Iron as a Central Player and Promising Target in Cancer Progression

Abstract

Iron is an essential element for virtually all organisms. On the one hand, it facilitates cell proliferation and growth. On the other hand, iron may be detrimental due to its redox abilities, thereby contributing to free radical formation, which in turn may provoke oxidative stress and DNA damage. Iron also plays a crucial role in tumor progression and metastasis due to its major function in tumor cell survival and reprogramming of the tumor microenvironment. Therefore, pathways of iron acquisition, export, and storage are often perturbed in cancers, suggesting that targeting iron metabolic pathways might represent opportunities towards innovative approaches in cancer treatment. Recent evidence points to a crucial role of tumor-associated macrophages (TAMs) as a source of iron within the tumor microenvironment, implying that specifically targeting the TAM iron pool might add to the efficacy of tumor therapy. Here, we provide a brief summary of tumor cell iron metabolism and updated molecular mechanisms that regulate cellular and systemic iron homeostasis with regard to the development of cancer. Since iron adds to shaping major hallmarks of cancer, we emphasize innovative therapeutic strategies to address the iron pool of tumor cells or cells of the tumor microenvironment for the treatment of cancer.

Keywords: iron chelators; iron homeostasis; lipocalin-2; macrophage polarization; tumor progression.

Figure 1

Schematic overview of the interplay between systemic and local iron homeostasis in the tumor. Dietary iron is absorbed by enterocytes through divalent metal transporter 1 (DMT-1) and released to the circulation through the iron exporter ferroportin (FPN). After its release, iron is rapidly loaded onto transferrin (Tf) for systemic transport. Macrophages (MΦ) take a central role in maintaining systemic iron homeostasis, which is accomplished through a continuous cycle of iron recycling from senescent red blood cells (RBCs). Iron then joins the labile iron pool (LIP) and is then donated to the circulation, where it is bound to Tf for its transport to cells and tissues having a need for iron or to the liver, where iron is stored. Systemic iron homeostasis is controlled by the expression of hepcidin from hepatocytes. During cancer, this cycle is deregulated and systemic iron availability is decreased through its sequestration within MΦ, finally causing anemia. At the tumor site, tumor-associated macrophages (TAM) adopt an iron-release phenotype and donate iron to the microenvironment. Iron can be released via FPN and loaded onto Tf for its uptake by cancer cells via the Tf receptor (TfR). Alternative iron donation pathways have evolved: (1) lipocalin-2 (Lcn-2)-bound iron is taken up by its high-affinity receptor Lcn-2R, and (2) macrophage-released ferritin (FT) might be taken up through Scara5 (FTL) or TfR (FTH) by tumor cells.