肝细胞指导肝脏中促转移生态位的形成,Nature

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肝细胞指导肝脏中促转移生态位的形成
Nature ( IF 50.5 ) Pub Date : 2019-03-01 , DOI: 10.1038/s41586-019-1004-y
Jae W Lee _{1,

2} , Meredith L Stone _{1,

2} , Paige M Porrett ₃ , Stacy K Thomas _{1,

2} , Chad A Komar _{1,

2} , Joey H Li _{1,

2} , Devora Delman _{1,

2} , Kathleen Graham _{1,

2} , Whitney L Gladney _{1,

2} , Xia Hua _{1,

2} , Taylor A Black _{1,

2} , Austin L Chien _{1,

2} , Krishna S Majmundar _{1,

2} , Jeffrey C Thompson _{1,

2} , Stephanie S Yee _{1,

2} , Mark H O'Hara _{1,

2} , Charu Aggarwal _{1,

2} , Dong Xin ₃ , Abraham Shaked ₃ , Mingming Gao ₄ , Dexi Liu ₄ , Mitesh J Borad ₅ , Ramesh K Ramanathan _{5,

6} , Erica L Carpenter _{1,

2} , Ailing Ji _{7,

8} , Maria C de Beer _{8,

9} , Frederick C de Beer _{7,

8} , Nancy R Webb _{8,

10} , Gregory L Beatty _{1,

2}

Affiliation

肝脏是转移性疾病最常见的部位1。尽管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”生态位的形成2,3。人们对引导这一生态位形成的机制知之甚少。在这里，我们发现肝细胞协调肝脏内的骨髓细胞积累和纤维化，从而增加肝脏对转移播种和生长的敏感性。在小鼠早期胰腺肿瘤发生过程中，肝细胞表现出信号转导子和转录激活子 3 (STAT3) 信号的激活以及血清淀粉样蛋白 A1 和 A2（统称为 SAA）的产生增加。肝细胞过度表达 SAA 也发生在已转移至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表现出循环 SAA 的增加。肝细胞中 STAT3 的激活以及随后 SAA 的产生取决于非恶性细胞将白细胞介素 6 (IL-6) 释放到循环中。IL-6–STAT3–SAA 信号传导成分的基因消除或阻断可防止促转移生态位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生态位的基础，并确定了新的治疗靶点。胰腺癌激活肝细胞中的 IL-6–STAT3 信号传导以诱导促转移生态位的形成在肝脏中。

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Hepatocytes direct the formation of a pro-metastatic niche in the liver

The liver is the most common site of metastatic disease1. 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 liver2,3. 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.Pancreatic cancer activates IL-6–STAT3 signalling in hepatocytes to induce the formation of a pro-metastatic niche in the liver.

更新日期：2019-03-01

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