Peritumoral stromal neutrophils are essential for c-Met-elicited metastasis in human hepatocellular carcinoma
Peritumoral stromal neutrophils are essential for c-Met-elicited metastasis in human hepatocellular carcinoma
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瘤周间质中性粒细胞对于 c-Met 引起的人肝细胞癌转移至关重要
DOI：
10.1080/2162402x.2016.1219828
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发表时间：
2016-01-01
期刊：
影响因子：
7.2
通讯作者：
Lao, Xiang-Ming
中科院分区：
文献类型：
--
作者：
He, Min;Peng, Anping;Lao, Xiang-Ming
摘要炎症是肿瘤进展机制的一个组成部分。中性粒细胞是许多肿瘤中常见的炎性浸润，但其在瘤形成中的调节和功能尚不清楚。在这里，我们在225例未经治疗的肝细胞癌（HCC）患者中详细研究了c-Met分子，发现HCC组织中嗜中性粒细胞的高度浸润决定了患者的恶性细胞c-Met相关临床结局。HCC中嗜中性粒细胞的高度浸润决定了患者的恶性细胞c-Met相关临床结局。浸润性肝癌的肿瘤边缘主要富集中性粒细胞，聚集的中性粒细胞是肝癌中c-Met配体HGF的主要来源。暴露于HCC环境导致中性粒细胞活化和随后的HGF产生。抑制Erk 1/2、p38和NF-κB的活性，但不抑制AKT或JNK的磷酸化，成功地减弱了HCC环境诱导的中性粒细胞HGF的产生。进一步的研究表明，GM-CSF是体内外恶性肿瘤细胞诱导中性粒细胞产生HGF的重要决定因素。此外，我们证明，肿瘤中性粒细胞，通过HGF/c-Met相互作用，积极增强恶性细胞在体外和体内的转移。这些数据提供了支持中性粒细胞在人类肿瘤进展中的关键作用的直接证据，并揭示了肿瘤环境中癌细胞和免疫细胞之间的微调协作作用，其将免疫激活重新路由到肿瘤促进方向。
ABSTRACT Inflammation is a component of tumor progression mechanisms. Neutrophils are a common inflammatory infiltrate in many tumors, but their regulation and functions in neoplasia are not understood. Here, we showed, in detailed studies of c-Met molecule in 225 untreated patients with hepatocellular carcinoma (HCC), that high infiltration of neutrophils in HCC tissues determined malignant cell c-Met-associated clinical outcome of patients. High infiltration of neutrophils in HCCs determined malignant cell c-Met-associated clinical outcome of patients. Neutrophils were enriched predominantly in invading tumor edge of HCCs; the accumulated neutrophils were the major source of c-Met ligand HGF in HCCs. Exposure to HCC environments resulted in neutrophil activation and the following HGF production. Inhibiting the activities of Erk1/2, p38, and NF-κB, but not the phosphorylation of AKT or JNK, successfully attenuated the neutrophil HGF production induced by HCC environments. Further investigation revealed that GM-CSF was an important determinant in malignant cell-elicited neutrophil HGF production in vitro and in vivo. Moreover, we demonstrated that tumor neutrophils, via HGF/c-Met interaction, actively enhanced the metastasis of malignant cells in vitro and in vivo. These data provide direct evidence supporting the critical role of neutrophils in human tumor progression and reveal a fine-tuned collaborative action between cancer cells and immune cells in tumor milieu, which reroutes the immune activation into a tumor-promoting direction.