Can diet affect prostate cancer?

For several years it has been known that manipulating dietary factors could influence the development of tumours in animals [1]. In 1975 Doll and Peto [2] reported that the rates of cancer among different populations corresponded with dietary variation, and in a later paper estimated that 35% of cancers in North America may be attributable to diet [3]. This argument is further strengthened by the fact that a migrating population will eventually assume the cancer rates of their host population, lending weight to the view that differences in cancer rates among populations are also a result of other than inherited factors, with diet being one of them. Numerous studies have examined the connection between diet and cancer, and a greater insight into the ways in which diet can affect carcinogenesis is currently developing. Recently there has been considerable interest in evaluating the link between diet and prostate cancer. To date, most of the dietary data on prostate cancer relate to fats, vitamin A or carotenoids, and vitamins D and E. Other dietary constituents include the trace elements cadmium and zinc, and alcohol, although the data are more limited for these factors. Fat is the dietary component most frequently associated with prostate cancer. The earliest observations showed an association between prostate cancer incidence and fat consumption among different populations [2,4,5]. Statlan [6] in 1992, reported this link; countries such as the USA, known to have high levels of fat consumption, were also found to have a high mortality rate for prostate cancer, whereas a country such as Japan, with one of the lowest rates of fat consumption in the world, has a low mortality rate for the disease. The constituent fatty acids in dietary fats can be divided into essential and inessential fatty acids; the latter are synthesized in the body whereas the former are derived from the diet. These essential fatty acids are all unsaturated and can be divided into omega-6 (derived from linoleic acid) and omega-3 fatty acids (derived from linolenic acid). Linoleic acid is mainly found in vegetable seed oils whereas linolenic acid is found mainly in fish oils. At a cellular level, these essential fatty acids are thought to influence cellular proliferation, the immune system and the potential of a tumour to invade locally and metastasize [7]. They are also reported to affect PG synthesis and sex hormone levels. Different fatty acids have been shown to have beneficial and detrimental effects on the growth of prostate cancer cells. For example, linoleic acid stimulates the growth of an androgen-unresponsive prostate cancer line, whilst the omega-3 (derived from linolenic acid) fatty acids, docosahexaenoic acid and eicosapentaenoic acid, inhibit the growth of this prostate cancer cell line [8]. These findings have also been reported by others [9,10] who showed that other prostate cell lines are promoted by omega-6 and inhibited by omega-3 fatty acids. The effects of these fatty acids are thought to be caused by their effects on PG synthesis. A case-control study was carried out by Norrish et al.[11] in 1999, to ascertain whether the intake of omega-3 fatty acids, found in fish oils, is indeed associated with a reduced risk of developing prostate cancer. They studied 317 men with prostate cancer matched with 480 controls, reporting a reduction in the risk of developing prostate cancer in men in whom they detected higher levels of eicosapentaenoic acid in their erythrocytes. The authors considered that this was caused by the effects on PG synthesis. As well as affecting PG synthesis, fatty acids also appear to influence sex hormone levels; androgenic (or oestrogenic) stimulation may be a causative factor in the development of prostate cancer, and this therefore raises the possibility of using fatty acids to reduce androgenic stimulation of the prostate. Testosterone is mainly produced in the testis (a small amount being produced in the adrenal glands) and is converted to its active form, DHT, by 5α-reductase. DHT is necessary for the continuing growth and development of prostate cancer. Liang and Liao [12] showed that linolenic acid reduced the activity of 5α-reductase, concluding that this fatty acid, along with palmitoleic and oleic acid (both from the omega-3 family), could play a role in preventing prostate cancer. Thus there appears to be a potential role for the use of dietary fats in prostate cancer, with current research suggesting that their main actions are in influencing PG synthesis, and sex-hormone production and activation. Omega-6 fatty acids promote the development of prostate cancer, whereas omega-3 fatty acids protect against it; in the future, dietary manipulation may be a valid component in preventing this disease. Despite this, several unresolved questions remain, e.g. when should the diet be modified to decrease the risk of prostate cancer, and how much should the diet be altered. As well as an apparent preventative role, the question of whether dietary fats have a role in the treatment of prostate cancer remains open to debate. Research continues into this question, although Weisberger [13] suggested that reducing the saturated fat content of the diet of men with prostate cancer may reduce the chance of actually dying from the disease, and potentially prolonging life. Many food substances are rich in vitamin A, e.g. carrots and liver, and therefore the dietary intake of this vitamin is usually high. The evidence to date suggests that dietary vitamin A does not protect against prostate cancer; indeed initial studies seemed to indicate that increased levels of vitamin A correlated with a higher risk of prostate cancer [14–16]. In 1983, Graham et al.[17] reported this positive association between a higher intake of total vitamin A and risk of prostate cancer, as did Kolonel et al.[18] in 1988. Subsequent studies have not confirmed this increased risk, and indeed, a protective association was shown in men in Japan [19], The Netherlands [20] and the USA [21]. Prospective data on the association between vitamin A intake and prostate cancer is sparse. A 20-year follow-up of 17 663 men in 1990 [22] detected no overall association between vitamin A intake and the risk of prostate cancer. When the subgroups of this study were analysed there was a higher risk in men aged < 75 years but this increase was counterbalanced by a protective association for men aged > 75 years. Therefore, in summary, the data for the effects of vitamin A on prostate cancer are at present equivocal. Studies are divided almost equally between positive and inverse associations. This suggests that vitamin A is unlikely to be an important factor in the development of prostate cancer, although this is not so in other cancers where, for example, a modest inverse association between vitamin A intake and breast cancer is reported [23]. The rationale for the use of soy and soy products in preventing prostate cancer came initially from epidemiological data. In Western societies prostate cancer is common but in Japan the incidence is much lower. This difference is probably not solely genetic, as the incidence of prostate cancer increases in Japanese migrants to the West. Soy is widely consumed in Japan, with one of the lowest incidences of prostate cancer in the world, and it is one of the dietary factors thought to be important in the aetiology of prostate cancer [24]. Soy is thought to have broad anticancer properties. There are two isoflavonoid components of soy, genistein and daidzein, which have mild oestrogenic effects, with the oestrogen effect causing programmed cell death in prostate cancer cells. These soy compounds have also been shown to inhibit enzymes and processes associated with cellular growth, motility and proliferation in vivo[25–27]; this has been reported for both human and mouse cancer cell lines. While the effects of soy protein on cancer induction have typically been attributed to its oestrogenic effects, soy protein diets often impede the induction of cancers not known to be hormone-dependent [28]. These observations make soy an ideal candidate for further trials in the chemoprevention of prostate cancer. Vitamin D is naturally synthesized under the influence of ultraviolet light, with the conversion into its biologically active compounds occurring by hydroxylation within the liver to 25-hydroxycholecalciferol and then further converted to the more active metabolite 1,25-dihydroxycholecalciferol (calcitriol) in the proximal convoluted tubules of the kidney. Vitamin D is principally involved in bone and calcium metabolism, and is also thought to have a role in preventing prostate cancer. The association between vitamin D deficiency and prostate cancer was initially noted in a study which showed a correlation between exposure to sunlight and rates of prostate cancer death [29]. In this study, prostate cancer mortality rates in the USA increased as exposure to ultraviolet light decreased and, as it is known that sunlight is essential for vitamin D synthesis, the role of vitamin D in decreasing the risk of developing prostate cancer was therefore suggested. This hypothesis was also used to partly explain the increased risk of African-American men developing prostate cancer, as their dark skin pigment may impair endogenous vitamin D synthesis [30]. In vitro studies examining the effect of calcitriol on human prostate cancer cell lines (LNCaP, PC-3 and DU 145) have provided promising results [31–34]. Calcitriol significantly inhibited LNCaP and had an intermediate effect on inhibiting PC-3 cells, but only minimal inhibition of DU 145 cells was reported [35,36]. In these early studies calcitriol was thought to induce cell-cycle arrest, although in a later study Blutt et al.[37] cited the induction of apoptosis as a further mechanism of action for calcitriol, through the down-regulation of the levels of Bcl-2 and Bcl-X (anti-apoptotic factors). Gross et al.[38] conducted a clinical trial in seven patients with early recurrent prostate cancer after radiotherapy or radical prostatectomy, each being treated with calcitriol. These results showed a slowing of the progression of prostate cancer, in terms of a PSA increase. Unfortunately, a trial conducted by Osborn et al.[39] did not mirror these results, as they failed to show any objective response in terms of PSA reduction in the 13 patients they treated with calcitriol. Despite these conflicting results many still consider that vitamin D is a valuable additional tool in the treatment of prostate cancer. Vitamin E is a major intracellular antioxidant and is thought to have a wide range of anticancer properties. A study conducted in Finland [40] assessing the effect of vitamin E on the incidence of lung and other cancers in male smokers showed that although vitamin E did not cause a reduction in lung cancer, there were fewer cases of prostate cancer. Indeed, at 6 years of follow-up, there was a 32% reduction in the incidence of prostate cancer and a 41% reduction in prostate cancer mortality in men who received supplementary vitamin E. Several other in vitro and in vivo cell lines from a variety of human cancers have been inhibited by vitamin E [41–43]. Although the precise mechanism of action of vitamin E is largely unknown, the effects may be attributable to its antioxidant properties. A study by Fleshner et al.[44] showed that when mice on high-fat diets and implanted with LNCaP cells were given supplemental vitamin E, the growth rates of the LNCaP cells were not significantly different from those in similar mice on lower fat diets. This suggests that vitamin E is of benefit in inhibiting the high-fat induced growth of prostate cancer cells, probably through its antioxidant properties. Other studies have reported the protective antioxidant effect in other dietary supplements, e.g. Clarke et al.[45] reported a 3–4 fold reduction in prostate cancer incidence in men with non-melanoma skin cancer who were treated with selenium supplements (another antioxidant). Clearly, further studies are required, one such being the American SELECT trial (selenium vitamin E chemoprevention trial) which is a double-blinded randomized study to assess the efficacy of selenium and vitamin E in preventing prostate cancer; it is envisaged that over 32 000 men will be recruited into this trial by 2005, with the initial results being expected in 2012. Exposure to the trace element cadmium primarily occurs through inhalation in industrial settings, although it is found in certain foods, e.g. shellfish. Levels of this trace element in the diet are usually low, but ingested cadmium can add to cadmium from other sources, e.g. cigarette smoke. For some time it has been appreciated that occupational cadmium exposure is a potential risk factor for prostate cancer, but data on dietary exposure to cadmium and its association with prostate cancer are limited. Abd Elghany et al.[46] found that there was an increased risk of prostate cancer when men were exposed to cadmium in their diet, from smoking and from industrial exposure. When considered alone, dietary exposure to cadmium did not incur a significantly increased risk of developing prostate cancer. Other dietary factors have been considered, including coffee [47], where the authors showed that coffee was not associated with an increased rate of prostate cancer. The association between vitamin C has also been considered; in some studies this has been reported as being positive [17] and in others negative [18]. The studies to date assessing zinc are similarly inconsistent. As noted, selenium is another agent promoted for its positive effects on the prostate gland. As early as 1972 Rotruck et al.[48] first highlighted the antioxidant biochemical function of selenium, reporting that glutathione peroxidase, an enzyme that protects the cell from oxidative damage, is selenium-dependent. More recently, several large epidemiological studies have shown that higher intakes of selenium may reduce the risk of prostate cancer, the largest of these being a case-control study assessing selenium levels in toenails and the risk of prostate cancer [49]. Further studies also showed the preventative effects of selenium on prostate cancer [50,51]. A dietary cause for prostate cancer would be consistent with the epidemiological observations in migrants and with the differences observed among different populations. Despite this, the precise role of diet in the aetiology of prostate cancer remains unclear. The evidence supporting an association between dietary fat intake and prostate cancer appears to be encouraging, in that omega-3 fatty acids (which act as anti-carcinogens) are associated with a reduced risk and omega-6 fatty acids (which act as tumour promoters) an increased risk of developing prostate cancer. Unfortunately, the effects of other dietary components on prostate cancer are less clear, e.g. the conflicting results from studies of vitamins A and C, and the significance of trace elements like cadmium in the diet. Although current results favouring some of these dietary supplements are encouraging, the present evidence for justifying their widespread use is insufficient. Therefore, research continues into diet and prostate cancer, and potentially some dietary components, particularly the omega-3 family of essential fatty acids, may have a role in the development of prevention and treatment strategies for prostate cancer. J.-P. Meyer, MRCS, Clinical Research Fellow. D.A. Gillatt, ChM, FRCS, Consultant Urologist. J.-P. Meyer, Bristol Urological Institute, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UKe-mail: [email protected]