Intracellular Iron Chelation Modulates the Macrophage Iron Phenotype with Consequences on Tumor Progression
Open accessAbstract
A growing body of evidence suggests that macrophage polarization dictates the expression of iron-regulated genes. Polarization towards iron sequestration depletes the microenvironment, whereby extracellular pathogen growth is limited and inflammation is fostered. In contrast, iron release contributes to cell proliferation, which is important for tissue regeneration. Moreover, macrophages constitute a major component of the infiltrates in most solid tumors. Considering the pivotal role of macrophages for iron homeostasis and their presence in association with poor clinical prognosis in tumors, we approached the possibility to target macrophages with intracellular iron chelators. Analyzing the expression of iron-regulated genes at mRNA and protein level in primary human macrophages, we found that the iron-release phenotype is a characteristic of polarized macrophages that, in turn, stimulate tumor cell growth and progression. The application of the intracellular iron chelator (TC3-S)2 shifted the macrophage phenotype from iron release towards sequestration, as determined by the iron-gene profile and atomic absorption spectroscopy (AAS). Moreover, whereas the addition of macrophage supernatants to tumor cells induced tumor growth and metastatic behavior, the supernatant of chelator-treated macrophages reversed this effect. Iron chelators demonstrated potent anti-neoplastic properties in a number of cancers, both in cell culture and in clinical trials. Our results suggest that iron chelation could affect not only cancer cells but also the tumor microenvironment by altering the iron-release phenotype of tumor-associated macrophages (TAMs). The study of iron chelators in conjunction with the effect of TAMs on tumor growth could lead to an improved understanding of the role of iron in cancer biology and to novel therapeutic avenues for iron chelation approaches.
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The iron-donating macrophage phenotype was directly linked to enhanced tumor cell proliferation and growth, both in vitro and in vivo.
“This iron-donating macrophage phenotype was directly linked to enhanced tumor cell proliferation and growth, both in vitro and in vivo [64,66,67,70,71,72].”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [72]
Upon intracellular reduction, (TC3-S)2 is converted to the thiol chelator TC3-SH, which re-programmed macrophages from an iron release to an iron sequestration phenotype.
“Upon intracellular reduction, (TC3-S)2 is converted to the thiol chelator TC3-SH, which re-programmed macrophages from an iron release to and iron sequestration phenotype [72].”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [72]
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Self-citation
- Authors
- Mertens, C., Akam, E. A., Rehwald, C., Brüne, B., Tomat, E., & Jung, M.
- Affiliations
- Goethe University Frankfurt (DE)
- University of Arizona (US)
- Corresponding author
- Tomat, Elisa
- Jung, Michaela
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-11-02
- Volume
- 11
- Issue
- 11
- Pages
- e0166164
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC5091876
- OpenAlex
- W2547167825
- Cited by
- 83
- References
- 57
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 14 · 2020: 11 · 2019: 10 · 2018: 9 · 2017: 10
- FWCI
- 5.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UA Campus Repository (The University of Arizona) (acceptedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by)
- Funders
- Fritz Thyssen Stiftung (Az.10.12.2.156)
- Deutsche Krebshilfe (111578)
- Doktor Robert Pfleger Stiftung
- Goethe-Universität Frankfurt am Main (Focus Line B)
- University of Arizona (New Faculty Start-Up Funds, Global Initiatives for travel funds)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- tumor-associated macrophages, macrophage polarization, iron homeostasis, iron release, iron sequestration, tumor progression, metastasis, tumor microenvironment, antineoplastic therapy
- MeSH terms
- Cell Movement, Cells, Cultured, Gene Expression Regulation, Homeostasis, Humans, Iron, Iron Chelating Agents, Macrophages, Phenotype, Spectrophotometry, Atomic, Culture Media, Conditioned, Cell Proliferation, Tumor Microenvironment, MCF-7 Cells
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