Intracellular Iron Chelation Modulates the Macrophage Iron Phenotype with Consequences on Tumor Progression

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.越来越多的研究证据表明，巨噬细胞极化（macrophage polarization）调控着铁调控基因（iron-regulated genes）的表达。向铁扣留表型极化会导致微环境铁耗竭，从而限制胞外病原体的增殖并促进炎症反应。与之相反，铁释放则可促进细胞增殖，这对组织再生至关重要。此外，巨噬细胞是大多数实体瘤浸润灶的主要组成成分。鉴于巨噬细胞在铁稳态（iron homeostasis）中的关键作用，且其存在与肿瘤患者不良临床预后密切相关，我们探索了采用细胞内铁螯合剂（intracellular iron chelators）靶向巨噬细胞的可行性。通过分析原代人巨噬细胞（primary human macrophages）中mRNA及蛋白水平的铁调控基因表达情况，我们发现铁释放表型是极化巨噬细胞的特征之一，这类极化巨噬细胞可反过来促进肿瘤细胞的生长与进展。应用细胞内铁螯合剂(TC3-S)₂处理可使巨噬细胞表型从铁释放转向铁扣留，这一结果通过铁基因表达谱及原子吸收光谱法（AAS）得以验证。此外，将未处理巨噬细胞的细胞上清添加至肿瘤细胞培养体系中可诱导肿瘤生长及转移表型，而经铁螯合剂处理的巨噬细胞上清则可逆转这一效应。铁螯合剂在多种癌症的细胞培养及临床试验中均展现出强效的抗肿瘤活性。我们的研究结果表明，铁螯合疗法不仅可作用于肿瘤细胞，还可通过改变肿瘤相关巨噬细胞（TAMs）的铁释放表型来调控肿瘤微环境。联合研究铁螯合剂与肿瘤相关巨噬细胞对肿瘤生长的影响，有望加深我们对铁在癌症生物学中作用的理解，并为铁螯合疗法开辟全新的治疗途径。