Local iron homeostasis in the breast ductal carcinoma microenvironment

Abstract

BackgroundWhile the deregulation of iron homeostasis in breast epithelial cells is acknowledged, iron-related alterations in stromal inflammatory cells from the tumor microenvironment have not been explored.MethodsImmunohistochemistry for hepcidin, ferroportin 1 (FPN1), transferrin receptor 1 (TFR1) and ferritin (FT) was performed in primary breast tissues and axillary lymph nodes in order to dissect the iron-profiles of epithelial cells, lymphocytes and macrophages. Furthermore, breast carcinoma core biopsies frozen in optimum cutting temperature (OCT) compound were subjected to imaging flow cytometry to confirm FPN1 expression in the cell types previously evaluated and determine its cellular localization.ResultsWe confirm previous results by showing that breast cancer epithelial cells present an ‘iron-utilization phenotype’ with an increased expression of hepcidin and TFR1, and decreased expression of FT. On the other hand, lymphocytes and macrophages infiltrating primary tumors and from metastized lymph nodes display an ‘iron-donor’ phenotype, with increased expression of FPN1 and FT, concomitant with an activation profile reflected by a higher expression of TFR1 and hepcidin. A higher percentage of breast carcinomas, compared to control mastectomy samples, present iron accumulation in stromal inflammatory cells, suggesting that these cells may constitute an effective tissue iron reservoir. Additionally, not only the deregulated expression of iron-related proteins in epithelial cells, but also on lymphocytes and macrophages, are associated with clinicopathological markers of breast cancer poor prognosis, such as negative hormone receptor status and tumor size.ConclusionsThe present results reinforce the importance of analyzing the tumor microenvironment in breast cancer, extending the contribution of immune cells to local iron homeostasis in the tumor microenvironment context.

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

“…This is particularly relevant since it was appreciated that tumor cells are not able to acquire a fully invasive potential without the recruitment and the support of tumor-infiltrating immune cells, especially MΦ [50–52]. Along this line, recent studies could show that lymphocytes and MΦ synthesize and secrete ferritin which, in turn, stimulates tumor cell proliferation in an iron-dependent manner [39, 53–55]. These data reinforce the importance of the tumor microenvironment in terms of the iron-handling capacity of tumor-infiltrating immune cells, in particular MΦ.…”

Targeting iron metabolism in drug discovery and delivery

“…D . Tissue iron stored as ferritin has found to be increased in MS271, AD272, PD264, AS259,273, and for cancer both high levels (glioblastoma)94 and low levels have been reported (breast)101. E .…”

“…However, the additional intracellular oxidative stress that is accompanied by the increased presence of labile iron may also make them more sensitive to ferroptosis65,67 and hinder tumour metastasis85, illustrating the complex relationship between iron, ROS and cancer cell survival. Furthermore, although a connection between iron and cancer growth has been demonstrated in several forms of cancers, with breast cancer90,91,99–101, prostate cancer98,102,103 and glioblastoma as established examples94,104, it seems reasonable that many, but not all, cancer types will demonstrate a similar iron dependency.…”

“…B . TfR1 upregulation has been found in MS258, atherosclerosis259, and cancer (colorectal257, breast95,101, glioblastoma94; normal TfR1 levels have been observed in AD260,261, while for PD normal levels262, and low levels have been reported263,264. C .…”

The Effects of Angelica Sinensis Polysaccharide on Tumor Growth and Iron Metabolism by Regulating Hepcidin in Tumor-Bearing Mice

“…Previous studies have revealed that increased serum hepcidin was related to multiple cancers, such as breast cancer, myeloma, renal cell carcinoma and prostate cancer [7][8][9][10]. Hepcidin is homeostatically regulated by iron and erythropoietic activity as well as inflammatory cytokines [9,11]. Hepcidin inhibits iron absorption from the duodenum and iron egress from macrophages and hepatocytes through binding and inducing degradation of iron exporter ferroportin [12,13].…”