Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA.
EMBO Mol Med. 2014 Feb;6(2):278-94. doi: 10.1002/emmm.201303373. Epub 2013 Dec 27.
The transmembrane metalloprotease-disintegrin ADAM8 mediates cell adhesion and shedding of ligands, receptors and extracellular matrix components. Here, we report that ADAM8 is abundantly expressed in breast tumors and derived metastases compared to normal tissue, especially in triple-negative breast cancers (TNBCs). Furthermore, high ADAM8 levels predicted poor patient outcome. Consistently, ADAM8 promoted an aggressive phenotype of TNBC cells in culture. In a mouse orthotopic model, tumors derived from TNBC cells with ADAM8 knockdown failed to grow beyond a palpable size and displayed poor vascularization. Circulating tumor cells and brain metastases were also significantly reduced. Mechanistically, ADAM8 stimulated both angiogenesis through release of VEGF-A and transendothelial cell migration via β1-integrin activation. In vivo, treatment with an anti-ADAM8 antibody from the time of cell inoculation reduced primary tumor burden and metastases. Furthermore, antibody treatment of established tumors profoundly decreased metastases in a resection model. As a non-essential protein under physiological conditions, ADAM8 represents a promising novel target for treatment of TNBCs, which currently lack targeted therapies and frequently progress with fatal dissemination.
跨膜金属蛋白酶-解聚素 ADAM8 介导细胞黏附以及配体、受体和细胞外基质成分的脱落。在这里，我们报告 ADAM8 在乳腺肿瘤及其衍生的转移灶中大量表达，与正常组织相比，在三阴性乳腺癌（TNBC）中表达更高。此外，高水平的 ADAM8 预示着患者预后不良。一致地，ADAM8 在体外促进了 TNBC 细胞的侵袭表型。在小鼠原位模型中，来源于 ADAM8 敲低的 TNBC 细胞的肿瘤无法生长到可触及的大小，并且血管生成不良。循环肿瘤细胞和脑转移也显著减少。从机制上讲，ADAM8 通过释放 VEGF-A 刺激血管生成，并通过β1 整合素激活促进跨内皮细胞迁移。在体内，从细胞接种时开始用抗 ADAM8 抗体治疗可减少原发性肿瘤负担和转移。此外，在切除模型中，对已建立的肿瘤进行抗体治疗可显著减少转移。作为一种在生理条件下非必需的蛋白质，ADAM8 代表了治疗 TNBC 的一个有前途的新靶点，目前 TNBC 缺乏靶向治疗，并且经常会致命地扩散。
