Micronutrients in the prevention of cancer – Part 2

It is believed that around a third of all cancer cases could be attributed to dietary and lifestyle factors. The link between nutrition and cancer risk is very complex, and it is difficult to establish the influence of individual dietary factors. The results of reviews have indicated that cancer-preventive diets above all consist of large quantities of plant-based foods such as fruit, vegetables, whole grains and pulses. With a low energy density, these foods supply the body with plenty of fiber, as well as varying amounts of essential micronutrients such as vitamins, carotenoids, minerals and trace elements, which are thought to potentially influence the specific mechanisms by which cancers develop. Several of these micronutrients are involved in the maintenance of genetic information (Deoxyribonucleic acid, DNA) and may therefore be able to prevent the formation of tumor cells.

Cancer cells develop from healthy cells that have lost certain characteristics and gained new ones due to a change in the DNA (mutation). Aggressive (malignant) cells can divide in an uncontrolled manner (independently of external signals), have unlimited growth potential, are immune to programmed cell death (apoptosis), can stimulate the formation of new blood vessels (angiogenesis) in order to supply themselves, and can infiltrate surrounding tissues or spread throughout the body (metastasize), thereby having a destructive effect on areas further away from the tumour. Supplying the cells with a sufficient amount of micronutrients can promote genetic stability by preventing oxidative damage to the DNA and its packaging, as well as supporting normal cellular processes like division, growth and death of cells (see also Part 1).

Carotenoids

Beta-carotene was the first carotenoid shown to exist in food and human blood. The results of early observational studies indicated that there was a link between reduced risk of lung cancer and increased beta-carotene intake, which was often confirmed by measurements of higher blood levels of beta-carotene (1, 2). In contrast to earlier retrospective studies, more recent prospective cohort studies were not all able to observe such a link between beta-carotene and lung cancer risk. An analysis of dietary carotenoid intake and lung cancer risk in two large US prospec-tive cohort studies, which followed the cases of 120,000 men and women over at least ten years, found no signifi-cant association between the two (3). However, men and women with the highest overall intakes of carotenoids and lycopene were at a considerably lower risk of getting lung cancer than those with the lowest intakes. In a 14-year-long study of more than 27,000 Finnish male smokers, an increased overall intake of carotenoids, lycopene, lutein and zeaxanthin, but not beta-carotene, was linked to a significantly reduced risk of lung cancer (4), while in a six-year-long study of more than 58,000 Dutch men, higher intakes of lutein and zeaxanthin alone were associated with a lower risk of lung cancer (5). Likewise, an analysis of the aggregated results of six prospective cohort studies carried out in North America and Europe also found no link between dietary beta-carotene intake and lung cancer risk, but study participants with the highest intakes of beta-cryptoxanthin were found to have a 24 percent lower risk of lung cancer than those with the lowest intakes (6). Results from more recent prospective studies based on estimations of dietary micronutrient intake have indicated that a diet rich in carotenoids may be associated with a reduced risk of lung cancer. That said, a recent systematic review of prospective cohort studies came to the con-clusion that the preventive effect of carotenoids against the development of lung cancer was probably very low and statistically non-significant (7).

Three large, randomized, placebo-controlled studies have investigated the effect of beta-carotene supplementation on the risk of getting lung cancer. In Finland, the Alpha-Tocopherol Beta-Carotene Cancer Prevention Trial (ATBC) assessed the impact of a daily intake of 20 mg beta-carotene and/or 50 mg vitamin E (alpha-tocopherol) in more than 29,000 male smokers (8). In the US, the CARET study investigated the effects of a combined daily supplemen-tation of 30 mg beta-carotene and 25,000 IU vitamin A (retinol) in more than 18,000 men and women (9). The participants were either heavy smokers, former smokers, or had been exposed to asbestos at some point during their working lives – all major risk factors for lung cancer. The surprising result was that participants of the ATBC study, who had taken the very high dose of beta-carotene for six years, were 16 percent more likely to get lung cancer after the study. For the participants of the CARET study, who took an even higher dose for four years, this risk increased to 28 percent. The US Physicians’ Health Study investigated the effects of supplementation with 50 mg beta-carotene every other day on cancer risk among more than 22,000 male doctors, 11 percent of whom were current smokers (10). Despite supplementation of a considerably high amount of beta-carotene for more than
12 years, no increase in lung cancer risk was measured. Although the reasons for a possible increased risk of lung cancer are not yet clear, several mechanisms have been discussed (11). Many experts believe that in the long term, the possible risks of high-dose beta-carotene supplementation outweigh the potential benefits with regards to lung cancer prevention, particularly among smokers and other population groups with a high cancer risk (12, 13). In 2012, the European Food Safety Authority (EFSA) declared that epidemiological studies had come to the conclusion that no increased risk of lung cancer could be found for strong smokers taking a 6–15 mg dose of beta-carotene every day for five to seven years (14). A daily supplementation (under 15 mg) of beta-carotene in fortified food or supplements was said to be no cause for concern with regards to health risks among the general population, including heavy smokers.

The results of several prospective cohort studies have shown that a diet rich in lycopene could be linked to a significant reduction in the risk of particularly more aggressive forms of prostate cancer (15). In a prospective study lasting over eight years, with more than 47,000 health professionals, those with the highest lycopene intakes were 21 percent less likely to develop prostate cancer than those with the lowest lycopene intakes (16). Those who consumed the most tomatoes and tomato products (constituting 82 percent of the dietary lycopene intake) had a
35 percent lower risk of getting prostate cancer and a 53 percent lower risk of getting aggressive prostate cancer than those who consumed the least. Likewise, a prospective study carried out on males also found that those who reported the highest tomato consumption levels were at a significantly lower risk of prostate cancer (17), echoed by a prospective study on US doctors, which observed a significantly lower risk of developing aggressive prostate cancer among participants with the highest plasma lycopene concentrations (18). However, a prospective study of more than 58,000 Dutch men found no link between dietary lycopene intake and prostate cancer risk (19). A meta-analysis combining the results of 11 case-control studies and ten prospective studies showed that men with the highest lycopene or tomato intake were 11–19 percent less likely to develop prostate cancer (20). A prospective study lasting over four years, with a cohort of 29,361 participants, found no link between diet-related lycopene intake and prostate cancer risk (21). Furthermore, a large prospective study showed no link between plasma lycopene or carotenoid concentrations and risk of developing prostate cancer (22). While there is considerable scientific interest in the potential of lycopene in the prevention of prostate cancer, it is not yet clear whether the lowered risk of prostate cancer observed in some epidemiological studies is associated with lycopene itself, other ingredients in tomatoes, or other factors that correlate with a lycopene-rich diet. Results from more short-term intervention studies, investigating the lycopene-rich diets of prostate cancer patients, have been very promising. However, it is not yet known how effective or safe long-term lycopene use is in the prevention or treatment of prostate cancer (23). Large-scale, controlled clinical studies would need to be carried out in order to confirm this.     

Minerals

Colorectal carcinoma is the third most common type of cancer among men and the second most common among women worldwide, responsible for around 8 percent of deaths (24). It is believed that colorectal cancer is caused by a combination of genetic and environmental factors, but the extent to which each of these factors affects colorectal cancer risk is extremely varied. While genetic factors are almost always the cause for those with a family history of a particular type of colorectal cancer, others’ risk of illness and other types of cancer may be affected more by diet-related factors. Results from animal studies make a very compelling case for the preventive role of calcium in colorectal cancer (25). Controlled clinical trials on humans have shown that daily supplementation of 1200–2000 mg calcium can slightly lower the recurrence rate of colorectal adenomas (pre-cancerous polyps) (26, 27). Another study showed that this preventive effect lasts up to five years beyond the end of the intervention (28). An analysis of all the results of ten prospective cohort studies, comprising a total of 534,536 men and women, confirmed that participants with the highest calcium intake from the diet alone were at a 14 percent lower risk of colorectal cancer than those with the lowest intakes: calcium intake across the ten cohorts ranged from 674 mg to 1,051 mg per day (29). Participants with the highest overall calcium intake from the diet and supplements had a 22 percent lower risk of developing colorectal cancer. For the studies included, total daily intake amounts of calcium ranged from 732 mg to 1,087 mg per day. Most large prospective studies, however, have only been able to observe a relatively weak link between higher calcium intake and lower risk of colorectal cancer. This less pronounced link could be conditioned by the fact that different groups of the population vary with respect to their reaction to calcium. For example, there is some evidence suggesting that people with higher blood concentrations of the Insulin-like growth factor 1 (IGF-1) have a higher risk of colorectal cancer, and could therefore benefit more than other population groups from a higher calcium intake. A case-control study of 511 men showed that calcium intake was more effective at reducing the risk of colorectal cancer among those with increased IGF-1 blood concentrations than among those with normal blood concentrations (30). However, more research is needed before we can draw clear conclusions about whether certain subgroups of the population require different amounts of calcium to reduce their risk of colorectal cancer.

Research on the use of calcium in the prevention of prostate cancer has so far proven contradictory: some epidemiological studieshave raised concern that high calcium intake calcium could be linked to an increased risk of prostate cancer. A large prospective cohort study carried out in the US investigated more than 50,000 health professionals over eight years and found evidence that men with a daily calcium intake of 2,000 mg or more could possibly be at three times greater risk of developing advanced prostate cancer and at four times greater risk of developing metastasized prostate cancer than men with a daily calcium intake of below 500 mg (31). A further prospective study of US doctors found that increasing daily calcium intake to 500 mg via milk products could be linked to a 16 percent increase in the risk of prostate cancer (at both advanced and non-advanced stages) (32). A further prospective study, examining a cohort of 29,133 male smokers over 17 years, showed that high calcium consumption (over 1,000 mg per day) could be linked to an increased risk of prostate cancer (33). The physiological mechanisms behind such a link remain unclear. Experimental studies carried out on prostate cancer cells and animal models have reported that high concentrations of calcium could lead to a lowered blood concentration of calcitriol (the active form of vitamin D), which has been shown to have cancer-preventive effects. However, the results of studies investigating people’s serum calcitriol concentrations and prostate cancer risk have been considerably less convincing. Not all epidemiological studies have shown a link between calcium intake and prostate cancer risk, and the results have been partly contradictory (34–37). The lack of consensus between the results of these studies suggests that there are complex interrelations between the various risk factors for prostate cancer, and possibly also reflects the difficulties in assessing and estimating daily calcium intake. According to the scientific societies of various nations, the recommended daily calcium intake for men is currently between 1,000 mg and 1,200 mg.

Epidemiological studies carried out predominantly in Asian countries have shown that an increased intake of cured, smoked or pickled foods can increase the risk of gastric cancer (38, 39). Although these foods have a high sodium-chloride (salt) content, they can also contain cancer-promoting substances (carcinogens) such as nitrosamine. Furthermore, population groups with a high intake of salty foods tend to eat less fruit and vegetables, which could have preventive effects (40). The risk of developing gastric cancer increases in cases of chronic inflammation of the stomach and bacterial infection with Helicobacter pylori. High concentrations of salt can damage the stomach cells and potentially increase the risk of cellular H. pylori infections and cancer-promoting genetic defects. Although there is little evidence to suggest that salt itself is carcinogenic, a high intake of particularly salty foods such as salted fish could increase the risk of gastric cancer among particularly sensitive people (39, 41, 42).  

Trace elements

It is well-documented that patients with liver cirrhosis are at a considerably higher risk of liver cancer (liver cell carcinoma) due to iron overload as a result of hereditary haemochromatosis. However, the link between dietary iron intake and cancer risk in patients without haemochromatosis is less clear (43). Several epidemiological studies have reported possible links between measurements of increased iron status and the more frequent occurrence of gastric cancer or pre-cancerous polyps (adenomas), but these observations have not been consistent. However, it seems as though dietary iron intake is more consistently linked to gastric cancer risk than measurements of iron status or iron stores (44, 45). Increased consumption of red meat has been linked to increased risk of gastric cancer, but there are a number of other possible factors linked to meat consumption that could negatively influence cancer risk (46). For example, red meat increases the rate of bile secretion, which may have a toxic effect on intestinal cells as well as exposing the body to the cancer-promoting compounds in cooked meat (47). As an extended bodily iron store, increased iron concentrations in the contents of the large intestine could increase the risk of bowel cancer by exposing the intestinal cells to potentially reactive oxygen species, borne out of iron-catalyzed reactions, particularly when combined with simultaneous intake of fat-rich foods. Although this possibility is currently under investigation, the link between dietary iron intake, iron stores and the risk of gastric cancer is as yet unclear.

Animal trials have provided strong evidence that high blood concentrations of selenium could influence the occur-rence of cancer. More than two thirds of the 100+ published studies investigating spontaneously, virally and chemically-induced tumors in 20 different animal species have shown that selenium may increase the frequency of cancer occurrences (48). These investigations have shown that methylated forms of selenium in particular, which are produced in their largest quantities via surplus selenium intake and increased selenium status, may have preventive effects against tumours (49, 50). Geographical studies have consistently observed higher cancer mortality in populations with low selenium intakes and in populations living in areas where the soil contains low levels of selenium. Results from epidemiological studies have also shown a trend for the more frequent occurrence of various types of cancer among people with low selenium concentrations in the blood and nails. However, this trend is less pronounced among women. A prospective study of more than 60,000 nurses in the US, for example, showed no link between selenium concentrations in the toenails and overall cancer risk (51).

It is well-known that hepatitis infections and smoking significantly increase the risk of various types of cancer, and a low dietary intake of selenium can also increase cancer risk. A chronic hepatitis B or hepatitis C infection, for example, can increase the risk of liver cancer. In a study of Taiwanese men suffering from chronic viral hepatitis B or C, low plasma concentrations of selenium were linked to an increased risk of liver cancer. This risk was particulaly pronounced in smokers and participants with low plasma concentrations of vitamin A and carotenoids (52). A case-control study, carried out as part of a prospective study of over 9,000 Finnish men and women, investigated the selenium serum concentrations of 95 individuals, who were later diagnosed with lung cancer, and 190 controls (53). Lower selenium concentrations were shown to be associated with increased lung cancer risk, a link that was more pronounced among smokers. These Finnish participants exhibited selenium concentrations that were only at around 60 percent of the level commonly observed in other Western countries. Results of a meta-analysis of 16 studies have indicated that selenium can have a preventive effect against lung cancer (54). In this analysis, a 54 percent lower risk of lung cancer was observed in participants with the highest content of selenium in the toenails (but not in the blood serum).

Some studies have reported an association between low selenium intake and increased risk of prostate cancer. A case-control study carried out as part of a prospective study of over 50,000 male health professionals in the US showed a significant relationship between increased selenium content in the toenails and lowered risk of prostate cancer (55). In this study, participants whose toenail content of selenium was equivalent to a daily selenium intake of 159 mcg were at 65 percent less risk of developing advanced prostate cancer compared to those with a daily selenium intake of just 86 mcg. Similarly preventive effects have emerged from a case-control study of 9,000 Japanese-American men (56) as well as further similar studies (57, 58). One of the biggest case-control studies observed a possible preventive effect of selenium against gastric cancer, but not against breast or prostate cancer (59). A meta-analysis of 20 epidemiological studies, mainly case-control studies, found that selenium content in serum or the toenails was significantly lower in patients with prostate cancer than in healthy controls (60). A prospective study with a cohort of over 295,000 men has indicated that frequent intake of multivitamin preparations (more than seven times a week) combined with selenium supplements could be linked to a significant increase in the risk of developing advanced and terminal prostate cancer (61). Other prospective studies and clinical studies have not yet confirmed this hypothesis.

In an intervention study, where 20,847 selenium-deficient Chinese people at risk of viral hepatitis B infections and liver cancer received sodium-selenite-enriched salt, the average frequency of occurrence of liver cancer was reduced by 35 percent after 8 years, while no such reduction in risk was found for the control groups (62). In the US, a randomised controlled study was carried out on more than 1,300 older adults and showed that men who were supplemented daily for a period of 7.4 years with 200 mcg selenium-enriched yeast had a 49 percent reduced risk of prostate cancer (63). The preventive effect of selenium was shown to be greatest in men with the lowest plasma concentrations of selenium and prostate-specific antigens (PSA) at the beginning of the study. Surprisingly, further findings from the study indicated that targeted intake of selenium might possibly increase the risk of a particular type of skin cancer (squamous cell carcinoma) (64), and lung cancer risk was also not significantly reduced (65). Although some studies have showed promising signs that supplementation with selenium could work preventively against prostate cancer, several large intervention studies investigating the role of selenium in the prevention of prostate cancer are still being carried out (50, 66, 67). However, a large randomised controlled study investigating selenium and vitamin E (SELECT study) was halted because it gave no indication that these could be used in the prevention of prostate cancer (68). In follow-up investigations, supplementation with selenium alone (200 mcg per day) or in com-bination with vitamin E were not shown to influence risk of prostate, lung or gastric cancer (69).

Several mechanisms have been discussed that might explain the possible preventive effects of selenium: 1) maximi-sation of antioxidative selenoenzyme activity and improvement of antioxidative status, 2) improvement in immune system function, 3) positively influencing the metabolism of cancer-promoting substances, 4) increased production of selenium metabolites, which inhibit growth of tumour cells, 5) positive effect of selenium on the death (apoptosis) of degenerate cells, 6) positive effect of selenium on DNA-repair, and 7) selenium as an anti-angiogenetic agent. A two-step model has been proposed to track the various anticarcenogenic activities of selenium in various doses: taken in typical dietary, or physiological, doses (ca. 40–100 mg per day in adults), selenium could maximise antioxidative sele-noenzyme activity, thereby improving immune system function. In higher, or pharmacological, doses (ca. 200–300 mcg per day in adults), the formation of selenium metabolites, in particular of the  methylated forms of selenium, could have an additional anti-carcinogenic effect (48, 49).

Essential fatty acids

Animal studies and numerous experiments on cell cultures have shown that omega-3 polyunsaturated fatty acids (omega-3 PUFAs) have preventive effects against cancer formation. Fish consumption is often described as a feature of healthy dietary patterns (70), with serum concentrations of omega-3 PUFAs strongly correlating with fish intake (71, 72). Several experimental studies support the hypothesis that risk of gastric cancer can be reduced by omega-3 PUFAs via various mechanisms (73–77). However, observational studies have produced contradictory results in this regard, thereby revealing just how difficult it is for studies to investigate the effects of multifactorial disease by only looking at selected foods. There is evidence, above all from case-control and experimental studies, that suggests that omega-3 PUFAs – in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) – have a positive effect on gastric cancer risk. Three case-control studies have reported a reduced risk among participants with the highest EPA and DHA intakes (78–80). Of five prospective studies, one showed no link (81), one showed an increased risk of gastric cancer (82), and three showed a reduced risk (83–85). In one of those latter three studies (83), only a single subgroup of participants – those who did not take aspirin – were shown to have a reduced risk.

Concerning prostate cancer risk, a case-control study (86) and a prospective study (87) showed no relation to overall intake amounts of omega-3 PUFAs, whereas a different case-control study (88) and prospective study (89) showed a reduced risk of prostate cancer among participants with the highest overall intake of omega-3 fatty acids and highest individual intake of EPA and DHA. One prospective study even provided an indication that a very high intake (on average 1.3 mg per day) of omega-3 fatty acids could potentially increase the risk of prostate cancer (90).

There is more and more evidence pointing towards a link between sufficient omega-3 PUFA intake amounts and reduced risk of breast cancer. Possible explanations for the partly contradictory results could be the varying amounts of omega-3 PUFAs administered in the studies as well as the various accompanying dietary habits of the participants. The results of both case-control studies and prospective cohort studies carried out in Asian countries, which have associated sufficient omega-3 PUFA intake with reduced risk of breast cancer, are mainly consistent with each other (91–94), with one exception (95). A US study also showed a reduced risk of breast cancer for users of fish oil supplements (96). As yet, no European study has observed a link between omega-3 PUFAs and breast cancer (97, 98). The heterogeneity of study results could be explained by the varying doses of omega-3 PUFAs administered to participants: the average intake amount of omega-3 PUFAs in the Chinese study that showed no risk reduction (95) was 200 mg per day, while in the other Asian studies that noted a preventive effect, it ranged from 300 mg up to more than 500 mg. Taken together, these studies show that it may be necessary to consume a high amount of omega-3 PUFAs in order to target their preventive effects. A meta-analysis confirmed a link between increased omega-3 PUFA intake and reduced risk of breast cancer for all women in the observed cohorts, but in particular for post-menopausal women (99).

Concerning gastric cancer, a Japanese case-control study has shown a link between reduced risk and increased omega-3 PUFA consumption (100). Possible effects of omega-3 PUFAs on the frequency of occurrence of lung cancer have not recently been investigated, but a relatively old prospective cohort study from Norway showed that a targeted intake of cod liver oil supplements reduced the risk of lung cancer (101).

According to studies carried out so far, alpha-linolenic acid (ALA) seems to neither be a risk factor nor a preven-tive factor in relation to cancer. Two case-control studies (79, 80), as well as one European (102) and one Japanese (85) cohort study, have shown no impact on colorectal cancer. A US study (81) initially reported a significant increase in cancer risk due to increased ALA intake, but on correction of the values concerning participants’ meat consumption, the study was no longer able to clearly attribute this risk to ALA. Two case-control studies (86, 88) and a cohort study (90) have shown no link between ALA intake and prostate cancer. One prospective study (87) has shown a reduced risk of prostate cancer and two (88, 89) have shown an increased risk in relation to ALA intake. It is biologically implausible, however, that ALA could have a cancer-promoting effect, which is also supported by experimental models. A link between ALA and breast cancer has not yet been observed in Asian countries (91, 94, 95). A French study (97) provided evidence that breast cancer risk could possibly be reduced if the source of ALA were vegetable oil, but could be increased if the source of ALA were processed food. This would mean that cancer risk might also be affected by numerous other components in food. Processed food may be a part of Western dietary patterns but not Asian dietary patterns, for example (103).