Iron in the Tumor Microenvironment-Connecting the Dots

Abstract

Iron metabolism and tumor biology are intimately linked. Iron facilitates the production of oxygen radicals, which may either result in iron-induced cell death, ferroptosis, or contribute to mutagenicity and malignant transformation. Once transformed, malignant cells require high amounts of iron for proliferation. In addition, iron has multiple regulatory effects on the immune system, thus affecting tumor surveillance by immune cells. For these reasons, inconsiderate iron supplementation in cancer patients has the potential of worsening disease course and outcome. On the other hand, chronic immune activation in the setting of malignancy alters systemic iron homeostasis and directs iron fluxes into myeloid cells. While this response aims at withdrawing iron from tumor cells, it may impair the effector functions of tumor-associated macrophages and will result in iron-restricted erythropoiesis and the development of anemia, subsequently. This review summarizes our current knowledge of the interconnections of iron homeostasis with cancer biology, discusses current clinical controversies in the treatment of anemia of cancer and focuses on the potential roles of iron in the solid tumor microenvironment, also speculating on yet unknown molecular mechanisms.

Keywords: ACD; TAM; anemia of cancer; ferroptosis; hepcidin; iron.

Figure 1

Systemic iron homeostasis in malignancy and potential effects of therapeutic intervention. After absorption by intestinal epithelial cells (IECs; depicted in the left lower corner) in the duodenum and upper jejunum, iron is loaded onto transferrin (TF) and distributed throughout the body as TBI (for transferrin-bound iron). TBI levels in the circulation are sensed by hepatocytes (depicted in the left upper corner) via transferrin receptors-1 and−2 (TFR1 and TFR2). An increase in iron levels in plasma results in the secretion of hepcidin antimicrobial peptide (HAMP). HAMP is also induced upon tissue iron loading, which results in the release of bone-morphogenic protein (BMP)-6 by liver sinusoidal endothelial cells (SECs; left upper corner). In addition, the cytokine interleukin-6 (IL-6) stimulates HAMP production by hepatocytes in inflammatory conditions, such as neoplasia. HAMP binds to ferroportin (FPN)-1 and blocks its iron export function, particularly in macrophages (MΦ; right upper corner), which results in iron sequestration and storage in ferritin (FT). FT can also be secreted by macrophages and taken up from plasma via specific receptors, such as SCARA5 (for scavenger receptor class A member-5). In the setting of malignancy, macrophages and other types of immune cells also secrete tumor necrosis factor (TNF). Among numerous functions, TNF inhibits the proliferation of erythroid progenitors (EP; right lower corner) in the bone marrow and their responsiveness to erythropoietin (EPO) produced in the kidneys (not depicted). Therapeutic options (depicted in orange) for cancer-related anemia include oral and intravenous iron preparations, anti-hepcidin strategies (AHS), erythropoiesis-stimulating agents (ESAs), and packed red blood cells (RBCs). All of these medications have potential side effects (depicted in turquois) on immune cells. For example, intravenous iron and packed RBCs can result in macrophage iron overload and impair their anti-tumor immune functions or facilitate the proliferation of tumor cells (Tu; depicted in the center, including dying [left-hand side] and proliferating [right-hand side] tumor cells). Cell types are indicated in bold; processes in italic. BMPR, BMP receptor; DMT1, divalent metal transporter-1; ERFE, erythroferrone; EPOR, EPO receptor.

Figure 2

Putative interactions of tumor cells and tumor-associated macrophages. Myeloid cells, including tumor-associated macrophages (MΦ; right-hand side) possess multiple mechanisms to acquire iron including the uptake of non-transferrin-bound iron (NTBI) via divalent metal transporter (DMT)-1, endocytosis of transferrin-bound iron (TBI) via transferrin receptor (TFR)-1 and phagocytosis of aged or damaged red blood cells (RBCs). RBCs contain large amounts of iron incorporated in hemoglobin. The degradation of hemoglobin by proteases and heme oxygenase (HMOX)-1 releases free iron into the labile iron pool (LIP). An increase in the LIP then facilitates the production of reactive oxygen species (ROS), which activate nuclear factor-kappa B. In contrast, labile iron impairs the generation of reactive nitrogen species (RNS) via nitric oxide synthase-2. In the extracellular space, iron is present in at least four molecular forms, i.e., bound to transferrin (TF), bound to lactoferrin (LF), bound to siderophores (Sid) and lipocalin (Lcn)-2, and incorporated in ferritin (FT). All these forms may supply iron to tumor cells (Tu; left-hand side) because of their expression of specific receptors, possibly including the scavenger receptor A member (SCARA)-5, which binds FT. In addition, non-transferrin-bound iron (NTBI) may be present in the tumor microenvironment and acquired via DMT1. Once in the tumor cell's cytosol, labile iron can stimulate cell growth and DNA replication, induce mutagenesis or result in ferroptosis. Ferroptosis is a specific form of programmed cell death which is initiated by an increase in the LIP and in ROS production. ROS inactivate glutathione peroxidase (GPX)-4 after depletion of glutathione (GSH). Similarly, the degradation of FT by ferritinophagy, an autophagic process requiring the FT chaperone NCOA4 (for nuclear receptor coactivator-4), frees iron and can induce ferroptosis. On the other hand, iron can also be exported from the cytosol via ferroportin (FPN)-1 on tumor cells. However, this process is reduced when levels of hepcidin antimicrobial peptide (HAMP) in the circulation or in the tumor microenvironment are high. Cell types are indicated in bold; processes in italic. DNA, deoxyribonucleic acid; Nrf2, nuclear factor (erythroid-derived 2)-like-2.