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.

Hereditary hemochromatosis promotes colitis and colon cancer and causes bacterial dysbiosis in mice

“…Surprisingly, this is not true; excess iron is actually a tumor promoter. Cancer cells accumulate iron by reprogramming iron-regulatory pathways to promote their growth [30,31]. The data presented in this paper as well as those in publicly available databases show that the expression of HFE is markedly down-regulated in colon cancer.…”

“…Because there is an increasing evidence that excess iron/heme drives carcinogenesis in multiple tissues [29][30][31], we examined if the expression levels of HFE and ferroportin, a transporter that exports iron from the cell, in colon cancer. Decreased expression of HFE disrupts iron homeostasis, leading to excessive iron accumulation Fecal DNA was extracted from wild-type mice and Hfe −/− mice and 16S metagenomic sequencing was performed to determine the bacterial composition in two animal groups.…”

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 ).…”