Iron Dysregulation in Human Cancer: Altered Metabolism, Biomarkers for Diagnosis, Prognosis, Monitoring and Rationale for Therapy

Abstract

Iron (Fe) is a trace element that plays essential roles in various biological processes such as DNA synthesis and repair, as well as cellular energy production and oxygen transport, and it is currently widely recognized that iron homeostasis is dysregulated in many cancers. Indeed, several iron homeostasis proteins may be responsible for malignant tumor initiation, proliferation, and for the metastatic spread of tumors. A large number of studies demonstrated the potential clinical value of utilizing these deregulated proteins as prognostic and/or predictive biomarkers of malignancy and/or response to anticancer treatments. Additionally, the iron present in cancer cells and the importance of iron in ferroptosis cell death signaling pathways prompted the development of therapeutic strategies against advanced stage or resistant cancers. In this review, we select relevant and promising studies in the field of iron metabolism in cancer research and clinical oncology. Besides this, we discuss some co-existing discrepant findings. We also present and discuss the latest lines of research related to targeting iron, or its regulatory pathways, as potential promising anticancer strategies for human therapy. Iron chelators, such as deferoxamine or iron-oxide-based nanoparticles, which are already tested in clinical trials, alone or in combination with chemotherapy, are also reported.

Keywords: cancer; diagnostic; iron homeostasis; prognostic; therapy.

Figure 1

(A): The enterocyte: absorption site of dietary heme and non-heme iron. The Fe in the diet is mainly in the form of ferric Fe (Fe³⁺). Before its absorption into the enterocyte, Fe is reduced by the action of a reductase, such as duodenal cytochrome b (DCYTB). The ferrous Fe (Fe²⁺) subsequently enters the cell via the divalent metal transporter 1 (DMT1). Heme Fe is absorbed by the action of the heme carrier protein 1 (HCP1). The heme is degraded by the action of heme oxygenase and then ferrous Fe is released. The Fe contained in the cell may be stored in ferritin-bound form or it may be delivered to the circulation by the action of ferroportin, also known as iron-regulated transporter 1 (IREG1). Before joining the systemic circulation, the Fe is oxidized by hephaestin; then, Fe binds to transferrin (Tf), which can bind two ferric atoms (Fe³⁺). apo-Tf, apotransferrin; holo-Tf, holotransferrin. (B): The hepatocytes: principal storage site of iron. In blood, transferrin-bound Fe binds to transferrin receptor 1 (Tfr1) at the plasma membrane. The transferrin receptor 2 (Tfr2) protein plays the role of an Fe sensor and contributes to Fe homeostasis. For the release of Fe into the cell, the complex transferrin–Fe and Tfr1 are endocytosed. In the endosome, ferric Fe is released from transferrin (Tf) and reduced to ferrous Fe (Fe²⁺) via the six-transmembrane epithelial antigen of prostate 3 (STEAP3) protein. The transferrin–Tfr1 complex joins the plasma membrane and transferrin can participate in further cycles of Fe absorption. The Fe²⁺ is transported out of the endosome by DMT1. This Fe is part of the active labile Fe pool (LIP) and participates in cellular metabolism. In the cell, Fe can also be stored in the ferritin. Iron can exit hepatocytes via ferroportin, also known as iron-regulated transporter 1 (IREG1). In blood, Fe²⁺ is reoxidized by plasma ferroxidase, known as ceruloplasmin, to allow loading onto the Tf. Ceruloplasmin is a copper-dependent ferroxidase, a major protein of copper homeostasis. Hepatocytes are regulators of Fe homeostasis via the secretion of the peptide hormone hepcidin. High levels of Fe cause the production and secretion of hepcidin in the blood. Hepcidin binds to ferroportin and this triggers its degradation. apo-Tf, apotransferrin; holo-Tf, holotransferrin.