Contribution of three-dimensional architecture and tumor-associated fibroblasts to hepcidin regulation in breast cancer.
Contribution of three-dimensional architecture and tumor-associated fibroblasts to hepcidin regulation in breast cancer.
复制标题
三维结构与肿瘤相关成纤维细胞在乳腺癌中铁调素调控中的作用
DOI：
10.1038/s41388-018-0243-y
复制
发表时间：
2018-07
期刊：
影响因子：
8
通讯作者：
Torti SV
中科院分区：
文献类型：
--
作者：
Blanchette-Farra N;Kita D;Konstorum A;Tesfay L;Lemler D;Hegde P;Claffey KP;Torti FM;Torti SV
铁调素是一种负性调节铁外排的肽类激素，在控制乳腺肿瘤生长中起重要作用。在乳腺癌患者中，铁调素和其膜靶点铁转运蛋白的联合表达可预测疾病结局。然而，在乳腺癌细胞中控制铁调素表达的机制在很大程度上仍然未知。在这里，我们使用来自细胞系和乳腺癌患者的三维乳腺癌球体来探测乳腺癌中铁调素调节的机制。我们观察到，铁调素诱导的程度和其调节途径在三维生长的乳腺癌细胞中发生了显着变化。在单层培养中，BMP，特别是BMP 6，调节铁调素的转录。当乳腺癌细胞作为球状体生长时，铁调素转录物存在>10倍的诱导。结合敲除实验的微阵列分析显示，GDF-15是这种变化的主要介质。随着乳腺细胞形成三维结构，铁调素的增加增加细胞内铁，如铁储存蛋白铁蛋白的增加所示。人乳腺肿瘤的免疫组织化学染色证实了GDF-15和铁调素在乳腺癌标本中表达。此外，在患者样品中，GDF-15的水平在mRNA和蛋白质水平上与铁调素的水平显著相关，这与GDF-15在人乳腺肿瘤中控制铁调素的作用一致。在乳腺癌球体中包含肿瘤相关成纤维细胞进一步诱导铁调素。这种诱导由成纤维细胞依赖性的IL-6分泌介导。作为球状体生长的乳腺癌细胞独特地接受肿瘤相关成纤维细胞对铁调素的IL-6依赖性诱导，因为IL-6在作为单层生长的细胞中不诱导铁调素。总的来说，我们的研究结果提出了一个新的范例，通过控制铁调素的肿瘤结构和乳腺肿瘤微环境的肿瘤介导的控制铁。
Hepcidin is a peptide hormone that negatively regulates iron efflux and plays an important role in controlling the growth of breast tumors. In patients with breast cancer, the combined expression of hepcidin and its membrane target, ferroportin, predict disease outcome. However, mechanisms that control hepcidin expression in breast cancer cells remain largely unknown. Here we use three-dimensional breast cancer spheroids derived from cell lines and breast cancer patients to probe mechanisms of hepcidin regulation in breast cancer. We observe that the extent of hepcidin induction and pathways of its regulation are markedly changed in breast cancer cells grown in three dimensions. In monolayer culture, BMPs, particularly BMP6, regulate hepcidin transcription. When breast cancer cells are grown as spheroids, there is a >10 fold induction in hepcidin transcripts. Microarray analysis combined with knockdown experiments reveal that GDF-15 is the primary mediator of this change. The increase in hepcidin as breast cells develop a three-dimensional architecture increases intracellular iron, as indicated by an increase in the iron storage protein ferritin. Immunohistochemical staining of human breast tumors confirms that both GDF-15 and hepcidin are expressed in breast cancer specimens. Further, levels of GDF-15 are significantly correlated with levels of hepcidin at both the mRNA and protein level in patient samples, consistent with a role for GDF-15 in control of hepcidin in human breast tumors. Inclusion of tumor-associated fibroblasts in breast cancer spheroids further induces hepcidin. This induction is mediated by fibroblast-dependent secretion of IL-6. Breast cancer cells grown as spheroids are uniquely receptive to IL-6-dependent induction of hepcidin by tumor-associated fibroblasts, since IL-6 does not induce hepcidin in cells grown as monolayers. Collectively, our results suggest a new paradigm for tumor-mediated control of iron through the control of hepcidin by tumor architecture and the breast tumor microenvironment.
登录
查看更多内容
影响因子：
--
作者：
Li YL;Chang JT;Lee LY;Fan KH;Lu YC;Li YC;Chiang CH;You GR;Chen HY;Cheng AJ
通讯作者：
Cheng AJ
影响因子：
3
作者：
Daniels, Tracy R.;Bernabeu, Ezequiel;Rodriguez, Jose A.;Patel, Shabnum;Kozman, Maggie;Chiappetta, Diego A.;Holler, Eggehard;Ljubimova, Julia Y.;Helguera, Gustavo;Penichet, Manuel L.
通讯作者：
Penichet, Manuel L.
GDF15促进结直肠癌的EMT和转移
影响因子：
--
作者：
Li C;Wang J;Kong J;Tang J;Wu Y;Xu E;Zhang H;Lai M
通讯作者：
Lai M
影响因子：
50.3
作者：
Hanahan, Douglas;Coussens, Lisa M.
通讯作者：
Coussens, Lisa M.
影响因子：
0.7
作者：
Aboussekhra, Abdelilah
通讯作者：
Aboussekhra, Abdelilah