Tumour stroma-derived lipocalin-2 promotes breast cancer metastasis
Tumour stroma-derived lipocalin-2 promotes breast cancer metastasis
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DOI：
10.1002/path.4724
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发表时间：
2016-07-01
影响因子：
7.3
通讯作者：
Jung, Michaela
中科院分区：
文献类型：
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作者：
Oeren, Bilge;Urosevic, Jelena;Jung, Michaela
肿瘤细胞分泌因子使渗入的免疫细胞向支持肿瘤的表型倾斜，表达促肿瘤致病介质。然而，Lipocalin-2(Lcn2)在肿瘤微环境中对转移级联反应的影响尚不清楚。在这里，我们探讨了基质来源的Lcn2，特别是巨噬细胞释放的Lcn2在乳腺癌进展中的作用。基因敲除研究和中和抗体方法表明，Lcn2在体外转移的早期事件中起作用。利用三维球体模型，巨噬细胞释放Lcn2诱导了MCF-7乳腺癌细胞上皮-间充质转化程序，并促进了局部迁移和对细胞外基质的侵袭。此外，在MMTV-PyMT乳腺癌模型和用野生型和Lcn2基因敲除的巨噬细胞的培养上清预处理的MCF-7细胞接种的异种移植模型中，Lcn2的全球缺失都减少了乳腺癌的转移。为了分析基质来源的Lcn2的作用，我们采用了一种原位乳腺肿瘤小鼠模型。将野生型PYMT肿瘤细胞移植到Lcn2基因缺陷小鼠体内后，原发乳腺肿瘤的形成没有改变，但特异性地减少了肿瘤细胞向肺部的扩散。我们得出结论，基质分泌的Lcn2促进了体外和体内的转移，从而促进了肿瘤的发展。我们的研究强调了基质释放的Lcn2的致瘤潜力，并建议Lcn2作为一个假定的治疗靶点。版权所有(C)2016年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
Tumour cell-secreted factors skew infiltrating immune cells towards a tumour-supporting phenotype, expressing pro-tumourigenic mediators. However, the influence of lipocalin-2 (Lcn2) on the metastatic cascade in the tumour micro-environment is still not clearly defined. Here, we explored the role of stroma-derived, especially macrophage-released, Lcn2 in breast cancer progression. Knockdown studies and neutralizing antibody approaches showed that Lcn2 contributes to the early events of metastasis in vitro. The release of Lcn2 from macrophages induced an epithelial-mesenchymal transition programme in MCF-7 breast cancer cells and enhanced local migration as well as invasion into the extracellular matrix, using a three-dimensioanl (3D) spheroid model. Moreover, a global Lcn2 deficiency attenuated breast cancer metastasis in both the MMTV-PyMT breast cancer model and a xenograft model inoculating MCF-7 cells pretreated with supernatants from wild-type and Lcn2-knockdown macrophages. To dissect the role of stroma-derived Lcn2, we employed an orthotopic mammary tumour mouse model. Implantation of wild-type PyMT tumour cells into Lcn2-deficient mice left primary mammary tumour formation unaltered, but specifically reduced tumour cell dissemination into the lung. We conclude that stroma-secreted Lcn2 promotes metastasis in vitro and in vivo, thereby contributing to tumour progression. Our study highlights the tumourigenic potential of stroma-released Lcn2 and suggests Lcn2 as a putative therapeutic target. Copyright (C) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.