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Iron and cancer: more ore to be mined

Key Points

  • Elemental iron is essential for cellular growth and homeostasis but it is potentially toxic to cells and tissues. Excess iron can contribute to tumour initiation and tumour growth.

  • Epidemiological evidence links increased body iron stores to increased cancer risk. High intake of dietary iron is associated with an increased risk for some cancers, particularly colorectal cancer. Hereditary haemochromatosis, a genetic disease that leads to excess iron accumulation, is associated with increased cancer risk.

  • Many types of cancer cells reprogramme iron metabolism in ways that result in net iron influx. They upregulate proteins that are involved in iron uptake, such as transferrin receptor 1 (TFR1), STEAP proteins and lipocalin 2 (LCN2), and decrease the expression of iron efflux proteins, such as ferroportin. Other iron-regulatory proteins, such as IRP1 and IRP2, contribute to cancer in ways that are less well understood.

  • Iron is crucial to many fundamental cellular processes, including DNA synthesis, proliferation, cell cycle regulation and the function of proteins containing iron–sulphur clusters. Iron–sulphur cluster-containing proteins include enzymes that contribute to maintaining genomic stability, as well as respiratory function.

  • Iron regulates crucial signalling pathways in tumours, including the hypoxia-inducible factor (HIF) and WNT pathways.

  • Measuring the expression of genes encoding proteins involved in iron metabolism may be useful in cancer prognosis. The expression of ferroportin, hepcidin, TFR1, haemochromatosis (HFE) and other genes involved in iron metabolism is linked to the prognosis of patients with breast cancer.

  • Iron is a target for cancer therapy. Iron chelators, TFR1 antibodies and cytotoxic ligands conjugated to transferrin (TF) represent some ways in which iron is being exploited therapeutically.

Abstract

Iron is an essential nutrient that facilitates cell proliferation and growth. However, iron also has the capacity to engage in redox cycling and free radical formation. Therefore, iron can contribute to both tumour initiation and tumour growth; recent work has also shown that iron has a role in the tumour microenvironment and in metastasis. Pathways of iron acquisition, efflux, storage and regulation are all perturbed in cancer, suggesting that reprogramming of iron metabolism is a central aspect of tumour cell survival. Signalling through hypoxia-inducible factor (HIF) and WNT pathways may contribute to altered iron metabolism in cancer. Targeting iron metabolic pathways may provide new tools for cancer prognosis and therapy.

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Figure 1: Key features of systemic iron homeostasis in humans.
Figure 2: Key steps in mammalian cellular iron metabolism.
Figure 3: Iron uptake and efflux in malignant and non-malignant cells.
Figure 4: Control of cellular iron metabolism by the IRE–IRP regulatory axis.
Figure 5: Links between iron, DNA metabolism and genomic integrity.
Figure 6: A role for iron in canonical WNT signalling.

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Acknowledgements

Supported in part by grants R01 CA171101 (F.M.T.) and R01DK071892 (S.V.T.) from the US National Institutes of Health.

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Glossary

Fenton reaction

A chemical reaction in which ferrous iron reacts with hydrogen peroxide to produce the hydroxyl radical. Iron oxidized during this reaction can be reduced back to ferrous iron in the presence of superoxide (a by-product of respiration). The sum of these reactions is the iron-catalysed formation of hydroxyl radicals from superoxide (termed the Haber–Weiss reaction).

Siderophore

A low molecular mass compound that has a high affinity for chelating iron.

Iron–sulphur clusters

Assemblies of iron and inorganic sulphur that function as protein cofactors.

Hereditary haemochromatosis

Inherited disorder caused by mutations in several different genes that leads to the accumulation of iron to excess levels in parenchymal tissues.

Phlebotomy

Drawing or removing blood from the circulation.

Enterocytes

Intestinal epithelial cells that have major roles in the absorption of nutrients, including iron.

Iron recycling

Reuse of cellular iron. Typically occurs through the catabolism of senescent red blood cells by macrophages of the liver and spleen.

Friedreich's ataxia

Inherited disorder of the neurodegenerative system.

Warburg effect

The propensity of cancer cells to shift from aerobic respiration to glycolysis for the generation of ATP, even in the presence of adequate oxygen levels. The name derives from the hypothesis proposed by Otto Warburg in 1924 that cancer is driven by the non-oxidative breakdown of glucose.

Acyl hydrazones

Chemical substances containing oxygen and nitrogen donor ligands that coordinate iron.

Cytoreduction

Decreasing the number of cancer cells.

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Torti, S., Torti, F. Iron and cancer: more ore to be mined. Nat Rev Cancer 13, 342–355 (2013). https://doi.org/10.1038/nrc3495

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