As on other Science Library pages, we do not present a lengthy narrative on each body system affected by cancer, but rather will briefly summarize or quote the most relevant take-home points and/or research conclusions from each study. Article titles are linked to abstracts archived at the U.S. National Library of Science.
Our Iron Science Library pages include:
This 1996 review provides a good general description of The role of iron in Cancer. “Numerous laboratory and clinical investigations over the past few decades have observed that one of the dangers of iron is its ability to favour neoplastic cell growth.
The metal is carcinogenic due to its catalytic effect on the formation of hydroxyl radicals, suppression of the activity of host defense cells and promotion of cancer cell multiplication.
In both animals and humans, primary neoplasms develop at body sites of excessive iron deposits. The invaded host attempts to withhold iron from the cancer cells via sequestration of the metal in newly formed ferritin.
The host also endeavours to withdraw the metal from cancer cells via macrophage synthesis of nitric oxide. Quantitative evaluation of body iron and of iron-withholding proteins has prognostic value in cancer patients.
Procedures associated with lowering host iron intake and inducing host cell iron efflux can assist in prevention and management of neoplastic diseases. Pharmaceutical methods for depriving neoplastic cells of iron are being developed in experimental and clinical protocols.”
This 2010-published review describes how excessive iron can increase disease risks across multiple conditions including many cancers. “Excessive or misplaced tissue iron now is recognized to pose a substantial health risk for an extensive array of endocrinological, gastrointestinal, infectious, neoplasmic, neurodegenerative, obstetric, ophthalmic, orthopedic, pulmonary and vascular diseases.
Ingested, injected, inhaled and decompartmentalized iron contributes not only to disease, but also to aging and mortality.Iron is dangerous by catalyzing free radical formation and by serving as an essential nutrient for microbial and neoplasmic cell invaders. Our body cells exhibit wide variation in sensitivity to iron toxicity. Efficacy of our iron withholding defense system is modulated by numerous environmental, behavioral and genetic factors. A notable variety of methods for prevention and therapy of iron toxicity are now becoming available. [Health-e-Iron note: Table 2 from this review appears below]
In this 2003 review molecular cellular iron uptake mechanisms are discussed in the context of tumor cell proliferation and growth. “…the rate of Fe (iron) uptake by proliferating cells was approximately 250% that of stationary cells. The maximum rate of Fe uptake by the TfR1– and NTfR1 (transferrin)-mediated process by proliferating cells was increased to 200% and 300% that of stationary cells, respectively.”
This 2010 study by Italian researchers reports that nipple aspirante fluids in female breast cancer patients contain substantially more iron (ferritin) than in matched healthy controls.
Ferritin levels were significantly higher in post-menopausal breast cancer patients than in post-menopausal controls, as well as in pre-menopausal cancer patients when compared to pre-menopausal controls.
The researchers concluded, “These data may support the involvement of inflammation and deregulation of iron homeostasis in breast cancer etio-pathogenesis. The significant accumulation of CRP (C-reactive protein) in NAF (Nipple aspirate fluid) in conjunction to the disruption of iron homeostasis may help to identify women at higher breast cancer risk.” [Health-e-Iron note; Figure 3 from this study appears below]
Figure 3. Ferritin concentrations in Nipple Aspirate Fluids from healthy subject and cancer women. FTN mean value in NoCancer NAFs (detectable in all healthy women without BC evidence, n=16) was significantly lower than that in Cancer NAFs (detectable in all BC bearing patients, n=19) (55.50±7.21 vs 280.25±32.32μg/L, P<0.0001, respectively).
In this 2002 review from Japan of recent findings, the author stated, “In the past few years, there have been great advances in the understanding of iron metabolism.” And...“recent new findings on iron metabolism are reviewed and the concept of the vulnerable sites explored. More effort to link iron metabolism with human carcinogenesis is anticipated.”
This is a review of the literature published in 2009 that provides a comprehensive account of the molecular transport of iron in human cancer and as observed in animal models. The author stated, “In the past few years, our understanding of iron metabolism, the molecular mechanism of hemochromatosis, and iron-induced carcinogenesis has expanded enormously.” [Health-e-Iron note: Figure 3 from this review appears below]
In this 1996 paper the author discusses the role free or catalytic iron in the production of reactive oxygen species. “There is an increasing number of reports of an association between increased body iron stores and increased risk of cancer. Iron-induced oxidative stress results in two possible consequences: (1) redox regulation failure that leads to lipid peroxidation and oxidative DNA and protein damage; (2) redox regulation that activates a variety of reducing and oxystress-protective mechanisms via signal transduction. Both consequences appear to play a role in iron-induced carcinogenesis.”
This 2006 review provides additional information on the role of free radicals, oxidative stress, transition metals and the role of protective antioxidants. The authors state, “Oxidative stress induces a cellular redox imbalance which has been found to be present in various cancer cells compared with normal cells; the redox imbalance thus may be related to oncogenic stimulation. DNA mutation is a critical step in carcinogenesis and elevated levels of oxidative DNA lesions (8-OH-G) have been noted in various tumours, strongly implicating such damage in the etiology of cancer.”
In this 2005 analysis of 6,309 people followed for up to 22 years in the National Health and Nutrition Examination Survey I (NHANES I) Epidemiologic Follow-Up Study, US adults (aged 25 to 74 years at baseline) were followed up from 1971-1974 to 1992 (N = 6,309). The researchers determined that a combination of transferrin saturation (TS%) more than 45%, together with high dietary iron intake (more than 18 mg per day) was associated with a 2.24-fold cancer risk. When the researchers tested a TS% of 41%, relative risk was reduced to 2-Fold
The researchers concluded and advised as follows: “Among persons with increased transferrin saturation, a daily intake of dietary iron more than 18 mg is associated with an increased risk of cancer. Future research might focus on the benefits of dietary changes in those individuals with increased serum transferrin saturation.” [Health-e-Iron note: Figure 1 and Table 2 from this research appear below]
This study reported in 1994 was based on another follow-up analysis based on NHANES I baseline data. Researchers determined that in 379 men who developed cancer over the period, TS% (transferrin saturation percentage) measurements were significantly higher among those who developed cancer, when compared to men who did not; and that for men and women, when TS% was between 40 – 50%, 50 – 60%, or above 60%, the respective relative risks were 1.16, 1.38, and 1.73.”
This study, published in 1994, analyzed data from a Finnish cohort of 41,276 men and women aged 20-74 years, initially free from cancer and, “…during a mean follow-up of 14 years, 2,469 primary cancer cases were diagnosed. Excess risks of colorectal and lung cancers were found in subjects with transferrin saturation levels exceeding 60%. The relative risks, adjusted for age, sex and smoking, were 3.04 for colorectal cancer and 1.51 for lung cancer, in comparison with subjects having lower levels.”
In 1995 researchers who undertook this European study concluded the following, “These results suggest that body iron stores are a risk factor for mortality due to cancer in postmenopausal women. This may be due to accumulation of stored iron among women after menopause.”
In this 2004 study of iron and mortality, which was also based on data from the NHANES I cohort study, researchers reported that, “…controlling for potential confounders, including comorbid diseases, smoking, and cholesterol, all-cause mortality is significantly greater for persons with a serum transferrin saturation of more than 55% (Hazard ratio = 1.60, 95% confidence interval [CI], 1.17-2.21), compared with those with (transferrin) saturations below this cutoff (hazards ratio [HR] = 1.60).” The researchers concluded, “…elevated serum transferrin saturation has implications for increased mortality risk. The additional mortality associated with elevated serum transferrin saturation would appear to affect many more persons than previously thought. A substantial proportion of the US adult population appears to share this risk.” [Health-e-Iron note: Figure 1 from the above study appears below with minor labeling adaptations]
This 2011 Danish population study followed 45,159 men and women for up to 18 years. The researchers reported that compared to transferrin saturation below 50%, for individual with higher transferrin saturation, men experienced 30%, and women 50% increased mortality during the period. [Health-e-Iron note: Figure 2 from study appears below]
This 2005 study was based on another analysis from NHANES I linked with the NHANES I Epidemiologic Follow-up Study. The researchers found that in a fully adjusted model, individuals falling above the 75th percentiles for both serum iron and total cholesterol experienced a 39% increased risk of cancer. When iron and cholesterol were above the 80th and 85th percentiles, the increased risks were 51% and 61% respectively. The researchers concluded, “These results support the theory that the iron induced oxidation of serum lipids is important in the pathogenesis of cancer.” [Health-e-Iron note: Figure 1 from the above study appears below with minor labeling adaptations]
Figure 1. Kaplan-Meier Curves of time to the Development of Cancer with Elevated Iron and
Cholesterol, defined as > the 75th Percentile*
In this study of Black Africans (in Africa), iron overload was associated with more than a 10-fold increased risk of hepatocellular cancer. The researchers stated, “We conclude that dietary iron overload may contribute to the development of HCC (hepatocellular cancer) in Black Africans.”
This 2005 study was to determine the risk of cancer among persons who had both elevated iron and lipids. The study was an analysis of data from the Framingham Offspring Study. In adjusted models, both elevated iron (hazard ratio (HR Hazard Ratio) = 1.66) and VLDL-Cholesterol (HR = 1.54) had significant independent risks for development of cancer. When elevated iron was combined with elevated VLDL-Cholesterol, the adjusted relative risk of cancer increased (HR = 2.68). Elevated iron and low HDL-Cholesterol also had a significant adjusted relative risk of cancer (HR = 2.82). The researchers concluded, “The results suggest that elevated serum iron levels coupled with either high VLDL-Cholestrol or low HDL-Cholesterol appear to interact to increase cancer risk in this cohort.” [Health-e-Iron note: Figure 1 from study appears directly below]
This 2009 study in China attributed the rapid changes in breast cancer incidence rates in China, at least in part, to dramatically increased meat consumption. Plasma ferritin levels and reported dietary iron intake were compared in 346 women with fibrocystic changes, 248 breast cancer cases and 1,040 controls. Increasing ferritin levels were significantly associated with increasing risk of nonproliferative fibrocystic changes (OR Odds Ratio: 2.51). Similar, but weaker, trends were observed for proliferative changes and for breast cancer. Risk of breast cancer relative to the risk of fibrocystic changes was associated with dietary iron intake in women with nonproliferative fibrocystic changes (OR: 2.63). The researchers concluded, “… this study finds significant associations between iron (stored and dietary) and fibrocystic disease and breast cancer.”
In a 2007 review from Albert Einstein College of Medicine in New York, “Reactive oxygen species produced by normal aerobic cellular metabolism can lead to the release of free iron from ferritin. In the presence of superoxide radical and hydrogen peroxide, stored ferric iron (Fe(3+)) is reduced to ferrous iron (Fe(2+)), which catalyzes the formation of the hydroxyl radical (*OH). *OH in turn can promote lipid peroxidation, mutagenesis, DNA strand breaks, oncogene activation, and tumor suppressor inhibition, increasing the risk of breast cancer. In addition to its independent role as a proxidant, high levels of free iron may potentiate the effects of estradiol, ethanol, and ionizing radiation – three established risk factors for breast cancer.” “In order to identify the role of iron in breast carcinogenesis, improved biomarkers of body iron stores are needed, as are cohort studies which assess heme iron intake.”
In this study reported in 2011, investigators noted, “Chronic oxidative stress and inflammation have been indicated as major mediators during carcinogenesis and cancer progression. Human studies have not considered the complexity of tumor biology during the stages of cancer advance, limiting their clinical application. The purpose of this study was to characterize systemic oxidative stress and immune response parameters in early (ED; TM I and II) and advanced disease (AD; TNM III and IV) of patients diagnosed with infiltrative ductal carcinoma breast cancer.” “Analysis of the results verified different oxidative stress statuses occur at distinct cancer stages.” “Plasma iron levels were significantly elevated in AD. The data obtained indicated that oxidative stress enhancement and immune response impairment may be necessary to ensure cancer progression to advanced stages and may result from both host and tumor inflammatory mediators.”
This 2010-published study was undertaken in Japan. The researchers noted, “excess iron storage induces DNA damage by generating hydroxyl radicals and thus promotes carcinogenesis. However, it remains unclear whether body iron levels that are commonly observed in a general population are related to oxidative DNA damage.”We examined the association between serum ferritin concentrations and levels of urinary 8-hydroxydeoxyguanosine (8-OHdG), a biomarker of systemic oxidative DNA damage and repair, in 528 Japanese men and women aged 21-67 years. Men had much higher ferritin levels than in women, and the levels were significantly greater in women aged 50 years or older than in women aged less than 50 years. Urinary 8-OHdG concentrations were significantly and positively associated with serum ferritin levels in all the subgroups. The Spearman rank correlation coefficients were 0.47, 0.76, and 0.73 for men overall, women aged less than 50 years, and women aged 50 years or older, respectively. These associations were materially unchanged after adjustment for potential confounding variables. In men, a more pronounced association was observed in nonsmokers than in smokers.” The researchers concluded, “Our results suggest body iron storage is a strong determinant of levels of systemic oxidative DNA damage in a healthy population.” [Health-e-Iron note: Figure #1 from this study appears below]
Fig. 1. Correlation between serum ferritin and urinary 8-hydroxydeoxyguanosine (8-OHdG) concentrations.
Based on this 2002 laboratory study done in Germany, the researchers concluded, “From these results we can conclude that iron is taken up by human colon cells and participates in the induction of oxidative DNA damage. Thus, iron or its capacity to catalyse ROS-formation, is an important colon cancer risk factor.”
Among other things relative to oxidative stress and cancer, this 2010 review reports, “Although at present it is impossible to directly answer the question concerning involvement of oxidatively damaged DNA in cancer etiology, it is likely that oxidatively modified DNA bases may serve as a source of mutations that initiate carcinogenesis and are involved in aging (i.e. they may be causal factors responsible for these processes).” “To counteract the deleterious effect of oxidatively damaged DNA, all organisms have developed several DNA repair mechanisms. The efficiency of oxidatively damaged DNA repair was frequently found to be decreased in cancer patients.”
This 2001 paper reviewed 33 studies. “Of the larger studies, approximately three-quarters supported the association of iron, in all three strata of exposure, with colorectal neoplasia risk. Because iron is broadly supplemented in the American diet, the benefits of iron supplementation need to be measured against the long-term risks of increased iron exposure, one of which may be increased risk of colorectal cancer.”
This 2010 editorial provides an in-depth review of the role of iron metabolism, oxidative stress and inflammation in colorectal carcinogenesis. The authors state, “This inherent redox property of iron, however, also renders it toxic when it is present in excess. Iron-mediated generation of reactive oxygen species via the Fenton reaction, if uncontrolled, may lead to cell damage as a result of lipid peroxidation and oxidative DNA and protein damage.”
Researchers from the national Cancer Institute reported the results of this research in 2011. “We estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between meat, meat components, and meat cooking by-products and risk of esophageal or gastric cancer in a large cohort study. During ∼10 years of follow-up, we accrued 215 esophageal squamous cell carcinomas, 630 esophageal adenocarcinomas, 454 gastric cardia adenocarcinomas, and 501 gastric non-cardia adenocarcinomas.” Among the relationships noted in greater detail in the full text, the researchers found, “Red meat intake was positively associated with esophageal squamous cell carcinoma (HR for the top versus bottom quintile = 1.79, 95% CI: 1.07–3.01, P for trend = 0.019).” and…”heme iron intake had a suggestive increased risk for esophageal adenocarcinoma …HR=1.47, 95% CI: 0.99-2.20, P for trend=0.063…” [Health-e-Iron note: Heme iron from red and processed meat is the primary source of iron in the U.S. diet. The authors summary review of their findings appears below]
In a more recent 2012 study from the National Cancer Institute the researchers noted, “Iron can cause oxidative stress and DNA damage, and heme iron can catalyze endogenous formation of N-nitroso compounds, which are potent carcinogens.” “We conducted a population-based case-control study of adenocarcinoma of the esophagus (n=124) and stomach (n=154) and 449 controls in Nebraska. Heme iron and total iron intake were estimated from a food frequency questionnaire and databases of heme and total iron.” After adjusting for known risk factors, the researchers found, “Esophageal cancer was positively associated with higher intakes of heme iron (ORQ4 vs. Q1=3.04, 95% CI: 1.20-7.72; P trend=0.009) and total iron from meat sources (ORQ4 vs. Q1=2.67, 95% CI: 0.99-7.16; P trend=0.050). Risk of stomach cancer was elevated among those with higher intakes of heme iron (ORQ4 vs.Q1=1.99, 95% CI: 1.00-3.95; P trend=0.17) and total iron from meat (OR=2.26, 95% CI: 1.14-4.46; P trend=0.11). Iron intake from all dietary sources was not significantly associated with risk of either cancer.” The investigators concluded, “Our results suggest that high intakes of heme and iron from meat may be important dietary risk factors for esophageal and stomach cancer and may partly explain associations with red meat.”
This 2009 paper describes how hepatocellular cancer likely occurs in the absence of fibrosis or cirrhosis. The author demonstrates how dietary iron might directly contribute to hepatocarcinogenesis. The author suggests, “Free iron generates reactive oxygen intermediates that disrupt the redox balance of the cells and cause chronic oxidative stress. Oxidative stress leads to lipid peroxidation of unsaturated fatty acids in membranes of cells and organelles. Cytotoxic by-products of lipid peroxidation, such as malondialdehyde and 4-hydroxy-2′-nonenal, are produced and these impair cellular function and protein synthesis and damage DNA.”
In this 2006 study of laboratory rats preformed in South Africa, the authors state, “Our findings are compatible with the hypothesis that the direct hepatocarcinogenic effect of free iron is mediated by the generation of oxygen reactive species and oxidative damage that are mutagenic and carcinogenic.”
The researchers concluded from this 2008 study of laboratory rats that, “Mutagenic effects of iron and alcohol are synergistically multiplicative implicating hydroxyl free radicals in hepatocarcinogenesis.”
In this 2011 review, the authors cover the three roles of redox-active iron in clear cell carcinoma of the ovary carcinogenesis. “This article reviews the English-language literature for molecular, pathogenetic, and pathophysiological studies on endometriosis and endometriosis-associated ovarian cancer (EAOC). In this review, we focus on the functions and roles of redox-active iron in CCC (clear cell carcinoma) carcinogenesis.”
This 2011 review updates the knowledge respecting “the three major processes in which iron is implicated in repeated events of hemorrhage and endometriosis in epithelial ovarian carcinoma: 1) increasing oxidative stress promotes DNA methylation; 2) activating anti-apoptotic pathways supports tumor promotion; and 3) aberrant expression of stress signaling pathways contributes to tumor progression.”
Published in March, 2012, this study was undertaken to to determine the quantities of non-heme iron accumulated over time in the ovaries of laboratory mice. The author stated, “Intraperitoneal iron overload in adult mice resulted in non-heme iron deposition in the entire st roma and generation of enlarged macrophages, suggesting that excessive iron accumulation induced macrophage morphological changes. The data indicated that non-heme iron accumulation in ovarian stromal tissue may be related to aging of the ovary due to increasing oxidative stress.”
In this 2011 review from Spain, the author suggests, “Iron has a pivotal role in homeostasis due to its participation in virtually all of the body’s oxidation-reduction processes. However, iron can also be considered a double-edged weapon, as its excess may lead to an increased risk of developing cancer, presumably by the generation of reactive oxygen species, and its role as substrate to enzymes that participate in cell proliferation. Thus, iron might as well be considered a cofactor in tumour cell proliferation. In certain pathological conditions, such as haemochromatosis, hepatitis B and C virus infection, asbestosis and endometriosis, iron overload may increase the risk of cancer. By contrast, iron depletion could be considered a useful adjunct in antitumour therapy. This paper reviews the current scientific evidence behind iron’s role as a protumoral agent, and the potential benefit of a state of iron depletion in patients with cancer.”
This is a review of the literature from Australia published in 2002. The authors focus on iron deprivation by chelation and the potential and importance that could have in arresting tumor growth.
This 2004 mortality risk study used data from the U.S. National Health and Nutrition Examination Survey 1976-1980 (NHANES II) and the NHANES II Mortality Study 1992. Population estimates were based on 9,229 persons aged 35 to 70 years at baseline. The adjusted survival analysis indicated that persons with elevated transferrin saturation who reported high dietary iron intake had a hazard ratio for death of 2.90 compared with those with normal transferrin saturation levels and reported low dietary iron intake. Persons who had a high transferrin saturation and reported high red meat consumption also had an increased hazard ratio for death 2.26 compared with those who had normal transferrin saturation and reported low red meat consumption. The researchers concluded, “Ingestion of large quantities of dietary iron and red meat in persons with high transferrin saturation is associated with an increase in mortality. Simple dietary restrictions may reduce the mortality risk associated with high transferrin saturation.”[Health-e-Iron note; Figures 1 and 2 from this study appear below]
This is a 2012-reported study based on an investigation undertaken in Spain. The investigators noted “Even though recent studies suggest that a high intake of heme iron is associated with several types of cancer, epidemiological studies in relation to gastric cancer (GC) are lacking.” “The aim of the study is to investigate the association between heme iron intake and GC risk in the European prospective investigation into cancer and nutrition (EURGAST-EPIC). Dietary intake was assessed by validated center-specific questionnaires. Heme iron was calculated as a type-specific percentage of the total iron content in meat intake, derived from the literature. Antibodies of H. pylori infection and vitamin C levels were measured in a sub-sample of cases and matched controls included in a nested case-control study within the cohort. The study included 481,419 individuals and 444 incident cases of GC that occurred during an average of 8.7 years of followup.” “We observed a statistically significant association between heme iron intake and GC risk (HR 1.13 95% CI: 1.01-1.26 for a doubling of intake) adjusted by sex, age, BMI, education level, tobacco smoking and energy intake.” The investigators concluded, “The positive association between heme iron and the risk of GC was statistically significant in subjects with plasma vitamin C <39 mmol/l only (log2 HR 1.54 95% CI (1.01-2.35). We found a positive association between heme iron intake and gastric cancer risk.”
[This study also appears in Hereditary Hemochromatosis Library] In 2011 this research team from Denmark reported the following, “Increased iron overload, whether or not owing to the presence of the haemochromatosis genotype C282Y/C282Y, may be associated with an increased risk of cancer. The aim of this study was to test the hypothesis that elevated transferrin saturation levels (as a proxy for iron overload) and haemochromatosis genotype C282Y/C282Y are associated with an increased risk of cancer.” The results were: “In women, transferrin saturation above 60% versus below 50% was associated with a hazard ratio of 3.6 … for any cancer; risk of liver cancer was increased in both women and men. In women, the corresponding absolute 10-year risk of any cancer was 34% and 30% in smokers and nonsmokers, respectively. In men, haemochromatosis genotype C282Y/C282Y versus wild type/wild type was associated with a hazard ratio of 3.7… for any cancer, with a similar trend in women. In men, the corresponding absolute 10-year risk of cancer was 39% and 27% in smokers and nonsmokers, respectively.” The researchers concluded, “We have demonstrated that elevated transferrin saturation levels in women and haemochromatosis genotype C282Y/C282Y in men are associated with increased risk of cancer. Thus, our results support the implementation of cancer screening programmes in patients with iron overload or with C282Y/C282Y.” [Health-e-Iron note; Figures 1 and 2 from this study appear below. An important finding from this study was that the increased risk of cancer in those with transferrin saturation above 50% was greater than the risk of smoking among individuals having transferrin saturation below 50%. Smoking alone increased the risk of cancer significantly less than the risk of transferrin saturation above 50%. Smoking increased cancer risk by similar degrees across all levels of transferrin saturation]
Fig. 1 Absolute 10-year risk of any cancer by transferrin saturation levels and haemochromatosis genotype C282Y⁄C282Y. Based on 8,763 individuals from the Copenhagen City Heart Study followed for 15 years, during which time 1,417 developed cancer.
Fig. 2 Meta-analysis of prospective studies of risk of any cancer (transferrin saturation ≤60% vs. reference group). The reference groups varied slightly across studies (≥30% to <60%) (see Supplementary Table S3). Horizontal lines indicate confidence intervals, and filled circles show the risk estimates.
This 2011 study was conducted in a group of Japanese atom bomb survivors, those with high ferritin (58 ng/mL) versus those with low ferritin (13.2 ng/mL), the high ferritin group experienced a 64% increase breast cancers. The authors concluded, “The results support the hypothesis that elevated body iron stores increase the risk of breast cancer. However, the study was inconclusive regarding the question of whether body iron alters radiation-induced breast cancer risk.”
This is a 2012 article that discusses NTBI (non-transferrin bound iron), The stated scope of the review was: “To show that: i) NTBI is present not only during chronic iron overload disorders (hemochromatosis, transfusional iron overload) but also in miscellaneous diseases which are not primarily iron overloaded conditions; ii) this iron species represents a potentially toxic iron form due to its high propensity to induce reactive oxygen species and is responsible for cellular damage not only at the plasma membrane level but also towards different intracellular organelles; iii) the NTBI concept may be expanded to include intracytosolic iron forms which are not linked to ferritin, the major storage protein which exerts, at the cellular level, the same type of protective effect towards the intracellular environment as transferrin in the plasma.” The authors conclude, “The NTBI approach represents an important mechanistic concept for explaining cellular iron excess and toxicity and provides new important biochemical diagnostic tools.”
This 2010 paper covers the advancement of research covering iron metabolism and cancer. “Numerous studies have found a positive correlation between iron storage and the risk of tumors, such as colorectal carcinoma, hepatic cancer, renal carcinoma, lung cancer, and gastric cancer.” The authors suggest, “New treatment strategies may be developed by combining imaging agents or targeted drugs with proteins related to iron metabolism, and specifically transferring to tumor cells through the latter.”
This is a 2010 editorial. “The carcinogenic potential of iron in colorectal cancer (CRC) is not fully understood. Iron is able to undergo reduction and oxidation, making it important in many physiological processes. This inherent redox property of iron, however, also renders it toxic when it is present in excess. Iron-mediated generation of reactive oxygen species via the Fenton reaction, if uncontrolled, may lead to cell damage as a result of lipid peroxidation and oxidative DNA and protein damage. This may promote carcinogenesis through increased genomic instability, chromosomal rearrangements as well as mutations of proto-oncogenes and tumour suppressor genes. Carcinogenesis is also affected by inflammation which is exacerbated by iron. Population studies indicate an association between high dietary iron intake and CRC risk. In this editorial, we examine the link between iron-induced oxidative stress and inflammation on the pathogenesis of CRC.”
This 2008 study from the U.K. examines the role import proteins the malignant progression esophageal cancer. The researchers firs note, “There is growing evidence that iron is important in esophageal adenocarcinoma, a cancer whose incidence is rising faster than any other in the Western world.” The authors conclude, “Progression to adenocarcinoma is associated with increased expression of iron import proteins. These events culminate in increased intracellular iron and cellular proliferation. This may represent a novel mechanism of esophageal carcinogenesis.” In this laboratory study the effect of iron loading on cellular proliferation and iron transporter expression was determined in several esophageal cell lines. The researchers observed, “Progression to adenocarcinoma is associated with increased expression of iron import proteins. These events culminate in increased intracellular iron and cellular proliferation. This may represent a novel mechanism of esophageal carcinogenesis.”
In this laboratory study the investigators explore the role of ferritin heavy chain and how this protein might function against asbestos and oxidative stress in malignant mesothelioma cells.
This is a 2005 study of iron status and cancer in a population of “middle-aged adults living in France where iron supplementation and iron-fortified foods are rarely used.” In this study more than 10,000 subjects, iron status was measured by serum ferritin. Women with ferritin above 160 ng/mL had an 88% increased risk of cancer. This association was not found among men. The researchers concluded, “After adjustment for confounding factors, our data do not support a major role of iron status or intake in the risk of cancer in men but suggest a potential deleterious effect of high iron status in women.” [Health-e-iron note: the male study cohort did indicate a 28% trend toward an increased cancer risk, but the result was not statistically significant]
This was a 2004 U.S. study of the results from the Second National Health and Nutrition Examination Survey. “For men and women combined, the adjusted RRs (95% confidence intervals, CI) for the four levels were 0.96 (0.57-1.61), 1.00 (reference), 1.12 (0.80-1.58), 1.86 (1.07-3.22) for iron… The authors concluded, “People with higher serum iron, transferrin saturation, or copper concentrations had an increased risk of dying from cancer.”
In this 2009 study, the researchers measured and compared markers of hepatic oxidative stress in 38 patients with non-alcoholic steatohepatitis (NASH), 24 simple steatosis (NAFLD or fatty liver disease) and 10 healthy subjects. Oxidative stress was significantly higher in NASH patients than in those with NAFLD, and was related to iron overload, glucose-insulin metabolic abnormalities, and severity of disease. Iron reduction using phlebotomy significantly reduced oxidative stress in NASH patients and resulted in concomitant reduction in liver serum transferase. The authors concluded, “… iron overload may play an important role in the pathogenesis of NASH by generating oxidative DNA damage and iron reduction therapy may reduce hepatocellular carcinoma incidence in patients with NASH.” [Health-e-Iron note; Figures 2 and 3 from this study appear below]
Figure 2. Correlations between 8-oxodG–positive hepatocytic nuclear counts and clinical variables in 38 NASH or 24 simple steatosis patients. A. 8-oxodG counts and serum glucose levels in NASH. B. 8-oxodG counts and HOMA-IR in NASH. C. 8-oxodG counts and serum iron levels in NASH. D. 8-oxodG counts and Total Iron Score TIS in hepatic tissues in NASH. Dotted vertical line indicates that the TIS is 0. E-1. 8-oxodG counts and extent of hepatic steatosis in NASH. E-2. 8-oxodG counts and extent of hepatic steatosis in simple steatosis.
Figure 3. Correlation between TIS in hepatic tissues and HOMA-IR in NASH patients. Dotted horizontal line indicates that the TIS is 0.
The author of this 2003 review discusses the role of iron in various cancers as reported in epidemiological, animal and cell culture studies.
The researchers of this study reported in 2012 first noted, “Prognosis of patients with pancreas cancer is very poor.” “The aim of the study was to test the significance of laboratory parameters in the prognosis of patients with pancreas cancer. The studied group included 57 patients (31 men, 26 women, mean age 65 ± 9 years). Blood was collected at the time of diagnosis of pancreas cancer and basic laboratory parameters, including nutritional and inflammatory markers and tumour markers were measured. Patients were followed up until death (median survival 147 days). Ferritin, iron, albumin, prealbumin, cholinesterase, haemoglobin, C-reactive protein, alkaline phosphatase and carcinoembryonic antigen were significant for patients’ prognosis in univariate analysis while CA 19-9, bilirubin, liver, pancreas and kidney tests and lipids were not. Multivariate Cox regression demonstrated ferritin, iron and albumin as independent mortality predictors (RR (95%CI), per standard deviation: ferritin 1.497(1.215-2.241), p = 0.002; albumin, 0.716(0.521-0.977), p = 0.035; iron, 0.678(0.504-0.915), p = 0.010).” “Patients who survived 100 days had significantly lower ferritin (median 239 μg/l vs. non-survivors 435 μg/l, p = 0.014), significantly higher albumin but the difference in serum iron was not quite significant.” The researchers noted, “This study points out ferritin as an independent mortality predictor in patients with pancreas cancer. High serum levels of ferritin at the time of diagnosis of pancreas cancer indicate bad prognosis of the patient.”
The abstract from this 1996 paper follows: “Oxygen is poisonous, but we cannot live without it. The high oxidizing potential of oxygen molecules (dioxygen) is a valuable source of energy for the organism and its reactivity is low; that is, spin forbidden. However, the dioxygen itself is a ‘free radical’ and, especially in the presence of transition metals, it is a major promoter of radical reactions in the cell. Humans survive only by virtue of their elaborate defense mechanisms against oxygen toxicity. Iron is the most abundant transition metal in the human body. Because iron shows wide variation in redox potential with different co-ordination ligands, it may be used as a redox intermediate in many biological mechanism. However, it is precisely this redox activeness that makes iron a key participant in free radical production. The current research on the relationship between iron and cancer is briefly reviewed. Research results are reported here which indicate that iron, when bound to certain ligands, can cause free-radical mediated tissue damage and become carcinogenic. The present study also suggests that iron may also have a significant role in spontaneous human cancer.”
In this 2008-reported study from research done in the US, the investigators noted, “Dietary iron and zinc affect the risk of cancer, with dietary iron generally correlated with increased risk and dietary zinc with reduced risk. However, zinc supplements have been found correlated with increased risk of cancer. An ecological study was conducted using state-averaged cancer mortality rate data for white Americans for 1970-94 with indices for alcohol consumption, smoking, Hispanic heritage, and urban residence plus dietary factors for four large U.S. regions. The dietary zinc index was inversely correlated with 12 types of cancer, whereas the dietary iron index was directly correlated with 10 types of cancer which correlated with both iron directly and zinc inversely were bladder, breast, colon, esophageal, gastric, rectal cancer, and Hodgkin’s lymphoma; those inversely with zinc only were laryngeal, nasopharyngeal, oral, skin and vulvar cancer. Solar UVB was inversely correlated with 10 of the 15 types of cancer for which the iron and/or zinc indices had significant correlations, the smoking and urban indices with nine, and the alcohol index with eight.” See the full paper for specific food types. The researchers concluded, “Although there are mechanisms that explain why zinc should reduce the risk of cancer, whereas iron should increase the risk, these indices may represent the dietary sources of these nutrients, e.g. whole grains for zinc and red meat for iron, and other components of these dietary factors.”