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Mechanisms for the Impact of Whole Grain Foods on Cancer Risk

Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, St. Paul, Minnesota

Address reprint requests to: Joanne Slavin, Ph.D., Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108

	ABSTRACT

TOP ABSTRACT INTRODUCTION WHOLE GRAIN FOODS EPIDEMIOLOGIC SUPPORT FOR THE... MECHANISMS FOR THE... CONCLUSION REFERENCES

 
Dietary guidance recommends consumption of whole grains for the prevention of cancer. Epidemiologic studies find that whole grains are protective against cancer, especially gastrointestinal cancers such as gastric and colonic, and hormonally-dependent cancers including breast and prostate. Four potential mechanisms for the protectiveness of whole grains against cancer are described. First, whole grains are concentrated sources of dietary fiber, resistant starch, and oligosaccharides, fermentable carbohydrates thought to protect against cancer. Fermentation of carbohydrates in the colon results in production of short chain fatty acids that lower colonic pH and serve as an energy source for the colonocytes. Secondly, whole grains are rich in antioxidants, including trace minerals and phenolic compounds, and antioxidants have been proposed to be important in cancer prevention. Thirdly, whole grains are significant sources of phytoestrogens that have hormonal effects related to cancer protection. Phytoestrogens are thought to be particularly important in the prevention of hormonally-dependent cancers such as breast and prostate. Finally, whole grains mediate glucose response, which has been proposed to protect against colon and breast cancer.

Key words: cancer, whole grains, phytoestrogens, lignans, antioxidants, oligosaccharides

Key teaching points:

• Whole grains are a rich source of fermentable carbohydrates.

• Whole grains are concentrated in natural antioxidants.

• Whole grains are a dependable source of phytoestrogens that may protect against hormonally-dependent cancers.

• Whole grains are digested and absorbed more slowly than refined carbohydrates.

• These mechanisms, alone or together, may explain the protectiveness of whole grains in disease prevention.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION WHOLE GRAIN FOODS EPIDEMIOLOGIC SUPPORT FOR THE... MECHANISMS FOR THE... CONCLUSION REFERENCES

 
Despite dietary recommendations to increase whole grain intake, little research has been conducted on the physiological effects of diets high in whole grains. Mechanistic studies are usually conducted with the magic bullet approach, where one dietary ingredient is isolated and fed to either animals or human subjects. Potter describes well the problems with this approach [1]. The effect of dietary ingredients will vary with the stage of the cancer process, the organ site, and will be modified by gender, age and genetic profile. Feeding whole foods makes it difficult to isolate mechanisms, but such an approach ensures the built-in redundancy of multiple agents with independent, overlapping and perhaps interactive mechanisms [1].

The objective of this review is to describe potential mechanisms whereby whole grains may protect against cancer. First, whole grains will be defined and described. Support for the relationship between whole grains and cancer protection will be highlighted. Finally, four potential mechanisms for the protectiveness of whole grains against cancer will be proposed.

	WHOLE GRAIN FOODS

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Measurement of whole grain intake is difficult since there are no accepted standards for whole grain foods. In the milling process, the bran and germ are separated from the starchy endosperm, and the latter is ground to flour. Micronutrients are generally present in higher concentrations in the outer part of the grain, so refined flours which comprise only starchy endosperm are lower in micronutrients than whole grains. Additionally, because the germ is high in unsaturated fats, it is often necessary from the perspective of shelf-life to remove the germ in order to prevent lipid oxidation.

Most whole and refined grains consumed in developed countries are processed to make acceptable products. Milling of whole grains has the most significant effect on nutrient content. When whole grain rye was milled into different fractions, the fractions varied considerably in gross chemical composition [2]. The starch content ranged from 3.0 g/100 g in the pericarp/testa to 73.3 g/100g in the endosperm. Protein, fat, ash and phosphorous were concentrated in the aleurone fraction. Dietary fiber characteristics also differed greatly between the rye milling fractions. Arabinoxylans composed the majority of dietary fiber components in all samples, but the milled fractions had different concentrations of lignin, cellulose and beta-glucans.

When the bran is removed in processing, associated substances are also removed. Phenolic acids, particularly the hydroxy-cinnamic acids, ferulic acid and p-coumaric acid, are found in plant cell walls generally linking cellulose to other polysaccharide components. These compounds are thought to decrease the fermentability of dietary fiber [3]. The total phenolic acid content of wheat, rice and oat flours ranges from 71 to 87 ppm, while maize flour contains 309 ppm [4]. Ferulic and p-coumaric acids and syringic acid are the principal phenolic acids. Oats contain a number of lipid-soluble esters of caffeic and ferulic acids, which function as natural antioxidants for the oat lipids. Ferulic acid is the most concentrated phenolic acid in wheat, and the more refined flours have lower phenolic acid contents [5].

	EPIDEMIOLOGIC SUPPORT FOR THE PROTECTIVE ROLE OF WHOLE GRAINS

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There is substantial scientific evidence suggesting that whole grains as commonly consumed in the United States and Europe reduce risk of cancer. Whole grain intake is difficult to assess in epidemiologic studies because existing food frequency instruments were not designed to measure this dietary component. In epidemiologic studies, various phrases have been used to identify whole grain intake including dark bread, brown bread, crisp bread, high-fiber cereal bread, whole grain bread and cereal, whole grain cereal, whole grain foods, whole grain pasta and wholemeal bread [6]. Although these classification categories are not perfect, they do allow researchers to differentiate between participants who are infrequent versus habitual or frequent consumers of whole grain products.

In a meta-analysis of whole grain intake and cancer [6], whole grains were found to be protective in 46 of 51 mentions of whole-grain intake and in 43 of 45 mentions after exclusion of six mentions with design/reporting flaws or low intake. Dose-response analyses were strong and similar for two types of dietary questionnaires, but weak for studies that used the most comprehensive questionnaires. A systemic review of case-control studies conducted using a common protocol in Northern Italy between 1983 and 1996 indicates that a higher frequency of whole grain consumption is associated with reduced risk for cancer [7]. Whole grain was consumed primarily as whole grain bread and some whole grain pasta in the Italian studies.

The relationship between colon cancer and dietary fiber intake continues to be debated. Recently it was widely reported that there was no relationship between dietary fiber intake and colon cancer in a large prospective study [8]. It should be noted that intake of dietary fiber was low in participants in the study, not unlike intake for most Americans. Additionally, dietary fiber is just one component of whole grains that is known to protect against colon cancer.

	MECHANISMS FOR THE PROTECTIVENESS OF WHOLE GRAINS IN CANCER

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1. Gastrointestinal Response
Whole grains are rich sources of fermentable carbohydrates including dietary fiber, resistant starch and oligosaccharides. Undigested carbohydrate that reaches the colon is fermented by intestinal microflora to short chain fatty acids and gases. Short chain fatty acids include acetate, butyrate and propionate, with butyrate being a preferred fuel for the colonic mucosa cells. Undigested carbohydrates increase fecal wet and dry weight and speed intestinal transit.

No studies have examined the effects of whole grains on gut fermentation. Research has been conducted on grain components, including dietary fiber, resistant starch and oligosaccharides. When the dietary fiber content of various whole grains is compared, oats, rye and barley contain about one-third soluble fiber and the rest insoluble fiber. Refining of grains removes proportionally more of the insoluble fiber than soluble fiber, although refined grains are low in total dietary fiber.

Disruption of cell walls can increase fermentability of dietary fiber. Coarse wheat bran has a greater fecal bulking effect than finely ground wheat bran when fed at the same dosage [9], suggesting that the particle size of the whole grain is an important factor in determining physiological effect. Coarse bran delays gastric emptying and accelerates small bowel transit [10]. The effect seen with coarse bran was similar to the effect of inert plastic particles, suggesting that the coarse nature of whole grains as compared to refined grains has a unique physiological effect beyond composition differences between whole and refined grains. Although it is generally assumed that more refined grains will have less gastrointestinal effect, a recent study found that particle size of wheat bran did not alter effect on stool weight [11]. The smaller particle size bran did have more effect on fecal concentrations of butyrate, suggesting increased bacterial fermentation.

Several mechanisms have been proposed for the protective action of dietary fiber against cancer. Increased fecal bulk and decreased transit time allow less opportunity for fecal mutagens to interact with the intestinal epithelium. Secondary bile acids are thought to promote cell proliferation, thus allowing increased opportunity for mutations to occur and increased replication of abnormal cells. The effect of fiber on the actions of bile acids may be attributable to the binding or diluting of bile acids. Fermentation of dietary fiber results in production of short chain fatty acids which lower intestinal pH; this inhibits the conversion of primary bile acids to secondary bile acids. At low pH, the solubility of free bile acids is reduced, diminishing their availability for cocarcinogenic activity. Fermentation of dietary fiber results in production of butyrate, a short-chain fatty acid that has been shown to be antineoplastic [12]. Results of animal studies with dietary fiber have been inconsistent. Potential reasons for this inconsistency include the different types of fiber being fed to animals, species differences, different tumor-inducing agents and overwhelming levels of dietary fat, fiber or carcinogens in experiments.

Few epidemiologic studies collect biomarkers of gut function such as stool weight or transit time. Cummings et al. [13] collected data from 20 populations in 12 countries and found that average stool weight varied from 72 to 470 grams/day and was inversely related to colon cancer risk. It is known that different dietary fibers have different effects on stool weight. Wheat bran is most effective in increasing stool weight, with each gram of fiber fed as wheat bran increasing stool weight by 5.4 grams [14]. In contrast, soluble fibers like pectin only increase stool weight by 1.2 grams per gram of fiber fed.

When oat bran and wheat bran were compared for their laxation response, they had the same effect on stool weight, even though wheat bran is mostly insoluble fiber while oat bran is mostly soluble fiber [15]. Bacteria and lipids were the major contributors to the increase in stool weight with oat bran consumption, while undigested plant fiber was responsible for much of the increase in stool weight with wheat bran consumption. Thus the laxation properties of a fiber source cannot be predicted based on the solubility of the fiber.

Not all starch is digested and absorbed during gut transit. Factors that determine whether starch is resistant to digestion include the physical form of grains or seeds in which starch is located, particularly if these are whole or partially disrupted, size and type of starch granules, associations between starch and other dietary components, and cooking and food processing, especially cooking and cooling [3]. Because the starch in whole grains is believed to be more resistant to digestion than refined starch, whole grains should improve the gut environment.

Besides dietary fiber and resistant starch, grains contain significant amounts of oligosaccharides. Oligosaccharides are defined as carbohydrates with low (2–20) degree of polymerization. Common oligosaccharides include oligofructose and inulin. Wheat flour contains from 1% to 4% fructan on a dry weight basis [16]. Fructans have also been found in rye and barley with very young barley kernels containing 22% fructan [16]. Van Loo has estimated that wheat provides 78% of the North American intake of oligosaccharides [16].

Oligosaccharides are thought to have similar effects as soluble dietary fibers in the human gut. Additionally, oligosaccharides have consistently been shown able to alter the human fecal flora. Many human studies [17,18] find that consumption of fructooligosaccharides (FOS) increases bifidobacteria in the gut while decreasing concentrations of E. coli, clostridia and bacteroides.

2. Antioxidants
Oxidative stress results when the balance between the production of reactive oxygen species overrides the antioxidant capability of the target cell. The accumulation of oxidative damage has been implicated in both acute and chronic cell injury, including possible participation in the formation of cancer [19]. Antioxidants are compounds that delay the onset or slow down the rate of oxidation of oxidizable substrates. Whole grains contain many antioxidants, including vitamins, trace minerals and non-nutrients such as phenolic acids, lignans and phytoestrogens, and antinutrients such as phytic acid [20]. Whole grains are concentrated sources of vitamin E, especially tocotrienols. Whole grains are also rich sources of selenium, although selenium content of grains varies with soils. Trace minerals such as copper, zinc and manganese are also concentrated in the outer layer of grains, so milled grains are poor sources of trace minerals.

Phenolic acids are located in the bran layer of grains, and grains are thought to be particularly rich sources of phenolic acids. Durum wheat bran has been shown to have antioxidant activity in an in vitro model [21]. Ferulic acid was the phenolic acid in highest concentration in the wheat bran. The potentially anticarcinogenic mechanism of phenolic compounds involves the induction of detoxification systems, specifically the Phase II conjugation reactions. Wattenberg [22] classified caffeic and ferulic acids as inhibitors acting both by preventing the formation of carcinogens from precursor compounds and by blocking the reaction of carcinogens with critical cellular macromolecules. Phytic acid, concentrated in grains, is a known antioxidant [23]. Phytic acid forms chelates with various metals which suppresses damaging iron-catalyzed redox reactions [24]. Colonic bacteria produce oxygen radicals in appreciable amounts, and dietary phytic acid may suppress oxidant damage to intestinal epithelium and neighboring cells.

Vitamin E is another antioxidant present in whole grains that is removed in the refining process. Vitamin E is an intracellular antioxidant which protects polyunsaturated fatty acids in cell membranes from oxidative damage. Another possible mechanism for vitamin E relates to its capacity to keep selenium in the reduced state. Vitamin E inhibits the formation of nitrosamines, especially at low pH. Wattenberg [22] has characterized vitamin E as a cancer inhibitor that exerts its effect by preventing the formation of carcinogens from precursor compounds. Taken as a whole, the results of animal experiments on the effect of dietary vitamin E in cancer prevention have been inconclusive.

Selenium is another compound that is removed in the refining process. Its food composition is proportional to the selenium content of the soil in which the grain is grown. Selenium functions as a cofactor for glutathione peroxidase, an enzyme that protects against oxidative tissue damage. It has a suppressive action on cell proliferation at high levels. Wattenberg classifies selenium as a suppressing agent, an inhibitor that prevents the expression of neoplasia in cells that have been previously exposed to a carcinogen.

3. Phytoestrogens
Phytoestrogens, which include isoflavones, coumestans and lignans, are estrogenic compounds found in plants that have structural similarity to endogenous estrogens. They are proposed to have chemoprotective benefits [25,26], some of which may be mediated through their effect on endogenous sex hormone production, metabolism and biological activity [27]. Lignans have a diphenolic structure similar to estrogenic compounds, thereby creating interest in a possible estrogenic function for these compounds (Fig. 1). Consumption of certain plants has been known to alter fertility.

View larger version (10K): [in this window] [in a new window]   Fig. 1. Mammalian lignans enterodiol and enterolactone; estradiol.

Consumption of dietary fiber has also been proposed to be chemoprotective due to its influence on endogenous sex hormone levels [39]. Dietary fiber may partially interrupt the enterohepatic circulation of estrogen [40], resulting in increased fecal excretion of estrogens [41]. In premenopausal women, dietary fiber reduced serum estrone and estradiol [42]. Wheat bran reduced serum estrone and estradiol in premenopausal women [43].

Limited information exists on the concentration of lignans and their precursors in food. Due to the association of lignan excretion with fiber intake, it is assumed that plant lignans are contained in the outer layers of the grain. Concentrated sources of lignans include whole grain wheat, whole grain oats and rye meal [44]. Seeds are also concentrated sources of lignans, including flaxseed seeds (the most concentrated source), pumpkin seeds, caraway seeds and sunflower seeds. This compositional data suggests that whole grain breads and cereals are the best ways to deliver lignans in the diet.

Grains and other high fiber foods increase urinary lignan excretion, which is an indirect measure of lignan content in foods [45]. Mammalian lignan production of plant foods was studied by Thompson et al. [46] using an in vitro fermentation method with human fecal microbiota. Oilseeds, particularly flaxseed flour and meal, produced the highest concentration of lignans, followed by dried seaweeds, whole legumes, cereal brans, whole grain cereals, vegetables and fruits. Lignan concentration produced from flaxseed was approximately 100 times greater than that produced from most other foods.

Differences in metabolism of phytoestrogens among individuals have been noted. Adlercreutz et al. [45] found total urinary lignan excretion in Finnish women to be positively correlated with total fiber intake, total fiber intake per kilogram of body weight and grain fiber intake per kilogram of body weight. Similarly, the geometric mean excretion of enterolactone was positively correlated with the geometric mean intake of dietary grain products (kcal/day) of five groups of women (r = 0.996).

Due to the association of lignan excretion with fiber intake, plant lignans are probably concentrated in the outer layers of the grain. Because current processing techniques eliminate this fraction of the grain, lignans may not be found in processed grain products on the market and would only be found in whole grain foods. Thompson et al. [47] found significant differences in lignan content of flaxseed, depending on variety, harvest location, and harvest year, suggesting that extensive analysis of the lignan content of whole grains is warranted.

Estrogen metabolism has become a growing area of interest due to its proposed role in the etiology of breast cancer. Phytoestrogens are thought to alter serum hormones. Flax powder (10 g/day) increased average luteal phase length of the menstrual cycle in pre-menopausal women [48]. Any significant lengthening of the overall cycle length would be potentially beneficial in lowering risk for hormonally-dependent cancers. Additionally, estradiol and its oxidative product, estrone, can be metabolized along two irreversible, mutually exclusive hydroxylation pathways. These pathways form the metabolites 2-OHEstrogen² (including 2-OHE1 and 2-OHE2) and 16-OHE1 (Fig. 2) [49,50]. These metabolites are proposed to have differences in biological activity which may affect breast cancer risk.

View larger version (19K): [in this window] [in a new window]   Fig. 2. Oxidative metabolism of estradiol, (1) 16-hydroxylase, (2) 2-hydroxylase.

Certain factors have been shown to influence estrogen metabolism and the 2/16-OHE1 ratio. Indole-3-carbinol, a compound found in broccoli and other cruciferous vegetables, has been studied extensively and found to increase the 2/16-OHE1 ratio [55]. We have found that daily consumption of 10 grams of ground flaxseed may offer some protection against breast cancer in post-menopausal women by significantly increasing the urinary 2/16-OHE1 ratio [56]. Bradlow et al. [57] have proposed that altered estrogen metabolism exists prior to the onset of cancer and is not a byproduct of it. This suggests that influencing the hormonal environment in a protective fashion may help prevent cancer initiation. Further research is required to understand the biological mechanisms and the role in this process of phytoestrogens in whole grains.

4. Insulin Response and Obesity
Obesity and overweight have long been linked as risk factors in the development of cancer. Giovannucci [58] proposed that insulin and colon cancer were linked. He suggests that insulin is an important growth factor of colonic epithelial cells and is a mitogen of tumor cell growth in vitro. Epidemiologic studies find similarity of factors which produce elevated insulin levels with those related to colon cancer risk, including obesity and low physical activity. Two recent studies support the relationship between increased blood glucose and colon cancer. Schoen et al. [59] found that incident colon cancer was linked to higher levels of blood glucose and insulin and larger body weight. Hu et al. [60] noted the similarity of lifestyle and environmental risk factors for type 2 diabetes and colon cancer. They examined the relationship between diabetes and risk of colorectal cancer in the Nurses’ Health Study and found that they were significantly related, with women with diabetes having increased risk of colorectal cancer.

Stoll [61] suggested that breast cancer also is linked to the insulin resistance syndrome. Incidence of breast cancer in the Western world runs parallel to that of the major components of the insulin resistance syndrome, hyperinsulinemia, dyslipidemia, hypertension and atherosclerosis. Nutritional and lifestyle modifications that improve insulin sensitivity may reduce breast cancer risk in women.

The glycemic index is used to compare the glycemic response to foods. The glycemic index is defined as the incremental area under the blood glucose response curve for the test food divided by the corresponding area after an equicarbohydrate portion of white bread, multiplied by 100. It is known that glycemic response is affected by many physiological factors. Other factors affecting the response include the form of the food, cooking, processing, fat content of the food and soluble fiber content of the food.

Whole foods are known to slow digestion and absorption of carbohydrates. Studies have shown that postprandial blood glucose and insulin responses are greatly affected by food structure [62]. Any process that disrupts the physical or botanical structure of food ingredients will increase the plasma glucose and insulin responses. Food structure was found to be more important than gelatinization or presence of viscous dietary fiber in determining glycemic response in a recent study [63]. Another recent study found the importance of preserved structure in foods as an important determinant of glycemic response in diabetics [64]. Refining grains tends to increase glycemic response, and, thus, whole grains should slow glycemic response [65].

Jenkins et al. [66] found that breads made with a high proportion of whole cereal grains reduced the postprandial blood glucose profiles in diabetics because they are more slowly digested than white bread controls or "whole meal" bread made from milled flour. Thus, bran alone may not be as effective as whole grains. This suggests that it is the combination of compounds, including resistant starch and phytate in grains, rather thanjust the dietary fiber that slows digestion and absorption of carbohydrates.

Heaton et al. [67] compared glucose response when subjects consumed whole grains, cracked grains, whole grain flour and refined grain flour. Plasma insulin responses increased stepwise, with whole grains less than cracked grains less than coarse flour less than fine flour. Oatbased meals evoked smaller glucose and insulin responses than wheat- or maize-based meals. Particle size influenced the digestion rate and consequent metabolic effects of wheat and maize, but not oats. They suggest the increased insulin response to finely ground flour may be relevant to the etiology of diseases associated with hyperinsulinemia and to the management of diabetes.

One of the environmental contributors to the obesity epidemic is our calorically dense food supply and lack of exercise. When obese teenage boys were studied, intake of high glycemic index foods was 81% greater than that of low glycemic index foods [68]. The authors conclude that the rapid absorption of glucose after consumption of high-GI meals induces a sequence of hormonal and metabolic changes that promote excessive food intake in obese subjects. Additional studies are needed on differences between grain products and glucose and insulin response.

	CONCLUSION

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Whole grains are rich in many components, including dietary fiber, starch, fat, antioxidant nutrients, minerals, vitamin, lignans and phenolic compounds, all of which have been linked to reduced risk of cancer. Most of the components are found in the germ and bran which are reduced in the grain refining process. The most potent protective components of whole grains need identification so efforts can be directed to minimize the losses of physiologically important constituents of grains during processing. Additional research on the mechanisms by which whole grains protect against cancer is needed.

Received February 1, 2000.

	REFERENCES

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