REVIEW

Dietary Fat and Prostate Cancer: Current Status

Laurence N. Kolonel, Abraham M. Y. Nomura, Robert V. Cooney

Affiliation of authors: Cancer Etiology Program, Cancer Research Center, University of Hawaii, Honolulu.

Correspondence to: Laurence N. Kolonel, M.D., Ph.D., Cancer Research Center of Hawaii, 1236 Lauhala St., Suite 407, Honolulu, HI 96813 (e-mail: larry{at}crch.hawaii.edu).


    ABSTRACT
 Top
 Abstract
 Introduction
 Role of Fatty Acids...
 Epidemiology
 Animal Studies
 Mechanistic Basis for Fat...
 Research Directions
 References
 
Efforts to elucidate the causes of prostate cancer have met with little success to date. All that is known with certainty is that the incidence increases exponentially with age, varies by geography and by race or ethnicity, and is higher among men whose father or brother had the disease. Because the incidence changes in migrants and their offspring, exogenous factors certainly contribute to the risk of prostate cancer. Early epidemiologic studies implicated dietary fat asa likely causal factor for this cancer. However, scientific support for such an association has diminished in recent years as more epidemiologic evidence has accrued. Accordingly, we reviewed the relevant English language literature on this topic, including epidemiologic and animal studies, as well as current concepts regarding the involvement of fat in carcinogenesis to re-examine the fat-prostate cancer hypothesis. We conclude that dietary fat may indeed be related to prostate cancer risk, although the specific fat components that are responsible are not yet clear. Given the diverse effects of fatty acids on cellular biology and chemistry, it seems likely that the relationship is complex, involving the interplay of fat with other dietary factors, such as antioxidant vitamins and minerals, or with genetic factors that influence susceptibility. Some suggestions for further research are offered.



    INTRODUCTION
 Top
 Abstract
 Introduction
 Role of Fatty Acids...
 Epidemiology
 Animal Studies
 Mechanistic Basis for Fat...
 Research Directions
 References
 
Compared with other major cancers, such as breast or colon, the epidemiologic literature on prostate cancer is not extensive (1). Furthermore, the body of animal data relevant to understanding carcinogenesis in the human prostate is also limited. This may explain, at least in part, why few risk factors for this cancer have been identified. The main predictors of risk for adenocarcinoma of the prostate are age, race, and a positive family history: The incidence increases dramatically above 50 years (2), is remarkably high in African-Americans (3), and is higher in men whose father or brother(s) have had the disease (4-7). Unfortunately, these are not modifiable risk factors; at best, they can be used to identify men who should receive heightened cancer surveillance.

Although little is known about specific causal factors, it is likely that endogenous androgen metabolism plays a role in the etiologic pathway. Androgens (especially dihydrotestosterone [DHT]) control cell growth in the prostate (8), and reduction in androgen production through orchiectomy or chemical inhibition has been a long-standing treatment for prostatic adenocarcinoma (9). Although the data on serum androgen levels in relation to prostate cancer risk are conflicting (1), serum levels of androgens may not adequately reflect concentrations at the site of interest, the prostate gland itself. Furthermore, polymorphisms in the androgen receptor gene may result in differential responsiveness of prostate tissue to androgen exposure. The identification of functional polymorphisms in this and other genes related to androgen metabolism (such as the 5{alpha}-reductase type II gene that controls conversion of testosterone to the more metabolically active DHT) may help to clarify hormone-cancer relationships (10-12).

The observation that rates of prostate cancer change in migrants and vary dramatically in ethnically similar populations residing in different geographic locations (13) strongly indicates that environmental factors can greatly influence the risk of this cancer. Diet is one exposure that varies among geographic areas and that can change dramatically in migrants. Furthermore, there is evidence that diet can influence endogenous androgen levels (14-16). Thus, diet has been an area of considerable research interest in the search for modifiable risk factors for prostate cancer.

Fat has been the focus of dietary studies of prostate cancer more than any other dietary component. Early epidemiologic studies of this relationship were surprisingly consistent and suggested a possible causal association (17,18). However, as the literature on the topic expanded, the evidence became less consistent, and what earlier appeared to be the strongest case for a fat-cancer association now became more tenuous (19). The purpose of this review, therefore, was to reassess the status of the fat-prostate cancer hypothesis by a systematic examination of the relevant epidemiologic and animal literature on specific components of fat and prostate cancer and a consideration of current concepts of fat carcinogenesis. Two questions we hoped to address were: Is further research on this topic worthwhile and likely to be productive? Are there particular gaps in knowledge that should be investigated? For this review, epidemiologic and animal studies on the subject of fat and prostate cancer were identified using the MEDLINE® database of the National Library of Medicine. Only studies published in English were included.

We begin with a brief review of the role of fat in human nutrition as a background for the uninitiated reader. This is followed by a review of the epidemiologic evidence and then the animal data on the role of fat in the causation of prostate cancer. This discussion is augmented by a brief review of plausible mechanisms for the carcinogenic effects of dietary fat, especially with regard to the prostate. In a concluding section, some suggestions are made for future research, as prompted by this review.


    ROLE OF FATTY ACIDS IN NUTRITION
 Top
 Abstract
 Introduction
 Role of Fatty Acids...
 Epidemiology
 Animal Studies
 Mechanistic Basis for Fat...
 Research Directions
 References
 
Fatty acids are generally found in foods and in the fat depots of humans as triacylglycerols (also called triglycerides or neutral fats), in which three fatty acids are esterified to one molecule of glycerol, or in cellular membranes as phopholipids, in which one of the fatty-acid esters is replaced with phosphate ester bound to a polar headgroup, such as choline, serine, inositol, or ethanolamine. Fatty acids, as part of phospholipids, are integral components of cellular membranes that function to maintain cellular integrity and regulate the activities of many membrane enzymes. Fatty acids usually contain even numbers of carbon atoms and are of three major classes (Fig. 1):Go the saturated fatty acids (containing no carbon-carbon double bonds), the monounsaturated fatty acids (one carbon-carbon double bond), and polyunsaturated fatty acids (two or more carbon-carbon double bonds). The polyunsaturated fatty acids are further classified according to the position of the first carbon-carbon double bond as counted from the methyl end of the fatty acid; e.g., an {omega}-3 fatty acid has a double bond at the third carbon from the methyl end (Fig. 1Go). Fatty acids provide a source of concentrated energy for cellular metabolic needs through the sequential removal and oxidation of two-carbon units. The energy yield from the complete oxidation of a fatty acid is approximately 9 versus 4 kcal/g for carbohydrates and proteins (20). The high energy content of fatty acids has made it difficult to separate the intrinsic effects of fat intake from those associated with higher caloric intake.



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Fig. 1. Representative structures of fatty acid classes. C = number of carbon atoms; DB = number of carbon-carbon double bonds; S = saturated; M = monounsaturated; and P = polyunsaturated.

 
Unsaturated fatty acids occur in two geometric conformations, cis and trans, but are generally found in nature as the cis form. Trans fatty acids are most often produced during the manufacturing process for many vegetable oil products such as margarine. Concern for the possible health effects of trans fatty acids has recently been raised (21); however, this aspect of dietary fat has yet received little attention in epidemiologic studies of prostate cancer.

Although membrane fatty acid levels can be altered somewhat by dietary manipulation (22), there is much evidence to suggest that cells regulate membrane composition of fatty acids to meet specific cellular needs, either through selection of particular fatty acids or by regulating synthesis of essential fatty acids (23). Temperature has been identified as one variable that can affect fatty acid composition in adipose tissue, allowing cells to maintain membrane fluidity despite variation in external temperature (24). Generally, fatty acids with unsaturated double bonds are found to have lower melting points and maintain a higher degree of fluidity in membranes (25); consequently, one often observes higher degrees of unsaturation in plant oils from colder climates (26). The higher saturated fat content of many mammals is likely facilitated by the higher body temperature of warm-blooded animals, whereas cold-water fish require higher levels of unsaturation. Fatty acid composition varies more between organs or tissues within a species than it does between species for the same organ or tissue (27), suggesting that fatty acid composition is regulated by cell type and serves specific functions in various tissues. Fatty acid metabolism is tightly controlled, so that degradation and synthesis are highly responsive to physiologic needs. Fatty acid synthesis is maximal when carbohydrates and energy are plentiful and when fatty acids are scarce (20). Humans can endogenously synthesize most of their necessary fatty acids, except for the polyunsaturated fatty acids linoleic (C18:2,{omega}-6) and linolenic acid (C18:3,{omega}-3) that are obtained from a variety of dietary sources, such as vegetable oils, red meat, and dairy products. Linoleic acid can be further metabolized to arachidonic acid, an important precursor for the biosynthesis of eicosanoids, such as prostaglandins (28).


    EPIDEMIOLOGY
 Top
 Abstract
 Introduction
 Role of Fatty Acids...
 Epidemiology
 Animal Studies
 Mechanistic Basis for Fat...
 Research Directions
 References
 
Total, Saturated, and Animal Fat

In most Western populations, animal foods are the primary source of saturated fat in the diet; thus, these two components are not easily distinguished. Similarly, since saturated fat comprises the largest proportion of total fat, these two measures are also highly correlated and not easily separated. Therefore, all three measures of dietary fat exposure are often combined in research reports and they are considered together here.

The hypothesis that dietary fat might be related to prostate cancer was suggested by initial ecologic analyses showing a strong positive correlation between prostate cancer mortality and per capita intake of fat, meat, and milk in international comparisons (29,30). Subsequent reports of ecologic analyses confirmed these findings and showed positive associations with animal and saturated fat in particular (Table 1)GoGoGo (31-36). Only one report, based on 24-hour diet records with adjustment for energy intake, found no association with saturated fat (37).


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Table 1. Summary of results from epidemiologic studies of total fat, animal fat, or saturated fat and prostate cancer

 

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Table 1 (continued). Summary of results from epidemiologic studies of total fat, animal fat, or saturated fat and prostate cancer

 

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Table 1 (continued). Summary of results from epidemiologic studies of total fat, animal fat, or saturated fat and prostate cancer

 
Several analytic epidemiologic studies (i.e., studies that relate exposures to disease outcomes in individuals) also examined the fat hypothesis in relation to prostate cancer, based on dietary recall information (Table 1GoGoGo). Many early studies computed total caloric intake by use of dietary protocols that were not sufficiently comprehensive; consequently, it was not possible to adjust for energy in these studies. Because dietary fat intake is very highly correlated with energy intake in most Western populations, a positive association with fat could represent an indirect measure of a relationship with caloric intake in the absence of energy adjustment.

Among the many case-control studies (40,41,44,46,49,50,53) that have examined total, saturated, or animal fat, several reported positive findings; however, only one of these studies (53) included energy adjustment. Other case-control studies (54,56,58,59) that adjusted for energy intake and two that did not make such adjustments (45,48) found no significant association with either total, saturated, or animal fat intake. Several studies (38,39,42,43,47,51,52,57) reported only on intake of foods, rather than of specific nutrients, and found positive associations between prostate cancer risk and the intake of meat, dairy items, or eggs, with but one exception (55).

Only two cohort studies (66,69) reported on dietary intake of total and saturated fat in relation to prostate cancer risk, and both included adjustment for energy intake (Table 1GoGoGo). One of these studies (66), which was based on 4 years of follow-up, found a positive association for advanced prostate cancer with consumption of total and saturated fat, although the association did not persist after additional adjustment for other fat components; a positive association with animal fat in this study was primarily due to the intake of red meat. The second study (69) was based on a much longer period of follow-up (>10 years) and found no association with either total or saturated fat intake. The remaining cohort studies reported only on associations with food intake. Several of these studies found positive associations with meat consumption (62,64,67,68) as well as with other high-fat foods (62-64,67). Two cohort studies (61,65) reported no associations with foods high in fat.

Two studies (60,68) that analyzed prediagnostic serum or plasma have reported on the relationship of specific saturated fatty acids to prostate cancer risk (Table 1GoGoGo). One of these studies (68) compared case patients and control subjects in a prospective cohort; of the saturated fatty acids examined, none was associated with prostate cancer risk. The other study (60) used stored samples from a serum bank in Norway and found a positive association for palmitic acid (C16:0) and an inverse association for tetracosanoic acid (C24:0). It is important to note that these analyses compared relative, rather than absolute, intakes of fatty acids. It is not known which of these measures may be more important in the causal mechanisms of prostate cancer.

Unsaturated Fat

Support for an association between unsaturated fats and prostate cancer based on ecologic studies (i.e., studies that relate disease to aggregate data on groups) is weak (Table 2).Go One study (36) showed a weak inverse correlation between monounsaturated fat consumption and prostate cancer incidence, whereas two other studies (34,37) that adjusted for energy intake found no association. The ecologic findings for total polyunsaturated fat, and for {omega}-3 and {omega}-6 polyunsaturated fats specifically, offer little support for an association with prostate cancer (34,36,37). One study (33) examined the consumption of vegetable fat, which is largely unsaturated, in relation to prostate cancer mortality and found no correlation.


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Table 2. Summary of results from epidemiologic studies of unsaturated fat and prostate cancer

 
Most analytic epidemiologic studies of dietary intake of monounsaturated fat and prostate cancer found no association (Table 2Go). These include five case-control studies (49,54,56,58,59), only one of which (49) reported a positive association, and two cohort studies (66,69), both of which had null findings. Except for the study with the positive finding, each of these studies adjusted for energy intake. On the other hand, two studies (60,68) based on prediagnostic serum levels of monounsaturated fatty acids found a positive association (although not a statistically significant one) with oleic acid (C18:1), and one of these studies (60) found a statistically significant positive association with palmitoleic acid (C16:1).

Findings for dietary intake of polyunsaturated fats as a group, including five case-control studies (49,54,56,58,59) and one cohort study (69), are also largely null. Positive associations were reported in two of the case-control studies (49,58), but only one of these was statistically significant (49) (Table 2Go). Two studies (60,71) based on measurements in prediagnostic serum also found no significant association with polyunsaturated fatty acids overall or by subgroup ({omega}-3 or {omega}-6).

A few studies have examined specific polyunsaturated fatty acids (Table 2Go). The results with regard to {alpha}-linolenic acid (C18:3, {omega}-3), an essential fatty acid (i.e., derived solely from the diet), have been particularly interesting. {alpha}-Linolenic acid—an {omega}-3 polyunsaturated fatty acid that comprises only a very small proportion of the fatty acids in tissues—is obtained from terrestrial foods (primarily red meat, dairy products, soybean, and rapeseed oils) but not from fish. Dietary intake of {alpha}-linolenic acid was assessed in one cohort study (66) that found a positive association with prostate cancer risk among advanced cases and in one case-control study (56) that did not find any association. Four other studies (60,68,70,71) examined this relationship based on biochemical analyses. Two of these studies (68,71) used prediagnostic serum or plasma from prospective cohorts in a nested case-control design and one study (60) selected case patients and control subjects from a serum bank. The fourth study (70), using a case-control design, examined fatty acids in blood erythrocyte membranes and in subcutanous fat samples. Two of the studies (60,68) found positive associations between {alpha}-linolenic acid level and prostate cancer risk (statistically significant in one of the studies), whereas the third study (71) reported no association with any {omega}-3 polyunsaturated fatty acids. The fourth study found a weak positive association with {alpha}-linolenic acid that was not statistically significant. Interestingly, marine {omega}-3 fatty acids did not show a similar positive association in any of these investigations (60,66,68,70).

A number of these studies (56,60,66,68,70,71) also examined linoleic acid (C18:2,{omega}-6), another essential fatty acid, found in high concentration in vegetable oils. Based on dietary intake data, an inverse association (not statistically significant) was found for linoleic acid in the cohort study (66) but not in the case-control study (56). Of the biochemical studies, one (68) reported a statistically nonsignificant inverse association for this fatty acid, one (70) a positive association (P = .05), and two (60,71) no association. These discrepancies in results may, in part, be related to the occurrence of two different isomers (cis- and trans-) of these unsaturated fatty acids in the diet. Whereas most naturally occurring fatty acids have the cis- configuration, industrial hydrogenation of liquid oils leads to the generation of substantial amounts of trans-fatty acids. These isomers may have different biologic properties, but most studies to date have not distinguished between them.

Cholesterol

Cholesterol has been examined in a few dietary studies of prostate cancer. Positive associations were reported in two case-control studies that did not adjust for energy intake (46,49) but not in two others that did (54,56). Eggs are an important dietary source of cholesterol but are a minor contributor to total fat intake. The major fatty acid in eggs is oleic acid (43%), followed by palmitic acid (27%) and linoleic acid (14%); {alpha}-linolenic acid is a very minor constituent of eggs (0.4%) (72). Two (51,53) of three case-control studies (51-53) reported positive associations between egg consumption and prostate cancer. However, four (62,64,65,67) of five (62-65,67) cohort studies found no association.

Other researchers investigated the relation between serum cholesterol and prostate cancer. Three (73-75) of four prospective cohort studies reported no association with prostate cancer incidence, while the fourth (76) found that men with low serum cholesterol levels had an increased risk. It was suggested that the inverse association may reflect preclinical disease. In a separate cohort study based on mortality, there was no relation of serum cholesterol to prostate cancer (77).

Interpretation of the Epidemiologic Evidence

Some limitations of the epidemiologic evidence reviewed above bear mentioning, since they may partially account for the inconsistencies in the literature. Already noted is the fact that dietary fat is highly correlated with total caloric intake in most Western populations, and only a few of the many studies were able to adjust for energy intake in the analyses. A second methodologic limitation is the potential for recall bias in case-control studies, because case patients may recollect their eating behavior differently from control subjects. Until very recently, however, it is likely that few men would have heard of the hypothesis that diet, and dietary fat in particular, is related to prostate cancer risk. Although recall bias should not be an issue in cohort studies, such studies usually obtain their dietary information at a single, arbitrary point in adult life (entry into the cohort). Substantial error can be introduced if dietary habits change over time and are not recorded in the study. A related concern is that the relevant time period for exposure to dietary fat in relation to prostate cancer risk has not been established. In one case-control study (78) that assessed dietary intake in adolescence as well as adulthood, a positive association was found with saturated fat intake in adulthood but not in adolescence, suggesting a role of fat as a promoter. However, the findings could also be accounted for by greater recall misclassification for more distant dietary intake, as pointed out by the authors.

Considering the epidemiologic evidence as a whole, and with these caveats in mind, an association between dietary fat and human prostate cancer must, at present, be viewed as tentative. There is a high degree of consistency to the findings with regard to consumption of animal foods, particularly meat, which are a major fat source in the diet of most of the populations studied. This association with meat, as well as that with dairy products in many studies, could account for the positive association of prostate cancer with {alpha}-linolenic acid in several studies. Although the findings with regard to meat and dairy items suggest a causal role for fat, this interpretation requires caution. Such a dietary pattern has many other correlates. A high-meat/high-fat diet generally entails a lower intake of plant foods that contain possible protective factors against prostate cancer. Studies of vegetable and fruit intake in relation to prostate cancer risk have been inconsistent, however, and few have shown clear inverse relationships (19). In addition to fat, a diet high in animal products results in greater exposure to other constituents of these foods, such as zinc or calcium, that may adversely affect the prostate. Meat, especially red meat, is a major source of zinc in the American diet (79). Epidemiologic data on zinc and prostate cancer are limited but suggest a possible positive association (46,80-83). Dietary calcium and foods high in calcium content have been associated with increased risk of prostate cancer in prospective (84-87) and case-control (39,88-91) studies. Finally, a diet high in meat can result in significant exposure to carcinogenic chemicals (notably polycyclic aromatic hydrocarbons and heterocyclic amines) that are generated when meats are prepared by such methods as smoking or grilling at high temperatures (92,93). A prevalent heterocyclic amine in such meats, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), was recently shown to be carcinogenic for the prostate in F344 rats (94).


    ANIMAL STUDIES
 Top
 Abstract
 Introduction
 Role of Fatty Acids...
 Epidemiology
 Animal Studies
 Mechanistic Basis for Fat...
 Research Directions
 References
 
Research on prostate cancer in humans has been hampered in the past by the lack of a suitable animal model. Small laboratory animals seldom develop this tumor. There is no record of any spontaneous prostatic neoplasm occurring in mice (95). Rats have a very low incidence of grossly observable cancerous lesions of this gland. The first report of a spontaneous tumor of the rat prostate was published in 1963 (96). A similar observation was made 10 years later in germfree Lobund Wistar rats (97). There is a single report of spontaneous prostatic adenocarcinoma occurring in two of 94 male Syrian hamsters (98).

In addition to the infrequent occurrence of this tumor in rodents, their prostate gland differs anatomically from that of humans. The rodent prostate gland has several separate lobes (95,99). In humans, the prostate is a rounded mass of smooth muscle and connective tissue filled with tubuloalveolar glands and is divided into a central and peripheral zone (100). The anatomy of the prostate gland in dogs and monkeys is more comparable to that of humans (95). It was reported that just 0.2% of male dogs developed prostatic carcinoma (101), but other researchers (102) found that 20 (2.6%) of 761 dogs, age 6 years or older, had invasive adenocarcinoma of the prostate. There has been one report (103) of a spontaneous prostatic carcinoma in a primate monkey. Although dogs have been domesticated by man, there have been, to our knowledge, no studies linking prostate adenocarcinoma in dogs with the diagnosis of the same lesion in their male owners. If this occurs more than expected, it would implicate exposures to similar environmental factors.

Among animals, the natural history of prostate cancer in dogs is closest to that of humans, but practical considerations necessitated that scientists focus their efforts on developing an experimental tumor model in rodents. Horning (104) was the first to induce prostate adenocarcinoma in mice in 1946. This was accomplished by wrapping crystals of 3-methylcholanthrene in sheets of mouse prostatic epithelium that were grafted under the skin. Ten years later, others were also able to produce adenocarcinomas of the prostate in Wistar rats treated with methylcholanthrene (105). This success with a chemical carcinogen was eventually followed by similar results with irradiation and hormones. In 1976, prostate adenocarcinoma was induced in four of 135 ICR/JCL mice after x-irradiation of the pelvis (106). The following year, prostatic adenocarcinoma was produced in an inbred strain of Nb rats after prolonged testosterone administration (107).

Before 1980, no clear attempt was made to evaluate the role of dietary fat in the occurrence of prostate tumors in laboratory animals. Preliminary studies (108) found no significant effect of dietary fat on prostate tumor incidence, latency time, or growth rate. In 1986, it was reported that a high-fat diet increased prostate cancer incidence and shortened the latent period in Lobund Wistar rats treated with exogenous testosterone (109). Two years later, other researchers showed that a fat-free diet reduced the growth of hormone-sensitive prostate adenocarcinoma in Dunning rats (110). Since then, it was found that feeding ACI/Seg rats a high-fat diet during pregnancy had a marked promotional effect on prostate carcinogenesis in the male offspring (111) and that lowering dietary fat intake reduced the growth rate of prostate tumors induced by injection of LNCaP cells in athymic nude mice (112). Furthermore, an increased-fat, Western-style diet fed to C57BL/6J mice produced epithelial cell hyperproliferation in the anterior and dorsal (but not ventral) lobes of the prostate (113). These animal studies suggest that dietary fat increases both the incidence and the rate of growth of adenocarcinomas of the prostate in laboratory animals. However, some experimental studies have not been successful in producing a promotional effect of a high-fat diet on prostate cancer induced by hormonal treatment alone (114) or by combined hormonal and chemical treatment (115,116) in Nb, F344, or other rats. This is also true for spontaneous prostate cancer occurring in ACI/Seg rats (117). The recent development of transgenic mouse models for prostatic neoplasia (118,119) appears to offer additional advantages for exploring the relation of fat to prostate cancer progression, since it allows for the study of genetically altered prostate cells without administration of systemic chemicals or foreign tumor cells. These models also more closely reflect the histologic progression of the disease seen in humans, though in a much shorter time span.

In addition to the effects described above for high fat intake, fat type has also been shown to influence prostate tumor cell growth both in vitro(120,121) and in vivo(122-124). Generally, these studies report that fish oils containing high levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid suppress prostate tumor growth, whereas oils high in polyunsaturated fatty acids, such as linoleic and linolenic acid, promote tumor growth. One study (121) found that even EPA promoted tumor cell growth at low doses and was inhibitory only at high concentrations. These whole-animal and in vitro studies are consistent with the limited epidemiologic evidence reviewed above that suggests that intake of the polyunsaturated fat linolenic acid may be associated with increased risk of prostate cancer and that fish oil consumption is not associated with decreased risk. However, these studies shed little light on the role, if any, of fat in the initial genetic changes leading to the development of a tumor.

Although current animal research does not provide strong mechanistic evidence for the role of fat in the early stages of prostate carcinogenesis, it does suggest that certain types of fat may accelerate tumor growth. As discussed above, current animal models all require some form of initiating factor (e.g., chemical, hormonal, or transgenic activating). Future development of animal models in which prostate tumors occur spontaneously may be more useful in elucidating carcinogenic mechanisms in prostate tissue. However, as for other cancers, extrapolation of results on causal factors from animal studies to humans will always be tenuous.


    MECHANISTIC BASIS FOR FAT-MEDIATED CARCINOGENESIS
 Top
 Abstract
 Introduction
 Role of Fatty Acids...
 Epidemiology
 Animal Studies
 Mechanistic Basis for Fat...
 Research Directions
 References
 
To advance beyond the positive association between fat intake and prostate cancer seen in many epidemiologic and some animal studies, a clear mechanistic understanding of the manner in which fat initiates and/or promotes the development of cancer is needed. The associations observed between animal fat and other tumors, such as colon (125) and breast (126), suggest that common pathways may be involved. However, these tissue sites also lack definitive modes of action for the role of fat in the carcinogenic process. Fatty acids have been shown to affect several physiologic and cellular processes that could influence, either positively or negatively, the development of prostate cancer (Fig. 2).Go The regulation of cellular proliferation in the presence of DNA damage and the associated processes of DNA repair and apoptosis are key elements in carcinogenesis (127), affecting all aspects relating to initiation, promotion, and progression of tumors. Other processes, such as angiogenesis and immune surveillance leading to elimination of aberrant cells, primarily affect tumor progression. The synergistic action of N-methyl-N-nitrosourea with testosterone in causing prostate tumors in rats (128) indicates the specific importance in prostate carcinogenesis of both DNA damage and cellular proliferation induced by hormonal stimulation. However, when endogenous processes are considered, the distinctions outlined in Fig. 2Go are often blurred, since many physiologic processes can affect both DNA damage and cellular proliferation/differentiation.



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Fig. 2. Cellular constituents and processes that may mediate the effects of dietary fat on carcinogenesis. Apoptosis = programmed cell death; angiogenesis = formation of new blood vessels; gap junctions = common intercellular junctions forming aqueous channels between cells (involved in intercellular communication); signal transduction = process by which signals for proliferation, differentiation, etc., are conveyed from the cell surface (i.e., membrane) to the nucleus.

 
Cellular Fat, DNA Damage, and Carcinogenesis

The generation of oxidative radical species is postulated to play a significant role in the aging process and the associated diseases of aging such as cancer (127,129). The polyunsaturated fatty acids offer a vulnerable target for many of these oxidizing species (130-132), forming lipid radicals and hydroperoxides that can generate additional oxygen radicals and/or DNA damage (133-135). Semen can be highly oxidizing due to the presence of leukocytes as well as of significant quantities of polyunsaturated fatty acids (including the prostaglandin precursor arachidonic acid and associated vinyl ethers) in prostatic tissue and fluid (136,137). The presence of oxidized fatty acids in cellular membranes can affect membrane and protein function; consequently, cells have evolved mechanisms to repair damaged membrane phospolipids. Phospholipase A2 is activated to remove damaged fatty acids (138), which are, in turn, acted on by glutathione peroxidase to remove the potentially damaging peroxides (139). The selenoenzyme phospholipid hydroperoxide glutathione peroxidase may be even more important than other repair enzymes in this process, since it reduces the peroxides while they are still attached to the phospholipid within the membrane (139). Activation of the phospholipases and the formation of lysophospholipids can also stimulate other signal transduction pathways leading to enhanced cellular proliferation (140).

The tocopherols (vitamin E) prevent lipid oxidation by preferentially reacting with radical species before they can react with unsaturated fatty acids in the membrane or by reducing fatty acid radicals back to the parent species (141). In plant oils, the tocopherol content is generally related to the level of polyunsaturated fatty acids present; consequently, consumption of plantbased oils is usually accompanied by increased intake of vitamin E. In contrast, the vitamin E content of animal fat is very low (142). As a result, a diet high in animal fat may cause increased oxidative stress due to increased unsaturated fat intake without protective antioxidants. Even plant-based oils may contain widely varying levels of antioxidants, including the tocopherols (which encompass many structurally related analogues of varying bioactivity), due to inherent differences among species, variations in growing conditions, or removal of antioxidants in the refining process.

There are many different oxidative chemicals generated endogenously—including hydroxyl radicals, nitrogen oxides, superoxide anions, peroxides, singlet oxygen, and peroxynitrite—each of which has different chemical properties and is quenched by different antioxidants to varying degrees. Some antioxidants, such as the tocopherols, show widely varying reactivities against specific oxidants such as NO2 (143,144). As a consequence, increased consumption of a particular antioxidant may be beneficial to some cell types and harmful to others. Because we do not know the precise chemical milieu of prostate tissue responsible for causing oxidative damage, it is difficult to conjecture beyond the epidemiologic literature at this point as to which fat-related antioxidants among the tocopherols, carotenoids, tocotrienols, and others might offer the greatest benefit. While a low-fat diet would be beneficial with respect to several putative mechanisms of carcinogenesis, it could also be detrimental if it were to result in decreased absorption of necessary fat-soluble vitamins and other antioxidants, such as vitamin D (145), vitamin E (146), and lycopene (147), particularly if any of these compounds were marginally deficient in the body.

The combination of prevention of lipid oxidation by tocopherols and repair of oxidized phospholipids by selenium-containing peroxidases may explain the interrelationship between polyunsaturated fatty acid intake, vitamin E status, selenium intake, and disease incidence (148). A particularly intriguing example of this interaction is provided by the pathogenesis of Keshan disease, in which the oxidative stress associated with viral infection and polyunsaturated fatty acids, together with deficiencies of vitamin E and selenium, causes myocardial injury and viral mutations that lead to increased virulence (149). Although observational epidemiologic studies provided limited support of a protective effect for vitamin E ({alpha}-tocopherol) (150,151) and selenium (152) against prostate cancer, two recent intervention trials (153,154) suggested that these agents might have chemopreventive effects. The lipophilic carotenoid lycopene, a potent quencher of singlet oxygen damage (155), concentrates in prostate tissue and has also been inversely associated with prostate cancer incidence in some reports (156-158). Dietary vitamin E and lignan consumption can also affect fatty acid composition in tissues and cells (159,160). Clearly, if dietary polyunsaturated fat is involved in the development of prostate cancer through a mechanism involving oxidative stress, future studies need to assess multiple parameters associated with such a mechanism. Variations in dietary and/or tissue levels of specific fatty acids, vitamin E, selenium, and other lipophilic antioxidants, as well as a history of prostate infection, could mask or enhance the effects of fat intake on prostate cancer development.

Effects of Fat on Cellular Proliferation and Differentiation

The role of fatty acids as structural components and as a source of cellular energy is well studied, yet recent research suggests that specific fatty acids may function in many cellular processes affecting cellular growth and communication that offer additional possibilities to explain potential effects of fat on growth and progression of neoplastic cells. Fatty acids can directly affect the activities of cellular proteins, such as protein kinase C (140,161,162), and can indirectly affect many proteins that are influenced by protein kinase C isoforms, such as phospholipase D (163). Covalent binding of myristic acid (C14:0) to proteins can also activate certain enzymes by permitting their translocation to membranes; e.g., the v-src protein must be bound to the plasma membrane via an amide bond between the N-terminal glycine and myristic acid in order to transform cells (164).

The carcinogenic process has also been linked to reduced gap-junctional communication between cells, and the majority of neoplastic cells show an impaired ability to establish functional communication with normal cells (165). Communication between cells via gap junctions is an important modulator of cellular proliferation that is significantly inhibited by polyunsaturated fatty acids, such as linolenic and linoleic acids (166-168). Indeed, linolenic acid completely blocks the enhanced gap-junctional communication induced by carotenoids in C3H 10T1/2 cells (167), a property of carotenoids that correlates with their ability to inhibit carcinogenesis in models in vitro. Dietary fat has also been shown to affect gene expression as well as the hormonal regulation of genes (169). Conversely, gene expression can significantly alter fatty acid composition in cells; e.g., bcl-2 overexpression increases the proportion of monounsaturated and {omega}-6 polyunsaturated fatty acids (170). The implications of these observations for understanding the mechanisms of human carcinogenesis in general, and of prostate cancer in particular, are as yet unclear.

One specific way in which dietary fat may affect prostate cancer incidence and progression is through its effects on male sex hormone levels. As noted above, testosterone synergistically and specifically increases prostate tumors in rats exposed to chemical carcinogens (128). In two human feeding studies (15,16), a high-fat diet with a high ratio of saturated to polyunsaturated fat was shown to increase total urinary androgens (15) and total plasma testosterone concentration (16), respectively. In a third trial (171), a reduction in intake of dietary fat led to a decrease in serum testosterone and androstenedione levels. These studies demonstrate that changes in dietary fat intake result in corresponding changes in endogenous androgen levels. A strong association between increasing plasma testosterone levels and risk of prostate cancer was found in a recent prospective cohort study (172) after adjustment for sex hormone-binding globulin levels.

Endogenous Processes Affecting Multiple Aspects of Carcinogenesis

Phosphatidyl serine has been identified as an endogenous inhibitor of inducible nitric oxide synthase (iNOS), an enzyme that produces nitric oxide, a free radical associated with cellular oxidation and carcinogenesis (173), and polyunsaturated fatty acids have also been observed to affect the activity of iNOS (174,175). The generation of nitric oxide by iNOS is associated with increased mutation (176) but is also believed to be an important component in the destruction of tumor cells (177) by the immune system and is involved in numerous signal transduction pathways, including those for apoptosis (178) and angiogenesis (179). Fat-mediated effects on nitric oxide synthesis and other endogenous free radicals may, therefore, affect multiple pathways leading to the development of a tumor, in addition to the radicals' direct effects on DNA damage and cellular proliferation (Fig. 2Go).

Fatty acids have also been shown to affect inflammation (28), immune responses (180), and prostaglandin production, all of which may play a role in prostate cancer (181). Arachidonic acid is converted into eicosanoids, which are key mediators of the inflammatory response (182). Marine {omega}-3 fatty acids, as well as nonsteroidal anti-inflammatory drugs such as aspirin, inhibit prostaglandin synthesis and associated inflammation. Use of these anti-inflammatory agents is inversely associated with such aging-related conditions as colon cancer and heart disease (183,184). Prostate tissue is also subject to inflammation and proliferation that is influenced by prostaglandin synthesis, and eicosanoids have been shown to stimulate prostate tumor cell growth (181). Although no conclusive evidence has been found to date in humans that links reduced prostate cancer incidence and mortality with prostaglandin inhibitors, future studies in this area are warranted.

Role of Fatty Acids in Tumor Progression

Tumor growth and metastasis have both been shown to be substantially affected by specific fatty acids in many animal and tissue culture model systems (120,181,185,186). In light of the pathologic and epidemiologic evidence showing similarly high prevalence rates of subclinical prostate cancer in different human populations despite widely variable rates of clinical disease (187), it seems likely that future research into the mechanisms by which prostate tumor cells progress from occult tumors to more aggressive neoplasms will contribute the most to the evidence for a role of fat in the development of prostate cancer.

Generally, it has been observed that the {omega}-6 fatty acids, such linoleic and {gamma}-linolenic, promote tumor growth and metastasis, whereas very long chain, {omega}-3 fatty acids inhibit tumor growth and metastasis (120,121). Inhibition of tumor growth in animals fed diets very low in fat is believed to result from a lack of the essential fatty acids, leading to a generalized growth inhibition (110). The effects of fatty acids on specific proteins (such as PKC, src, iNOS, and the gap-junction protein connexin), as described above, may also help explain the influence of fatty acids on DNA damage, tumor growth, angiogenesis, and metastasis (Fig. 2Go).

Undoubtedly, the fatty acid composition of cellular membranes may affect the activities of virtually all membrane-associated proteins. More research is needed, however, to determine if the small variations in membrane composition associated with qualitative and quantitative differences in fat intake in the general population can cause alterations in enzymatic activities, gene expression, and physiologic processes sufficient to explain observed differences among population subgroups in prostate cancer incidence and progression.


    RESEARCH DIRECTIONS
 Top
 Abstract
 Introduction
 Role of Fatty Acids...
 Epidemiology
 Animal Studies
 Mechanistic Basis for Fat...
 Research Directions
 References
 
This review indicates that there is some epidemiologic support for a role of dietary fat in the pathogenesis of prostate cancer, although the evidence is inconclusive and not specific with regard to particular fat components. While the data from animal studies are sparse for this cancer, the studies do offer limited support for the hypothesis, particularly with regard to the enhanced growth and malignancy of occult tumors. Furthermore, there are reasonable mechanisms to account for a carcinogenic or promotional effect of fat in prostatic (as well as other) tissue. Taken together, this suggests that research in this area can still be productive and should be encouraged. Following are some ideas that emerge from the preceding discussion on this topic.

1) Prostatic adenocarcinoma is unique among human cancers in the high prevalence of occult tumors that do not progress. If the clinical tumors are part of the same pathway, then highest priority should be given to the identification of those factors that lead to the progression of the subclinical lesions. Dietary fat is certainly a reasonable candidate, since both laboratory and epidemiologic evidence points to a role of fat in cancer promotion and progression, rather than in initiation (188).

2) Carcinogenesis in the human prostate, as in other tissues, is likely to be a complex process that cannot be unraveled by univariate approaches. Future epidemiologic studies of fat and prostate cancer will need to incorporate other factors that may either increase or decrease risk (e.g., vitamin E, selenium, and calcium) into more complex analytic models based on concepts of functional interactions, rather than treating them simply as confounders. More precise and comprehensive dietary cohort studies with repeated nutritional assessments are needed to clarify the association of prostate cancer with different dietary exposures. Variations in genetic susceptibility should also be included so that gene-environment interactions can be studied. Although such studies will require very large sample sizes, the high incidence of this cancer makes them feasible.

3) Epidemiologic findings showing racial/ethnic differences in the strength of the association of dietary fat with prostate cancer (46,53) and in the nature of hormonal relationships to prostate cancer (189,190) suggest that further studies of the interaction between these two factors should be pursued, particularly with respect to the effects of dietary fat on gene expression and on the hormonal regulation of genes.

4) Little work has been devoted to studying specific effects of endogenous fat in prostate tissue. This might be a productive area for research in the future. Prostatic fluid is rich in lipids and, in rats, contains significant quantities of vinyl ethers, whose function is not defined. The unique role(s) of specific fatty acids and related chemicals, such as the vinyl ethers, in prostatic function may shed additional light on the possible influence of dietary fat on prostatic cancer.

5) Because it is difficult to study the effects of specific components of fat in human prostatic tissue, laboratory studies that use the most relevant animal models (especially the dog and possibly primates) should be encouraged, since these could help both to establish causal relationships and to elucidate mechanistic processes.


    NOTES
 
Supported by Public Health Service grants P01CA33619 and R01CA54281 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; and by grant CN-158 from the American Cancer Society.


    REFERENCES
 Top
 Abstract
 Introduction
 Role of Fatty Acids...
 Epidemiology
 Animal Studies
 Mechanistic Basis for Fat...
 Research Directions
 References
 

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Manuscript received May 19, 1998; revised December 3, 1998; accepted December 31, 1998.


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