Dr. Weeks’ Comment: This is a helpful review of a misunderstood topic. “…Population-based studies have taken four general approaches to examine the relationship between iron and cancer risk. Although the results are not always consistent, these studies collectively support a model in which increased levels of iron in the body are associated with increased cancer risk…”
Int J Mol Sci. 2019 Jan; 20(1): 95.Published online 2018 Dec 27. doi: 10.3390/ijms20010095PMCID: PMC6337236PMID: 30591630
Iron Metabolism in Cancer
Executive Summary
- 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
Demanded as an essential trace element that supports cell growth and basic functions, iron can be harmful and cancerogenic though. By exchanging between its different oxidized forms, iron overload induces free radical formation, lipid peroxidation, DNA, and protein damages, leading to carcinogenesis or ferroptosis. Iron also plays profound roles in modulating tumor microenvironment and metastasis, maintaining genomic stability and controlling epigenetics. in order to meet the high requirement of iron, neoplastic cells have remodeled iron metabolism pathways, including acquisition, storage, and efflux, which makes manipulating iron homeostasis a considerable approach for cancer therapy. Several iron chelators and iron oxide nanoparticles (IONPs) has recently been developed for cancer intervention and presented considerable effects. This review summarizes some latest findings about iron metabolism function and regulation mechanism in cancer and the application of iron chelators and IONPs in cancer diagnosis and therapy.
6. Conclusions
As far as we know, iron diversely functions in tumor initiation, progression, metastasis, and microenvironment. A large amount of iron in cancer cells is needed for the proliferation and progress. The expressions of numerous iron metabolism-related proteins are aberrantly regulated in malignant tumors, and a variety of signaling pathways and physiological processes are altered by iron in cancer, manifesting the essential roles of iron in cancer development. Overall, aberrant iron homeostasis is to some extent a hallmark of cancer. Thus, strategies based on remodeling iron homeostasis should offer promising choices for cancer therapy. Apart from diminishing intracellular iron content by iron chelators, targeting iron-associated proteins for drug delivery or impairing the redox status by elevating intracellular iron level have all been confirmed as feasible ways for cancer treatment. Despite amounts of iron-related signaling in cancer development have been illustrated in the existing studies, detailed understandings on the mechanisms of iron homeostasis maintenance, iron-associated proteins functions, and global effect on epigenetics and microenvironment involved of iron require further exploration. Last but not least, the efficiency and safety of the strategies based on iron metabolism regulation for cancer therapy still need more efforts to be improved.