Iron and Cancer: 2020 Vision

Abstract

New and provocative insights into the relationships between iron and cancer have been uncovered in recent years. These include delineation of connections that link cellular iron to DNA repair, genomic integrity, and oncogenic signaling as well as the discovery of ferroptosis, a novel iron-dependent form of cell death. In parallel, new molecules and pathways that regulate iron influx, intracellular iron trafficking, and egress in normal cells, and their perturbations in cancer have been discovered. In addition, insights into the unique properties of iron handling in tumor-initiating cells (cancer stem cells), novel contributions of the tumor microenvironment to the uptake and regulation of iron in cancer cells, and new therapeutic modalities that leverage the iron dependence of cancer have emerged.

Figure 1.. Intracellular and intercellular iron trafficking in the tumor microenvironment.

Intracellular trafficking: Plasma membrane proteins involved in iron uptake are heme transporters FLVCR2 and HRG1; lipocalin 2 receptor LCN2R (also called 24p3R), which binds a lipocalin 2-siderophore-iron complex; DMT1 (which is also involved in endosomal iron efflux), which transports Fe²⁺; CD44, which binds an iron-hyaluronate complex; and TFR1, which binds diferric transferrin. Iron taken up by these pathways is delivered to a pool of redox-active iron termed the labile iron pool to supply iron to iron-containing proteins. The chaperone PCBP1 delivers iron to ferritin and LOX15, among other targets. Ferritin stores excess iron in a non-toxic bioavailable form. Iron in ferritin can also be redistributed following binding to NCOA4 and lysosomal degradation (ferritinophagy), or ferritin-bound iron can be effluxed from the cell via a multivesicular body (MVB)/exosome pathway. The major route of iron efflux is ferroportin (FPN), which is degraded by the secreted peptide hepcidin. Iron participates in producing the oxidized membrane lipids that mediate ferroptotic cell death. Ferroptosis inducers disable endogenous pathways that reduce oxidized lipids, including the peroxidase GPX4 and the cystine/glutamate antiporter SLC7A11. Intercellular trafficking: Pro-tumorigenic effects are mediated by tumor-associated macrophages, which provide iron to tumor cells, as well as by tumor-associated fibroblasts (TAFs). TAFs express the iron-dependent enzyme lysyl hydroxylase 2 (LH2) an enzyme that enhances matrix stiffness; TAFs also secrete IL6, which upregulates hepcidin, degrades ferroportin, and limits iron efflux from tumor cells. Anti-tumorigenic effects are exerted by PD-L1-stimulated CD8+ T cells, which promote ferroptosis by secreting interferon gamma and inhibiting SLC7A11. Excess exogenous iron resulting from hemolysis or provided by iron-containing nanoparticles can trigger a shift of M2-type tumor associated macrophages to a tumoricidal M1 phenotype. Note that this figure consolidates findings from multiple different tumor types; not all pathways are operant in all cancers.