Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Cell. 2012 Aug 17;150(4):764-79. doi: 10.1016/j.cell.2012.06.035.
The mechanistic underpinnings of metastatic dormancy and reactivation are poorly understood. A gain-of-function cDNA screen reveals that Coco, a secreted antagonist of TGF-β ligands, induces dormant breast cancer cells to undergo reactivation in the lung. Mechanistic studies indicate that Coco exerts this effect by blocking lung-derived BMP ligands. Whereas Coco enhances the manifestation of traits associated with cancer stem cells, BMP signaling suppresses it. Coco induces a discrete gene expression signature, which is strongly associated with metastatic relapse to the lung, but not to the bone or brain in patients. Experiments in mouse models suggest that these latter organs contain niches devoid of bioactive BMP. These findings reveal that metastasis-initiating cells need to overcome organ-specific antimetastatic signals in order to undergo reactivation.
转移休眠和激活的机制基础理解得很差。功能获得 cDNA 筛选显示，Coco 是 TGF-β 配体的一种分泌拮抗剂，可诱导肺休眠的乳腺癌细胞重新激活。机制研究表明，Coco 通过阻断肺衍生的 BMP 配体发挥此作用。尽管 Coco 增强了与癌症干细胞相关的特征的表现，但 BMP 信号会抑制它。Coco 诱导了一个离散的基因表达特征，该特征与患者肺转移复发强烈相关，但与骨或脑无关。在小鼠模型中的实验表明，这些后两种器官中含有缺乏生物活性 BMP 的小生境。这些发现表明，起始转移的细胞需要克服特定于器官的抗转移信号，才能重新激活。
