The matricellular protein CYR61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and suppressing anoikis.
The matricellular protein CYR61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and suppressing anoikis.
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DOI：
10.18632/oncotarget.13677
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发表时间：
2017-02-07
期刊：
影响因子：
--
通讯作者：
Rüegg C
中科院分区：
文献类型：
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作者：
Huang YT;Lan Q;Lorusso G;Duffey N;Rüegg C
基质细胞蛋白在原发性肿瘤生长、局部侵袭和肿瘤血管生成中起着多种作用。然而，它们对转移的贡献和所涉及的假定机制还不太清楚。在ER阴性的人乳腺癌中，基质细胞蛋白富含半胱氨酸的血管生成诱导物61（CYR 61）的表达水平升高与更具侵袭性的进展相关。在此，我们使用三阴性人乳腺癌细胞系MDA-MB-231和SUM 159研究CYR 61在乳腺癌肺转移中的作用。CYR 61的沉默显著降低了原位植入预辐照或未处理乳腺组织中的肿瘤的肺转移，并且在尾静脉注射后。组成型CYR 61沉默在尾静脉注射后的前24小时期间损害癌细胞外渗至肺。相比之下，在癌细胞注射后24小时开始的CYR 61诱导型沉默对肺转移形成没有影响。体外实验表明，CYR 61沉默降低了癌细胞的跨内皮迁移和运动性，降低了细胞表面的CYR 61水平，并使癌细胞对失巢凋亡敏感。此外，我们证明了在非粘附条件下CYR 61依赖性细胞存活至少部分依赖于β1整合素连接和AMPKα信号传导，而不依赖于AKT、FAK和ERK 1/2激活。我们的数据提供了第一个证据，CYR 61促进乳腺癌肺转移，促进肿瘤细胞外渗和保护从失巢凋亡在初始种植到肺。CYR 61-β1整合素-AMPK α轴可能是预防乳腺癌肺转移的潜在治疗靶点。
Matricellular proteins play multiple roles in primary tumor growth, local invasion and tumor angiogenesis. However, their contribution to metastasis and the putative mechanisms involved are less well characterized. In ER-negative human breast cancer, elevated expression levels of the matricellular protein Cysteine-rich angiogenic inducer 61 (CYR61) are associated with more aggressive progression. Here, we investigated the role of CYR61 in breast cancer lung metastasis using the triple negative human breast cancer cell lines MDA-MB-231 and SUM159. Silencing of CYR61 significantly decreased lung metastasis from tumors orthotopically implanted in pre-irradiated or naive mammary tissue and upon tail vein injection. Constitutive CYR61 silencing impaired cancer cell extravasation to the lung during the first 24 hours after tail vein injection. In contrast, CYR61 inducible silencing starting 24 hours after cancer cell injection had no impact on lung metastasis formation. In vitro experiments revealed that CYR61 silencing decreased cancer cell transendothelial migration and motility, reduced CYR61 levels present at the cell surface and sensitized cancer cells to anoikis. Furthermore, we demonstrate that CYR61-dependent cell survival under non-adhesive conditions relied, at least partially, on β1 integrin ligation and AMPKα signaling while it was independent of AKT, FAK and ERK1/2 activation. Our data provide the first evidence that CYR61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and protecting from anoikis during initial seeding to the lung. The uncovered CYR61-β1 integrin-AMPKα axis may serve as a potential therapeutic target to prevent breast cancer metastasis to the lung.