Early dissemination seeds metastasis in breast cancer.
Early dissemination seeds metastasis in breast cancer.
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DOI：
10.1038/nature20785
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发表时间：
2016-12-22
期刊：
影响因子：
64.8
通讯作者：
Klein CA
中科院分区：
文献类型：
--
作者：
Hosseini H;Obradović MMS;Hoffmann M;Harper KL;Sosa MS;Werner-Klein M;Nanduri LK;Werno C;Ehrl C;Maneck M;Patwary N;Haunschild G;Gužvić M;Reimelt C;Grauvogl M;Eichner N;Weber F;Hartkopf AD;Taran FA;Brucker SY;Fehm T;Rack B;Buchholz S;Spang R;Meister G;Aguirre-Ghiso JA;Klein CA
越来越多的数据表明，转移性播散往往发生在肿瘤形成的早期，但早期转移性播散的机制尚未得到解决。在这里，我们研究了HER2驱动的小鼠乳腺癌模型中的转移，发现在HER2激活后不久，炔雌醇诱导的信号传导触发了癌细胞从早期病变中的迁移，但促进了晚期原发性肿瘤细胞的增殖。从迁移到增殖的转换受HER2表达升高和肿瘤细胞密度增加的调节，涉及miRNA介导的孕酮受体（PGR）下调，并且是可逆的。来自早期低密度病变的细胞比来自致密晚期肿瘤的细胞显示出更多的干细胞特征，迁移更多，发现更多的转移灶。引人注目的是，我们发现至少80%的转移来自早期播散性癌细胞（DCC）。人类播散性癌细胞和原发性肿瘤的核型和表型分析证实了这些发现与人类转移性播散的相关性。
Accumulating data suggest that metastatic dissemination often occurs early during tumour formation but the mechanisms of early metastatic spread have not yet been addressed. Here, we studied metastasis in a HER2-driven mouse breast cancer model and found that progesterone-induced signalling triggered migration of cancer cells from early lesions shortly after HER2 activation, but promoted proliferation in advanced primary tumour cells. The switch from migration to proliferation was regulated by elevated HER2 expression and increased tumour cell density involving miRNA-mediated progesterone receptor (PGR) down-regulation and was reversible. Cells from early, low-density lesions displayed more stemness features than cells from dense, advanced tumours, migrated more and founded more metastases. Strikingly, we found that at least 80% of metastases were derived from early disseminated cancer cells (DCC). Karyotypic and phenotypic analysis of human disseminated cancer cells and primary tumours corroborated the relevance of these findings for human metastatic dissemination.