The Disturbed Iron Phenotype of Tumor Cells and Macrophages in Renal Cell Carcinoma Influences Tumor Growth

Abstract

Accumulating evidence suggests that iron homeostasis is disturbed in tumors. We aimed at clarifying the distribution of iron in renal cell carcinoma (RCC). Considering the pivotal role of macrophages for iron homeostasis and their association with poor clinical outcome, we investigated the role of macrophage-secreted iron for tumor progression by applying a novel chelation approach. We applied flow cytometry and multiplex-immunohistochemistry to detect iron-dependent markers and analyzed iron distribution with atomic absorption spectrometry in patients diagnosed with RCC. We further analyzed the functional significance of iron by applying a novel extracellular chelator using RCC cell lines as well as patient-derived primary cells. The expression of iron-regulated genes was significantly elevated in tumors compared to adjacent healthy tissue. Iron retention was detected in tumor cells, whereas tumor-associated macrophages showed an iron-release phenotype accompanied by enhanced expression of ferroportin. We found increased iron amounts in extracellular fluids, which in turn stimulated tumor cell proliferation and migration. In vitro, macrophage-derived iron showed pro-tumor functions, whereas application of an extracellular chelator blocked these effects. Our study provides new insights in iron distribution and iron-handling in RCC. Chelators that specifically scavenge iron in the extracellular space confirmed the importance of macrophage-secreted iron in promoting tumor growth.

Iron-Bound Lipocalin-2 from Tumor-Associated Macrophages Drives Breast Cancer Progression Independent of Ferroportin

“…Taking our previous work regarding the role of MΦ as cellular source of iron within the TME [ 12 , 13 ] and the role of both FPN and Lcn-2 in determining the MΦ iron-release phenotype into account, we aimed at clarifying the role of stromal FPN and Lcn-2 for tumor progression. Data mining of the publicly available GSE data sets using the GEOQuery package for GNU R from the CRAN archive showed that both FPN and Lcn-2 are elevated in tumor stroma compared to the stroma of the healthy breast ( Figure 2 a).…”

“…The crosstalk of MΦ and neoplastic cells especially involve a complex network of cytokines, chemokines, exosomes as well as metabolites, including iron [ 8 , 9 , 10 , 11 ]. Our previous studies provide evidence that MΦ cells acquire an iron-release phenotype in both mammary [ 12 ] and renal [ 13 ] cancer. We concluded that MΦ may serve as an important source of iron to fuel the elevated iron demand of neoplastic cells, which, in turn, fosters tumor growth and progression.…”

“…FPN down-regulation in cancer cells enhanced tumor growth and metastasis, both in patients [ 19 ] as well as in experimental tumor models. Moreover, we recently proved enhanced FPN expression in tumor-associated macrophages (TAM) in renal cancer [ 13 ]. However, we did not observe any correlation with tumor stage or grade, suggesting that FPN expression is not a crucial feature of the TAM iron-release phenotype.…”

Mechanisms Underlying the Inhibition of Tyrosine Kinase Inhibitor-Induced Anorexia and Fatigue by Royal Jelly in Renal Cell Carcinoma Patients and the Correlation between Macrophage Colony Stimulating Factor and Inflammatory Mediators

“…Similar to those in most cancers, the activities and accumulation of various immune cells, for example, lymphocytes, natural killer cells, and neutrophils, within the tumor microenvironment are considered important determinants of cancer-related inflammation in RCC [ 9 , 10 ]. In addition, macrophages within the tumor microenvironment (i.e., tumor-associated macrophages or TAMs) play important roles in cancer-related inflammation in RCC patients [ 9 , 11 , 12 , 13 ]. A variety of cytokines, including IL-6, TNF-α, and TGF-β, are produced from TAMs in RCC [ 11 , 14 ].…”

Insights into Urological Cancer

“…This Urological Cancer 2020 Special Issue includes two articles and one perspective on renal neoplasia [ 16 , 17 , 18 ]. Schnetz et al [ 16 ] analyzed the role of macrophage-secreted iron in tumor progression of patients with CCRCC, papillary renal cell carcinomas (PRCC), and chromophobe renal cell carcinoma (ChRCC). They have found that genes regulating iron homeostasis are associated with tumor stage and grade through the pro-tumorigenic activity of a specialized subset of macrophages present in the local microenvironment.…”