Hepatocytes direct the formation of a pro-metastatic niche in the liver
Hepatocytes direct the formation of a pro-metastatic niche in the liver
复制标题
DOI：
10.1038/s41586-019-1004-y
复制
发表时间：
2019-03-14
期刊：
影响因子：
64.8
通讯作者：
Beatty, Gregory L.
中科院分区：
文献类型：
--
作者：
Lee, Jae W.;Stone, Meredith L.;Beatty, Gregory L.
肝脏是转移性疾病最常见的部位（1）。虽然这种转移向性可能反映了循环肿瘤细胞的机械捕获，但肝转移也至少部分依赖于支持肿瘤细胞扩散到肝脏的“促转移”小生境的形成（2，3）。指导这种生态位形成的机制知之甚少。在这里，我们表明肝细胞协调肝脏内的骨髓细胞积聚和纤维化，并在这样做的过程中，增加了肝脏转移性播种和生长的易感性。在小鼠早期胰腺肿瘤发生期间，肝细胞显示信号转导和转录激活因子3（STAT 3）信号传导的激活以及血清淀粉样蛋白A1和A2（统称为SAA）的产生增加。SAA通过肝细胞的过表达也发生在已经转移到肝脏的胰腺癌和结直肠癌患者中，并且许多患有局部晚期和转移性疾病的患者显示循环SAA增加。肝细胞中STAT 3的激活和随后SAA的产生取决于非恶性细胞向循环中释放白细胞介素6（IL-6）。IL-6-STAT 3-SAA信号传导组分的基因消融或阻断防止促转移小生境的建立并抑制肝转移。我们的数据确定了以肝细胞为基础的细胞间网络，该网络形成了肝脏中促转移小生境的基础，并确定了新的治疗靶点。
The liver is the most common site of metastatic disease(1). Although this metastatic tropism may reflect the mechanical trapping of circulating tumour cells, liver metastasis is also dependent, at least in part, on the formation of a 'pro-metastatic' niche that supports the spread of tumour cells to the liver(2,3). The mechanisms that direct the formation of this niche are poorly understood. Here we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver and, in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth. During early pancreatic tumorigenesis in mice, hepatocytes show activation of signal transducer and activator of transcription 3 (STAT3) signalling and increased production of serum amyloid A1 and A2 (referred to collectively as SAA). Overexpression of SAA by hepatocytes also occurs in patients with pancreatic and colorectal cancers that have metastasized to the liver, and many patients with locally advanced and metastatic disease show increases in circulating SAA. Activation of STAT3 in hepatocytes and the subsequent production of SAA depend on the release of interleukin 6 (IL-6) into the circulation by non-malignant cells. Genetic ablation or blockade of components of IL-6-STAT3-SAA signalling prevents the establishment of a pro-metastatic niche and inhibits liver metastasis. Our data identify an intercellular network underpinned by hepatocytes that forms the basis of a pro-metastatic niche in the liver, and identify new therapeutic targets.