Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

Abstract

Iron is an essential nutrient that plays a complex role in cancer biology. Iron metabolism must be tightly controlled within cells. Whilst fundamental to many cellular processes and required for cell survival, excess labile iron is toxic to cells. Increased iron metabolism is associated with malignant transformation, cancer progression, drug resistance and immune evasion. Depleting intracellular iron stores, either with the use of iron chelating agents or mimicking endogenous regulation mechanisms, such as microRNAs, present attractive therapeutic opportunities, some of which are currently under clinical investigation. Alternatively, iron overload can result in a form of regulated cell death, ferroptosis, which can be activated in cancer cells presenting an alternative anti-cancer strategy. This review focuses on alterations in iron metabolism that enable cancer cells to meet metabolic demands required during different stages of tumorigenesis in relation to metastasis and immune response. The strength of current evidence is considered, gaps in knowledge are highlighted and controversies relating to the role of iron and therapeutic targeting potential are discussed. The key question we address within this review is whether iron modulation represents a useful approach for treating metastatic disease and whether it could be employed in combination with existing targeted drugs and immune-based therapies to enhance their efficacy.

Iron: An Essential Element of Cancer Metabolism

“…Interestingly, LCN2 can either import or export iron and, consequently, promotes proliferation or apoptosis [189][190][191]. A clear correlation between LCN2 levels and tumor grade was found in in breast and thyroid cancers, whereas the opposite was suggested in ovarian and pancreatic cancers [192]. Similarly, both LCN2 overexpression and knockout reduced orthotopic pancreatic cancer tumor growth in mouse models [193][194][195].…”

Ferroptosis in Acute Central Nervous System Injuries: The Future Direction?

“…On the contrary, using some iron chelators [e.g., DFP ( Wu et al, 2020 ), DFO ( Wu et al, 2018 ; Chen et al, 2020 ), and BPS ( Codenotti et al, 2018 )] may suppress ferroptosis and provide a potential therapeutic approach for diseases. In fact, there are some iron-chelating agents under clinical development for the treatment of cancers [for review see Brown et al (2020) ]. Moreover, inhibition of the IREB2 increases the expression of FTL and FTH1, thus decreasing sensitivity to ferroptosis ( Gammella et al, 2015 ).…”

Extracellular Citrate Fuels Cancer Cell Metabolism and Growth

“…The expression of ferritin, responsible for iron storage inside the cells, is also expressed at higher levels in cancer cells (Wang et al, 2018). Increased intracellular Fe levels in cancer cells (Brown et al, 2020a) will facilitate the transition of c-ACN from IRP1 to the mediator of citrateto-isocitrate conversion. With pmCiC and NaCT functioning to bring extracellular citrate into the cancer cells, excess iron FIGURE 2 | The cartoon summarizes current data on the role of CAF-derived metabolites and the regulation of cancer phenotypes (gray boxes) and especially the influence CAFs have on epithelial-mesenchymal transition (EMT), invasion, metastasis and angiogenesis (white boxes).…”