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Major studies of the Mediterranean dietary pattern on cancer outcomes have been few, but they suggest a general reduction in diet- related cancers for consumers of these diets (Table 6.1). In addition to diet, other lifestyle factors, such as exercise, may make positive contributions to health and diseases, but some lifestyle factors also may have adverse effects. For example, cigarette smoking remains an impor-tant adverse factor for diet- related cancers and lung cancer, which continue to be major causes of death in many Mediterranean nations. Because cancer has many contributing factors, both positive and adverse, researchers have had difficulty teas-ing out specific dietary factors, such as antioxidant nutrients and phytochemicals, that may help reduce cancer morbidity and mortality. Nevertheless, several plant foods common to Mediterranean diets are considered to help reduce the risks of the diet- related cancers, especially when used together in an overall healthy dietary pat-tern (see below).

The associations (or linkages) between various dietary risk factors and cancer remain incompletely understood and somewhat speculative, but we know that nutri-tion has an enormous impact on cell funcnutri-tioning in the various organ systems and on aging and longevity. Both excessive dietary energy (caloric intake) and fat con-sumption have been linked to higher cancer rates. Beneficial health associations (i.e., lower rates of breast or colon cancer) have been suggested for diets low in fat

and high in vegetables and whole grains. Cancer causation is complex and involves many lifestyle factors in addition to a specific dietary intake pattern. Animal studies, for example, suggest that a high- fat diet promotes breast cancer development, but the initiation (first event) has to have been triggered by some other factor than dietary fat. Specific information about dietary factors involved in human carcinogenesis remains difficult to establish. Differences in dietary patterns between Western and Asian nations may provide clues about the beneficial or adverse effects of dietary variables (Table 6.2). Mediterranean diets, although more Western in specific food

TABLE 6.1

Mediterranean Diets and Cancer Prevention: Protective versus Pro- Cancer Nutrients or Components

Protective Nutrients or Components Pro- Cancer Nutrients or Components Modest energy (macronutrients) Excessive energy

Moderate MFAs and omega-3 PFAs High SFAs

Moderate vitamins and minerals Low amounts of vitamins and minerals High amounts of phytochemicals Low amounts of phytochemicals

Moderate amounts of sodium and potassium High amounts of sodium; low amounts of potassium Variety of plant foods Emphasis on animal foods

Olive oil Butter or corn- based margarine

Red wine Beer and liquor

Note: MFA, monounsaturated fatty acid; PFA, polyunsaturated fatty acid; SFA, saturated fatty acid.

TABLE 6.2

Differences in Dietary Patterns between Western and Asian Nations

Nutrient Intakes Western Nations (e.g., United States) Asian Nations (e.g., Japan)

Energy High, typically excessive Modest

Dairy fats Moderate to high Low

Meat fats High Low to moderate

Fish protein Low Moderate to high

Seafood protein Low Moderate to high

Carbohydrates Wheat- based breads and the like Rice, rice- based foods

Dark greens Low Moderate to high

Beans, soy, and so on Low to moderate Moderate to high

Fruits Low to moderate Moderate

Salt Low to moderate High

Typical Cancers Western Nations Asian Nations

Breast/ prostate Moderate to high Low to moderate

Colon Moderate to high Low to moderate

Gastric Low Moderate to high

Diet- Related Cancers and Other Diseases 71

choices, do contain many of the same food items found in Asian diets, and the gener-ally well- accepted Mediterranean dietary patterns have a high likelihood of provid-ing many cancer chemopreventive components.

excessive energy, fAt, And diet- relAted cAncers

Findings from experimental animal studies, from migration studies, and from other epidemiological studies have established strong associations, if not causation, between dietary factors and various types of cancers.

Total caloric intake is a risk factor for cancer. Excessive caloric intake has recently been closely linked with cancer as a result of excessive body fat and high body mass index (BMI). Calorie- restricted diets in experimental animals clearly have resulted in decreased tumor rates and increased longevity without any other treatment, but similar human studies have not been able to duplicate these reduc-tions. Excessive body weight has been shown in epidemiologic studies to contribute to increased cancer rates, but linkages with specific dietary variables have not been found consistently.

Dietary fat long has been suspected as a major factor in cancer causation, but data have failed to support a significant linkage between total fat intake and cancer. Type of fat, however, may be more significant for cancer causation than total fat. Animal data on dietary fats help distinguish these two variables. High- fat intakes contribute to increased tumor rates, especially if the fat consumed is high in polyunsaturated fatty acids (PFAs; both omega-3 and omega-6) because the double bonds in mem-brane components readily are attacked by free radicals. Human experimental stud-ies, however, have not provided data that clearly link dietary fat or type of fat and cancer. Epidemiologic studies suggested a relationship between obesity and breast cancer, but data on fat per se or the specific types of fatty acids are conflicting. One study of a large population (cohort) in Japan, however, reported that increased fat consumption from meats among more affluent women contributed to significantly higher rates of breast cancer among those over 50 years of age. Yet, a large study in the United States, the Women’s Health Initiative, failed to find a significant contribu-tion of total dietary fat to breast cancer. Human studies examining the relacontribu-tionship between type of fat, such as omega-3 fatty acids, and breast cancer have not yet been reported. Recent studies strongly support the hypothesis that obesity, from excessive energy intake relative to activity rather than fat per se, is a major factor in the devel-opment of cancers of the breast, prostate, and possibly the colon.

Olive oil, primarily virgin oil, is considered to be a major anticarcinogenic com-ponent of Mediterranean diets. Olive oil provides considerable amounts of mono-unsaturated fatty acids (MFAs), mainly oleic acid, plus antioxidants. These two components act by different mechanisms to prevent cancer or to reduce cancer rates.

Tumor growth and progression are decreased, according to experimental data, from long- term consumption of olive oil. Cancer development may take several decades before it can be detected. Healthy dietary habits should begin as early in life as pos-sible to be most effective in cancer reduction through adult life. Late- life dietary changes are still thought to help protect against cancer.

Protein intakes at high levels (i.e., 20% or more of total energy consumption) have not been found to be consistently and independently associated with cancer rates in epidemiologic studies. The fat association is stronger and probably masks any effect of protein per se because the intakes of fat and protein are highly cor-related. In animal studies, high intakes of protein at levels several times the daily requirements, however, contribute to increased cancer rates. Low intakes of protein, on the other hand, may inhibit carcinogenesis. Human evidence on this association is almost nonexistent; therefore, an explanation based on protein intake is highly speculative. In terms of mechanisms, insulin and insulin- like growth factors (IGFs) have been implicated in cancer initiation. Insulin and IGFs promote growth when energy intakes are adequate or excessive; hence, they may overstimulate some rap-idly dividing cells into hyperproliferation and subsequent cancer.

The immune system is also thought to play an important role in cancer develop-ment. The immune system, especially the cell- mediated arm, is sensitive to deficien-cies of the macronutrients, especially high- quality protein, and of several vitamins and trace elements. The immune system (i.e., cells involved in defense against viruses and bacteria) may function less well when a healthful nutritional pattern is not fol-lowed (i.e., intakes remain below the optimal range). For example, excessive energy intake coupled with micronutrient deficits may reduce the efficacy of the immune system in both the neutralization of viruses and foreign agents and in removal of precancerous and cancerous cells. Viruses (such as hepatitis and human papilloma viruses) and other infectious agents are less well defended against by the humoral arm (immunoglobulins and other related molecules in blood) of immune defense mechanisms. The cellular arm of immunity (i.e., lymphocytes and monocytes) also may be far less effective. The complexity of involvement of the immune system in cancer development should be recognized, but further development of this topic is beyond the scope of this text. Healthy balanced nutrition typically supports both arms of the immune system in their protective roles against infectious organisms and cancer development.

insufficient i^ntAkesof MicronutrientsAnd AntioxidAnts And diet- relAted cAncers

Micronutrients in the diet that protect against the development of cancer are known as anticarcinogens because they either counteract the action of carcinogens or prevent the activation or expression of carcinogens. Examples of anticarcinogens include β- carotene (a precursor of vitamin A), vitamin C (ascorbic acid), vitamin E, antioxidant food additives, selenium, and possibly a few other micronutrients. (See further discussion in this section for the opposite outcome in cigarette smokers who took antioxidant supplements.) The mechanisms by which these substances act and possibly interact in cancer inhibition are emerging. Although not fully established, a common mechanism may explain the action of many of these anticarcinogens.

Antioxidants prevent, in theory at least, the oxidative step or steps that are appar-ently necessary for the activation of carcinogens. Cancers may result when such naturally occurring micronutrient antioxidants, such as β- carotene and vitamins C

Diet- Related Cancers and Other Diseases 73

and E, are chronically deficient in the diet. The potential cancer chemopreventive roles of micronutrients (i.e., vitamins and minerals), a few phytochemicals, and other nutrients characteristic of Mediterranean diets are listed in Table 6.3. The potential cancer chemopreventive roles of specific nutrients and phytochemicals are presented in this section.

Whole grains provide many micronutrients that have chemopreventive properties.

Several vitamins or minerals are removed from the “germ” and “bran” fractions of cereals, at least in part, during the processing of wheat and other grains. Therefore, selected chemopreventive components are reduced by the processing, the losses being greater with greater processing. See Chapter 10 for more information on the milling process and fortification of flour.

Among the B vitamins, deficiency of dietary folic acid has been shown in epide-miologic investigations to be associated with colonic disorders, including adenomas;

however, other B vitamins also could play a role in the prevention of cancer.

Therefore, folic acid and probably a few other B vitamins may need to be consumed at recommended dietary allowance (RDA) levels to protect against the development of diverse cancers. Choline, classified as a B vitamin, also may have an anticarcino-genic role because of its chemical properties.

Vitamin C, or ascorbic acid, also serves as an antioxidant and, hence, as an anti-cancer nutrient. Vitamin C prevents conversion of carcinogen precursors to carcino-gens (e.g., by blocking the modification of nitrites or nitrates to nitrosamines). It also serves as an antioxidant in cells and plays a role in immune defense. However, vitamin C has been examined for its protective role against cancer in animal stud-ies and human populations without conclusive results. Some data suggest that lower cancer incidence rates, especially for gastric and esophageal cancers, are associated with reasonable consumption of foods containing vitamin C, but the protective role of vitamin C against breast cancer and other hormone- dependent cancers has not been supported by epidemiologic findings. In addition to inhibiting carcinogens in the oral cavity and esophagus, vitamin C may help prevent cancers in the lungs and urinary bladder, but it does not appear to be critical in the prevention of reproduc-tive cancers and colon cancer. Clearly, much more work is needed on the vitamin C– cancer linkage.

TABLE 6.3

Significant Dietary Items of Mediterranean Diets that Help Reduce the Risks of Various Cancers

Antioxidants Binders in Gut Other Functions Vitamins^a: C, E Dietary fiber Choline: methyl donor Minerals: Se, Zn Calcium, magnesium Folate: cell maturation Phytochemicals, phenolics,

resveratrol, other

Omega-3 fatty acids:

membrane stability Note: Se, selenium; Zn, zinc.

a β- Carotene and other carotenoids also function as antioxidants.

Vitamin E (tocopherols and tocotrienols) protects membranes against free radical damage and may prevent chemically induced cancers in animals. Beta- hydroxytoluene (BHT) and beta- hydroxyanisole (BHA), antioxidant food additives, are thought to act in a similar manner. Little human data, however, exist to make specific dietary recommendations for vitamin E intake. Plant foods, especially whole grains, remain the primary sources of vitamin E. Adults have great diffi-culty obtaining sufficient amounts of dietary vitamin E to meet their DRIs (Dietary Reference Intakes), but even so, deficiency signs of this vitamin have not been found in practically all regions of the world. Vitamin E and β- carotene supplements were not found, however, to protect against cancer growths in the lungs of supplemented cigarette- smoking men in Finland. These antioxidant supplements probably promote growth after the initiation of lung and possibly other cancers. Normal food intake of these antioxidant nutrients is considered safe and healthful. For example, vitamin E molecules in both unfortified and fortified foods are still considered to be important anticarcinogens (i.e., protective prior to cancer initiation). The distinction between food- borne and supplemental antioxidant nutrients is critical.

An interaction between vitamins E and C operates in close association with cell membranes. Vitamin E is stored within the fat component of membranes and vita-min C in the watery compartment of cells near the membranes. Vitavita-min C molecules help reduce vitamin E molecules so that they can continue to function as antioxi-dants while vitamin C molecules are oxidized and subsequently excreted in urine.

Vitamin E does not therefore need to be replaced in the diet on a regular basis, but vitamin C molecules must be replaced daily to help maintain functional vitamin E molecules within cell membranes.

A few macrominerals, or bulk elements, also may serve in chemopreventive roles in cells. For example, a dietary deficiency of calcium (with or without sufficient vita-min D) also may contribute to the development of colon cancer and possibly prostate cancer. Results of a few recent trials in the United States suggest that increasing dietary calcium, and increasing vitamin D, may offer some protection against colon cancer and possibly prostate and other cancers. A more effective use of calcium by

BOX 6.1 ANTIOXIDANTS AND CANCER