The Endothelin-Integrin Axis Is Involved in Macrophage- induced Breast Cancer Cell Chemotactic Interactions with Endothelial Cells*
The Endothelin-Integrin Axis Is Involved in Macrophage- induced Breast Cancer Cell Chemotactic Interactions with Endothelial Cells*
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DOI：
10.1074/jbc.m113.528406
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发表时间：
2014-04-04
影响因子：
4.8
通讯作者：
Huang, Tze-Sing
中科院分区：
文献类型：
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作者：
Chen, Chia-Chi;Chen, Li-Li;Huang, Tze-Sing
背景：肿瘤浸润性巨噬细胞与肿瘤细胞向血管迁移/侵袭的关系尚不清楚。结果：巨噬细胞诱导内皮素-整合素轴刺激乳腺癌细胞向内皮细胞趋化、粘附和跨内皮细胞迁移。结论：我们的数据表明巨噬细胞如何影响癌细胞与内皮细胞的相互作用。意义：内皮素-整合素轴在乳腺癌微环境中起关键作用。肿瘤组织中巨噬细胞浸润升高与乳腺癌转移有关。癌细胞向血管生成微血管的迁移/侵袭是转移扩散的关键步骤。因此，我们研究了巨噬细胞如何刺激乳腺癌细胞与内皮细胞的相互作用。巨噬细胞产生白细胞介素-8和肿瘤坏死因子-等细胞因子，刺激乳腺癌细胞和人脐血管内皮细胞（HUVECs）中内皮素（ET）和ET受体（ETR）的表达。ET-1被HUVECs诱导的程度大于乳腺癌细胞，导致密度差异，促进癌细胞向HUVECs趋化。巨噬细胞还能刺激乳腺癌细胞对huvec的粘附和跨内皮细胞迁移，而ET-1抗体或ETR抑制剂可抑制这一过程。ET轴在乳腺癌细胞和HUVECs中诱导整合素(V)和(1)及其反配体（如细胞间粘附分子-2和p -选择素），针对这些整合素的抗体有效抑制巨噬细胞刺激的乳腺癌细胞与HUVECs的相互作用。ET-1在乳腺癌细胞中诱导ets样激酶-1 （Elk-1）、转录信号传导和激活因子-3 （STAT-3）和核因子- b （NF-B）磷酸化。使用抑制剂来防止显性阴性IB的磷酸化或异位过表达会干扰et -1诱导的整合素(V)和整合素(1)的表达。这三种转录因子与两种整合素的基因启动子的物理关联进一步被染色质免疫沉淀试验证实。最后，我们的小鼠原位肿瘤模型显示了巨噬细胞刺激的乳腺癌细胞的ET轴介导的肺转移，这表明ET轴参与了巨噬细胞增强的乳腺癌细胞内皮相互作用。
Background: The relation between tumor-infiltrating macrophages and tumor cell migration/invasion toward blood vessels remained unclear. Results: Macrophage induced the endothelin-integrin axis to stimulate breast cancer cell chemotaxis and adhesion toward endothelial cells and transendothelial migration. Conclusion: Our data suggest how macrophages affect cancer cell interactions with endothelial cells. Significance: The endothelin-integrin axis has a pivotal role in breast cancer microenvironment.Elevated macrophage infiltration in tumor tissues is associated with breast cancer metastasis. Cancer cell migration/invasion toward angiogenic microvasculature is a key step in metastatic spread. We therefore studied how macrophages stimulated breast cancer cell interactions with endothelial cells. Macrophages produced cytokines, such as interleukin-8 and tumor necrosis factor-, to stimulate endothelin (ET) and ET receptor (ETR) expression in breast cancer cells and human umbilical vascular endothelial cells (HUVECs). ET-1 was induced to a greater extent from HUVECs than from breast cancer cells, resulting in a density difference that facilitated cancer cell chemotaxis toward HUVECs. Macrophages also stimulated breast cancer cell adhesion to HUVECs and transendothelial migration, which were repressed by ET-1 antibody or ETR inhibitors. The ET axis induced integrins, such as (V) and (1), and their counterligands, such as intercellular adhesion molecule-2 and P-selectin, in breast cancer cells and HUVECs, and antibodies against these integrins efficiently suppressed macrophage-stimulated breast cancer cell interactions with HUVECs. ET-1 induced Ets-like kinase-1 (Elk-1), signal transducer and activator of transcription-3 (STAT-3), and nuclear factor-B (NF-B) phosphorylation in breast cancer cells. The use of inhibitors to prevent their phosphorylation or ectopic overexpression of dominant-negative IB perturbed ET-1-induced integrin (V) and integrin (1) expression. The physical associations of these three transcriptional factors with the gene promoters of the two integrins were furthermore evidenced by a chromatin immunoprecipitation assay. Finally, our mouse orthotopic tumor model revealed an ET axis-mediated lung metastasis of macrophage-stimulated breast cancer cells, suggesting that the ET axis was involved in macrophage-enhanced breast cancer cell endothelial interactions.