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.

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

“…Iron homeostasis is achieved through regulating gene transcription, protein synthesis, and degradation ( Figure 2). Metabolism of iron and oxygen are inexplicably linked and share some of the same regulatory mechanisms which are reviewed by Renassia et al (14), Shah et al (15), and in the context of cancer by Pfeifhofer-Obermair et al (16). When iron homeostasis is disrupted excess levels cause oxidative stress resulting from an imbalance between the abundance of ROS and antioxidants.…”

Spatially resolved analyses link genomic and immune diversity and reveal unfavorable neutrophil activation in melanoma

“…We also observed recurrent dysregulation of ferritin and HSP90-related genes, suggestive of an enhanced acute-phase protein reaction, iron loading and molecular stress in the context of chromosome 7 gain and immunotherapy failure. Iron availability is known to influence tumor cell survival and the function of numerous immune cell types including T cells; however, these competing outcomes have been poorly studied in solid tumors such as melanoma 39,40 . Nevertheless, a potential role for immunosuppressive neutrophil phenotypes and iron trafficking within the TME warrants further evaluation.…”

Identification of an appropriate cell line for the renal cell carcinoma model

“…Iron is usually dysregulated in cancers. Cancer cells often show higher levels of TfRC, down-regulation of FPN, and lower levels of ferritins, which lead to an increased intracellular labile iron pool [6,20]. Although it is mostly utilized for tumor growth by cytosolic and mitochondrial iron enzymes, excessive amounts can promote increased oxidative stress via ROS accumulation and result in ferroptosis.…”

“…RCC is not sensitive to conventional chemotherapy and is at least partly resistant to apoptosis [3], but known among the cancer cell lines to be susceptible to lipid repair enzyme GPX4-regulated ferroptosis [4]. Ferroptosis is a speci c form of programmed cell death, which is initiated by an increase in the labile iron pool and lipid reactive oxygen species (ROS) production [5][6][7]. The chelation of iron by deferoxamine rescues the experimental induction of ferroptosis [8], but inhibition of the cysteine uptake (system Xc − (xCT)) by erastin or sulfasalazine or the inactivation of GPX4 by (1S,3R)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1- [4-(methoxycarbonyl)phenyl]-1H-pyrido [3,4-b]indole-3-carboxylic acid, methyl ester (RSL3) induces ferroptosis [5,7].…”

“…In our previous report [19], yeast extract treatment decreased TfRC and increased ferritin in metastatic RCC cells, but decreased GPX4 in primary RCC cells. Altered iron metabolism may differentially contribute to growth inhibition or ferroptosis induction in various RCC cell lines since iron itself contributes to mutagenicity and malignant transformation, and the transformed malignant cells require high amounts of iron for proliferation [6,20]. Herein, we aimed to investigate a feasible candidate for an appropriate cell line for RCC model since most RCCs remain resistant cancers against various cell death-related therapeutic strategies.…”