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).
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ABSTRACT |
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INTRODUCTION |
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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-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.
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ROLE OF FATTY ACIDS IN NUTRITION |
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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,-6) and linolenic acid (C18:3,
-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).
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EPIDEMIOLOGY |
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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) (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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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 1). 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 1). 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). 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
-3 and
-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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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 2). Two studies (60,71)
based on measurements in prediagnostic serum also found no significant association with
polyunsaturated fatty acids overall or by subgroup (
-3 or
-6).
A few studies have examined specific polyunsaturated fatty acids (Table 2). The results with regard to
-linolenic acid (C18:3,
-3), an essential fatty
acid (i.e., derived solely from the diet), have been particularly interesting.
-Linolenic
acidan
-3 polyunsaturated fatty acid that comprises only a very small proportion
of the fatty acids in tissuesis obtained from terrestrial foods (primarily red meat, dairy
products, soybean, and rapeseed oils) but not from fish. Dietary intake of
-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
-linolenic acid level and prostate cancer risk (statistically significant in one of the studies),
whereas the third study (71) reported no association with any
-3
polyunsaturated fatty acids. The fourth study found a weak positive association with
-linolenic acid that was not statistically significant. Interestingly, marine
-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,-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%); -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 -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).
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ANIMAL STUDIES |
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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.
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MECHANISTIC BASIS FOR FAT-MEDIATED CARCINOGENESIS |
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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 endogenouslyincluding hydroxyl radicals, nitrogen oxides, superoxide anions, peroxides, singlet oxygen, and peroxynitriteeach 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 (-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 -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. 2).
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 -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 -6 fatty acids, such linoleic and
-linolenic,
promote tumor growth and metastasis, whereas very long chain,
-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. 2
).
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.
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RESEARCH DIRECTIONS |
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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.
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Manuscript received May 19, 1998; revised December 3, 1998; accepted December 31, 1998.
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