Local iron homeostasis in the breast ductal carcinoma microenvironment.
Local iron homeostasis in the breast ductal carcinoma microenvironment.
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DOI：
10.1186/s12885-016-2228-y
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发表时间：
2016-03-05
期刊：
影响因子：
3.8
通讯作者：
Lopes C
中科院分区：
文献类型：
--
作者：
Marques O;Porto G;Rêma A;Faria F;Cruz Paula A;Gomez-Lazaro M;Silva P;Martins da Silva B;Lopes C
虽然乳腺上皮细胞中铁稳态的失调已被承认，但肿瘤微环境中基质炎症细胞中与铁相关的改变尚未被探索。在原发性乳腺组织和腋窝淋巴结中对铁调素、铁转运蛋白 1 (FPN1)、转铁蛋白受体 1 (TFR1) 和铁蛋白 (FT) 进行免疫组织化学分析，以剖析上皮细胞、淋巴细胞和巨噬细胞的铁分布。此外，对冷冻在最佳切割温度 (OCT) 化合物中的乳腺癌核心活检进行成像流式细胞术，以确认先前评估的细胞类型中的 FPN1 表达并确定其细胞定位。我们证实了之前的结果，表明乳腺癌上皮细胞呈现出“铁利用表型”，铁调素和 TFR1 表达增加，FT 表达减少。另一方面，浸润原发肿瘤和转移淋巴结的淋巴细胞和巨噬细胞表现出“铁供体”表型，FPN1和FT的表达增加，同时伴随着TFR1和铁调素的较高表达所反映的激活谱。与对照乳房切除术样本相比，较高比例的乳腺癌在间质炎症细胞中出现铁积累，表明这些细胞可能构成有效的组织铁库。此外，不仅上皮细胞中铁相关蛋白的表达失调，淋巴细胞和巨噬细胞上的铁相关蛋白表达失调也与乳腺癌不良预后的临床病理标志物相关，例如阴性激素受体状态和肿瘤大小。目前的结果强调了分析乳腺癌肿瘤微环境的重要性，扩展了免疫细胞对肿瘤微环境中局部铁稳态的贡献。
While 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. Immunohistochemistry 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. We 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. The 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.