Inflammation Triggers Zeb1-Dependent Escape from Tumor Latency.
Inflammation Triggers Zeb1-Dependent Escape from Tumor Latency.
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DOI：
10.1158/0008-5472.can-16-0608
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发表时间：
2016-12-01
期刊：
影响因子：
11.2
通讯作者：
Weinberg RA
中科院分区：
文献类型：
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作者：
De Cock JM;Shibue T;Dongre A;Keckesova Z;Reinhardt F;Weinberg RA
癌症患者在原发性肿瘤的初始成功治疗后多年或数十年出现转移性疾病是有据可查的，但在分子水平上知之甚少。最近的研究已经开始探索导致播散性肿瘤细胞进入潜伏期的细胞内在程序以及维持潜伏状态的周围非许可组织微环境中的细胞信号。然而，相对较少的是知道的机制，使扩散的肿瘤细胞逃避癌症休眠或肿瘤潜伏期。我们在这里描述了一个在肺实质孤立转移潜伏期的体内模型。由脂多糖（LPS）治疗引发的肺部局部炎症的诱导，触发了这些细胞的觉醒，这些细胞发展成肉眼可见的转移。逃避潜伏期依赖于Zeb1的表达，Zeb1是上皮向间充质转化（EMT）的关键调节因子。此外，激活EMT程序本身，如Zeb1精心策划的，足以通过使癌细胞稳定地进入转移起始细胞状态来刺激转移性生长。
The emergence of metastatic disease in cancer patients many years or decades after initial successful treatment of primary tumors is well documented but poorly understood at the molecular level. Recent studies have begun exploring the cell-intrinsic programs causing disseminated tumor cells to enter latency and the cellular signals in the surrounding non-permissive tissue microenvironment that maintain the latent state. However, relatively little is known about the mechanisms that enable disseminated tumor cells to escape cancer dormancy or tumor latency. We describe here an in vivo model of solitary metastatic latency in the lung parenchyma. The induction of a localized inflammation in the lungs, initiated by lipopolysaccharide (LPS) treatment, triggers the awakening of these cells, which develop into macroscopic metastases. The escape from latency is dependent on the expression of Zeb1, a key regulator of the epithelial-to-mesenchymal transition (EMT). Furthermore, activation of the EMT program on its own, as orchestrated by Zeb1, is sufficient to incite metastatic outgrowth by causing carcinoma cells to enter stably into a metastasis-initiating cellstate.