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Excess iron intake or storage has been demonstrated to have a role in the aetiology of a number of different cancers, predominantly of the colon and liver. The colon is particularly susceptible, as only 15-35% of dietary haem iron is absorbed in the duodenum, resulting in luminal exposure with the potential to cause direct oxidative damage to the colorectal lumen (Manual). Hepatocellular carcinoma (HCC) is very strongly associated with hemochromatosis and other iron-overload diseases. (SACN)
A number of epidemiological studies have established a link between iron and colorectal cancer (CRC). A recent meta-analysis has identified a consistent and significant association between high intakes of haem iron from meat and the increased risk of CRC. Five prospective cohort studies published between 2004 and 2010 were included, with data on 566,607 individuals and 4,734 cases of CRC. The overall relative risk of C was 18% in the individuals with the highest intake of haem iron compared to those with the lowest intake (Nadia). The meta-analysis had a number of limitations, including that the studies did not all consider the same factors. For example, calcium has a proven role in animal models in inhibiting certain carcinogenic activities of haem iron in the colon (22). This was considered in two out of the five studies, which both demonstrated higher associations between haem iron and CRC than the other three studies (17-18). Experimental studies in rats are consistent with the epidemiological studies. (Pierre F).
The risk of HCC relating to hereditary hemochromatosis (HH) was first quantified in a cohort study in 1985, which concluded that there was a 200-fold increased risk of HCC in patients with HH (Bradbear). Studies since this initial finding have confirmed the high association and shown increased risks of 20-200, occurring predominantly where liver cirrhosis was already present. (Kris). A population-based cohort study performed in Sweden in 2003 is believed to indicate the true incidence and prevalence of HCC in HH, as it was possible to establish an overall standardized incidence ratio of HCC in the population. It found that patients with HH were at a 20-fold risk of liver cancer with an almost unaltered risk of all other cancers (Elmberg).
The mechanism for iron's role in the aetiology of CRC is largely unknown, but a number of hypothesis were discussed in a meta-analysis in 2011 (pdf). They are based on iron having a catalytic role in the formation of carcinogenic N-nitroso compounds known to cause DNA damage, contributing to p53 and K-ras mutations. This is hypothesised to initiate and promote tumour growth (46). Iron is also believed to have a catalytic effect on lipoperoxidation, increasing cytotoxic and genotoxic aldehydes. (61)
Research carried out by Cancer Research UK scientists in 2012 discovered bowel cancers were 2-3 times more likely to develop in mice after adenomatous polyposis coli (APC) gene deletion that were fed high amounts of iron compared to mice who still had a working APC gene or those with gene deletion but a low intake of iron. Following deletion of the gene, proteins inducing iron accumulation are expressed, leading to a cancer signalling cascade. It was also found that increased luminal iron (but not systemic) promoted tumorigenesis (APC Pdf).
Iron accumulation in HH is deposited in tissues, including the liver and is considered to be a co-factor for the progression of liver disease, including cirrhosis developing into HCC. Iron overload can enhance the effects of oxidative stress. (Nahon)
Metabolic inhibitors represent an important class of anti-tumour agents . Aroylhydrazone and thiosemicarbazone iron chelators have demonstrated marked and selective anti-tumour activity in vitro and in vivo against a wide spectrum of tumours without inducing whole body iron-depletion or disturbances in haematological or biochemical functions (DR Richardson). Calcium salts, vitamin C and polyphenols may also have a role e.g. the addition of vitamin C to processed meats to inhibit the formation of NOC in meat (Nadia).
Individuals with colorectal adenomas and inflammatory bowel disease are at particular risk of developing CRC. As they often present with iron-deficiency anaemia due to intestinal bleeding, common practice is to supplement with high doses of oral iron which is conversely likely to further increase their risk of developing CRC. To resolve the anaemia and prevent this risk, a possible future direction would be to supplement systemically with intravenous infusions of iron and provide iron chelation therapy (APC pdf).
Anaemia and gastric cancer?
2. Vitamin A
The role of vitamin A in the prevention and treatment of cancer has been extensively researched due to its antiproliferative effects at a cellular level, with the potential to induce apoptosis of cancer cells . In a meta-analysis of English and Chineese studies, both performed vitamin A and the carotenoids have been identified to be protective towards cervical cancer (Zhang) and towards breast cancer in another meta-analysis (Eliasson). Despite this plausible role in the treatment of cancer, studies have largely produced inconclusive or negative results (American cancer society). In particular, beta-carotene (although normally considered less potent than performed vitamin A and with the added antioxidant properties associated with decreasing oxidative stress, with the potential to cause cancer) has been associated with an increased risk of lung cancer among smokers (Heidi).
Studies undertaken to assess the role of beta-carotene in the aetiology of lung cancer have demonstrated that this role is exclusively present in individuals already at a high risk of lung cancer, e.g. active smokers, those with a significant smoking history or those past asbestos exposure. A study examining the relationship between dietary beta-carotene and lung cancer risk in U.S. non-smokers ironically found beta-carotene to be 30 % protective for lung cancer (Susan).
A meta-analysis from 2008 examined four large randomized studies reporting on the effect of beta-carotene and the incidence of lung cancer in high-risk populations. It included the ATBC (The effect) and CARET (omen) studies and showed a 24% increased risk of lung cancer associated with beta-carotene supplementation among participants who were current smokers and 10% among those with a significant smoking history (Tawee )
In 2010, a meta-analysis of 9 randomized control trials (RCTs) showed that the incidence of lung and gastric cancers were significantly increased in individuals supplemented with 20-30 mg beta-carotene per day. An increased risk of developing gastric cancer of 20% was seen in smokers, while this increased to 54% in asbestos workers compared to the placebo group (Nathalie).
The exact mechanism of the carcinogenesis is not fully understood. The high oxygen concentration of the lungs combined with exposure to lung irritants and conditions of high oxidative stress may result in carotene acting as a pro-oxidant (gibney). A high concentration of beta-carotene was demonstrated in vitro to activate free radical production with increasing concentration in peripheral blood mononuclear cells (de Oliv). The type of radicals involved is another contributing factor in determining the role of beta-carotene as a pro or anti-oxidant (van Held). Carotenoid cleavage products, including highly reactive aldehydes and epoxides, are formed during the course of antioxidative action. They increase oxidative stress by impairing mitochondrial function, resulting in cellular damage and carcinogenesis (Siems).
The most recent National Health and Nutrition Examination Survey found that 37% of vitamin and mineral supplements contained beta-carotene (balluz), while large increases in the use of multi-vitamins in Europe have occurred in recent years (Reinert). Lung cancer patients surveyed on their use of complementary and alternative therapies revealed that multi vitamin combinations were the most common therapy used, with 17% of patients using them (Micke). Considering that 90% of lung cancer is attributed to smoking (cancer research UK), it is apparent that healthcare professionals need to be more vigilant in advising patients about the adverse effects of supplements containing beta-carotene.
Selenium has been considered to possess anticancer effects since the early 1970s. Numerous mechanistic, experimental and epidemiological studies and clinical supplementation trials have since confirmed this consideration, although results have been controversial from other studies (3).
A meta-analysis of 9 randomised controlled supplementation trials in 2011 found selenium supplementation to have a 24% preventive effect on cancer incidence. This effect was increased further in populations with a low baseline serum selenium level and in high cancer risk populations (Lee EH). Another meta-analysis examining prospective observational studies found that this protective effect was more pronounced in men than in women (Dennert). Selenium has been particularly associated with a reduced risk of cancer of the bladder, the lungs and the gastrointestinal tract.
A meta-odds ratio was calculated based on seven epidemiological studies examining selenium status and the risk of bladder cancer, resulting in a 39% protective effect, predominantly in women (bladder). The gender difference in relation to bladder cancer is hypothesised to be due to differences in excretion rates, half-lives and sensitivity to selenium among males and females (Patterson B).
A more controversial relationship exists between selenium and lung carcinogenesis risk. The protective effect of selenium only appeared to be present in populations with lower baseline selenium status, with an increased risk of lung cancer seen in those with higher selenium status, when supplemented (Heidi). Of the RCTs, the large Nutritional Prevention of Cancer trial found a 57% reduced incidence of lung cancer (Reid) while the Selenium and Vitamin E Cancer Prevention Trial (SELECT) study found a 12% increased risk associated with selenium supplementation (Lippman). Therefore, although selenium may be effective for lung cancer prevention among individuals with lower selenium status, it should not be used prophylactically for lung cancer prevention (Heidi).
A large number of studies have shown an inverse relationship between selenium and prostate cancer risk (Hurst). This has become controversial following the conflicting results of the SELECT trial, which was terminated prematurely following identification of an increased risk of prostate cancer of up to 22% with selenium supplementation (Eric).
GI - potentially found to decrease risk. (Bjel)
Selenium occurs in over 30 selenoproteins as selenocysteine. Glutathione peroxidase enzymes (GPx) are important selenoproteins with potent antioxidant activity against hydrogen peroxide and lipid peroxidation, as are thioredoxin reductases, important in regulating DNA expression, both believed to be involved in the prevention of cancer (gibney). Primarily, these two systems are associated with exerting selenium's antineoplastic effects (rayman mechanism). By protecting cells externally and internally from damage by free radicals, GPx prevents the activation of oncogenes (Sch). Thioredoxin reductases have a role in carcinogen metabolism, controlling cell division and may enhance p53 activity, resulting in either DNA repair or apoptosis (Smith).
Other functions associated with selenium which may contribute to its chemoprotective effects include its role in thyroid function and T cell immunity (Ashton). More recent laboratory investigations have proposed that selenium has additional mechanisms capable of preventing cancer development, including growth inhibitory, proapoptotic activity for selenometabolites in premalignant cells (Ip)
At present, a new study examining the efficacy of selenium in the prevention of cancer in 33,000 European individuals, The Prevention of Cancer by Intervention with Selenium (PRECISE) clinical trial, is at the pilot study stage (http://clinicaltrials.gov/show/NCT00022165). When studying the NPC and the SELECT trial, both with conflicting results, it is important to observe that different forms of selenium were used. Therefore, it is suggested that selenized yeast may give rise to peak anticancer effects (Rayman type)
Geographic correlation studies first linked Vitamin D and cancer, when it was observed that an inverse relationship existed between sunlight exposure levels at different latitudes and the rates of incidence and death for certain cancers in that area. Despite the lack of knowledge regarding the antineoplastic effects of vitamin D at the time, vitamin D status was hypothesized to explain this observed relationship (Garland). Vitamin D's role in cancer prevention has since been extensively researched and documented.
Of all cancers, vitamin D is understood to have the most significant role in the prevention of colorectal cancer (CRC). A meta-analysis in 2011 examined the incidence and recurrence of CRC according to serum 25(OH)D levels in 8 studies and 2 studies respectively. The summary risk ratios for an increase of 25(OH)D by 20 ng/ml were 0.82 for incidence, 0.87 for recurrence and 0.84 for both outcomes combined (Yin). Another meta-analysis from the same year, including the Physicians' Health Study and eight individual prospective studies, also demonstrated a significant and consistant association between colorectal adenomas and circulating vitamin D. Colon cancer and rectal cancer were also examined separately in this meta-analysis, with a stronger association for rectal cancer found (0.50 for rectal cancer and 0.77 for colon cancer). (Jung)
Data from studies on vitamin D intake and breast cancer have shown a 9% protective factor for high versus low vitamin D intake. This factor is further increased to 45% when the highest quantile of circulating 25(OH)D is compared with the lowest quantile (Chen). A meta-analysis of longitudinal studies reviewed the association between circulating 25(OH)D and the risk of ovarian cancer, revealing a tentative protective factor of 17% (Yin L ovaran). Published literature provides little evidence to support a major role of vitamin D in preventing prostate cancer or its progression. (Gilbert).
Vitamin D may decrease cancer risk through a number of mechanisms. Proposed mechanisms involve promoting bile acid catabolism, direct effects on the cell cycle, growth factor signaling and immunomodulation (Bostick). This includes the regulation of progression, differentiation and apoptosis of cancer cells and potentially the inhibition of angiogenesis (lamprecht).
As studies tend not to quantify the optimum level of 25(OH)D, studies investigating dose-response relationships between circulating levels of vitamin D and cancer risk would be beneficial for public health nutrition (CINDY). The potential role of vitamin D in the prevention of ovarian cancer is another area worth investigating further, as the clinical and public health impact would be exceptional were this association profound (Yin L ovaran).