-6 fatty It has been that inhibition of colon carcinogenesis by DHA is the of a of a large of nuclear n-3 PUFAs effects in the colon the of nuclear of the nuclear are factors that cell and are studies to indicate that inducible nitric oxide synthase which is at the is in human colon and in chemically induced colon tumors of laboratory animal data also indicate that the of by is to carcinogenesis process and induces DNA lesions, thus in DNA and in the by family of also These data suggest a role for in tumor promotion and Studies conducted in our laboratory indicate that acid induces in intestinal with specific expression that one of the by which tumor including acids may an increase in expression of pathway that colon It is known that the fatty acid composition of is to diet. Studies conducted in our laboratory indicate that levels of dietary fish oil in rats increased the omega-3 fatty acids, DHA and in the colonic at the of omega-6 PUFAs such as linoleic acid and acid, the that the DHA and of fish oil the of by acid and linoleic acid in the Therefore, the types of dietary fat the fatty acid composition of colonic It is well that acid and of its including play an important role in the signaling pathway associated with cell proliferation and gene increase cell promote and of which are in tumor The by which n-3 PUFAs colon carcinogenesis are in of an important role in colon and who have in the of of rat intestinal epithelial have that of lead to the of high intake of saturated fat and omega-6 PUFAs acid from and 41 levels of have been observed in human colon tumors and chemically induced colon tumors in rodent and human colon levels of that are by Northern Recent have a between the potential of APC mutations and by that of the gene reduces the of tumors in mice for an by more than Additional evidence a role for from our which show a in colon tumors in rodents with Recent studies conducted in our laboratory have provided convincing evidence that an diet AOM-induced expression of and from acid in colon tumors of rats, whereas the diet inhibits the levels of In this study, administration of the diet of in the colon tumors, significantly higher levels than the corn oil diet or the diet 28 indicating higher This suggests that inhibition of the modulation of may be important for the of n-3 PUFAs to colon Also, colon tumors of fed the diet a lower than was observed in the colon tumors of rats fed the diet. The of these studies indicating that of in the tumors of fed the diet in to the diet inhibits and the tumor the that of lead to the of In colon tumors, the levels of may be to by proliferation and induction of and thus tumor A major that to be is which signaling are in of the These not only a between dietary fatty acids, and of colon but also molecular targets for colon cancer prevention by which n-3 PUFAs colon carcinogenesis. The potential and molecular events by n-3 PUFAs against colon carcinogenesis. The of molecular events by n-3 PUFAs include including and specific and factors including that cell and High dietary n-3 PUFAs by with the modification and of modulation of thus Recent studies from our laboratory have that high dietary n-6 PUFAs enhance of including that have been or in colon tumor whereas diet containing n-3 PUFAs to the of these a gene family of that play in signaling events and are in proliferation and include several with unique to the from the et reported that chemopreventive efficacy of dietary fish oil is associated with the alterations in colonic a that is by PUFAs may influence the of the which a of It is interesting that several have been to in The a of ras that is to the of in the of cell of are in the etiology of human colon It is also known that of from to is facilitated by a of closely including which is by It that inhibition of ras association of and neoplastic of Studies conducted in our laboratory have provided data to indicate that high dietary n-6 PUFAs increases expression in colonic tumors, whereas high dietary n-3 PUFAs appear to by with modification and of the modulation of thus Several have demonstrated against in both cell and laboratory animal in DNA have facilitated the of in promotion and of colon cancer. of is correlated with the development of certain of has also been to induce an effect that with and cell have recently that expression of was in colon tumors of rats than in colon Colon tumors from rats fed the diet containing high levels of n-6 PUFAs very low levels of whereas the tumors from fed the diet containing high amount of n-3 PUFAs did not of These correlate with colon tumor incidences by dietary n-3 and n-6 PUFAs. It appear that modulation of a significant role in n-3 colon tumor inhibition and Additional studies conducted in our laboratory have demonstrated that DHA inhibits of colon cancer in and induces we also the effects of DHA on the genetic of human colon cancer at the using DNA in gene expression due to DHA treatment was observed to be in the multiple signaling in the of cell and of DHA on cell and induction of were by an increase in the of several of family of and of such as and of several of these and factors the of the chemopreventive efficacy of DHA and other important n-3 PUFAs present in fish oil and thus colon cancer. Also, of these and factors provided several expressed biologic many of which suggest as molecular targets for by chemopreventive including nutritional is a major of and mortality in patients with cancer, including colorectal cancer. Several clinical studies have provided evidence for effects of fish oil administration in cancer during Omega-3 fatty acids have been to have effects on in cancer in patients with cancer is to and is associated with a time and of A fish nutritional has the potential to be a and of a fish oil preparation of and and a preparation in patients with 85 The of of the of which in the of of cancer patients and death from attributable to of of in cancer by and this may be one of the for inhibition of tumor Also, fish oil at a of during In on the basis of epidemiologic evidence from ecologic and it is reasonable to suggest that diets high in saturated fats increase the risk of colorectal cancer, whereas diets high in n-3 PUFAs not increase its risk. The studies both epidemiologic and evidence for the effects of diets rich in n-3 in the prevention of colorectal cancer. Also, recent clinical demonstrate effects of fish oil administration in cancer and during and studies have provided convincing evidence that colon tumor-promoting effect of dietary fat depends on its fatty acid that the composition of dietary fatty acids is more to colon cancer risk than is the total amount of fat. studies also demonstrate that a diet high in including saturated fats of animal origin as well as high dietary n-6 PUFAs had a higher potential to promote colon tumorigenesis than of a diet on amount of fat containing n-3 PUFAs. Although the by which diets high in saturated fats as those in Western and n-6 PUFAs promote colon carcinogenesis are not fully the studies conducted thus far indicate that increased levels of colonic acids, modulation of the influence on and the expression of by the types of dietary fat, especially n-6 PUFAs, may play a role in colon carcinogenesis. Further studies are to the role of n-3 PUFAs on the modulation of that are in colon and other types of cancer. The of prevention is to decrease the and mortality from colorectal cancer. and those of others suggest that nutritional prevention has the potential to be a major of colorectal cancer especially prevention in the are and in n-3 PUFAs be before they are for cancer Although there are no data to indicate and n-3 PUFAs should be for prevention of colorectal cancer, levels of dietary n-3 PUFAs should be consistent with the on epidemiologic studies of disease as by several These studies suggest that fish or as as g/day of fish the risk of Although a dietary for n-3 PUFAs not there is a that consumption of amount of fish in our on the epidemiologic studies may also reduce the risk of colorectal cancer. et has that the of n-6 PUFAs to n-3 PUFAs may be important for The varied risk for and several types of cancer among Mediterranean and Western European populations may at in be on the basis of n-6 to n-3 of and 10 in their on preclinical and epidemiologic studies on and et for a in the intake of linoleic acid and increase in the intake of n-3 PUFAs that a of 2 be for prevention of and that this is in Western countries for prevention of and and This may well be for the prevention of colorectal cancer in the consumption of and is also for those in Western countries to reduce the risk of colorectal cancer. In the prevention of colorectal cancer in omega-3 fatty acids are in and of be It should be recognized that with nutritional supplements and/or diet modification may not be for prevention of colorectal cancer in patients such as those with polyposis and sporadic colon This to colon cancer is of importance as have not been fully in the high incidence or low of colorectal cancer. However, by diet modification as to the with chemopreventive agents that or the development of those which with and progress to and is an for prevention of colon cancer in these high-risk This is important when chemopreventive agents demonstrate significant efficacy but may effects at higher It is certain that colon cancer prevention be a significant of and in high-risk by molecular targets that or stop the process of carcinogenesis. there is a to clinical in patients with sporadic colon polyps using the n-3 diets in with a chemopreventive to the of events leading to The for preparation of the and studies on n-3 PUFAs in colon cancer prevention are supported by the Cancer Institute and

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