Intracellular Iron Chelation Modulates the Macrophage Iron Phenotype with Consequences on Tumor Progression
Akam, Eman Abureida
AffiliationUniv Arizona, Dept Chem & Biochem
MetadataShow full item record
PublisherPUBLIC LIBRARY SCIENCE
CitationIntracellular Iron Chelation Modulates the Macrophage Iron Phenotype with Consequences on Tumor Progression 2016, 11 (11):e0166164 PLOS ONE
Rights© 2016 Mertens et al. This is an open access article distributed under the terms of the Creative Commons Attribution License.
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AbstractA 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.
NoteOpen Access Journal.
VersionFinal published version
SponsorsFritz Thyssen Stiftung [Az.10.12.2.156]; Goethe-University Frankfurt; Doktor Robert Pfleger Stiftung; University of Arizona Office of Research and Development; University of Arizona Global Initiatives; Deutsche Krebshilfe