Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma
Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma
复制标题
瘤周中性粒细胞通过促进肝细胞癌中的血管生成将炎症反应与疾病进展联系起来
DOI：
10.1016/j.jhep.2010.08.041
复制
发表时间：
2011-05-01
影响因子：
25.7
通讯作者：
Zheng, Limin
中科院分区：
文献类型：
--
作者：
Kuang, Dong-Ming;Zhao, Qiyi;Zheng, Limin
背景与目的：大量证据表明炎症是肿瘤进展的关键组成部分。肝细胞癌（HCC）通常源自发炎的肝硬化肝脏并伴有广泛的白细胞浸润。中性粒细胞是肿瘤中常见的炎症浸润，但其在人类癌症中的性质和调节仍然难以捉摸。方法：随机入组 238 名 HCC 患者。使用免疫组织化学和SuperArray实时PCR分析中性粒细胞在不同显微解剖区域的分布和临床相关性。通过体外和体内研究评估中性粒细胞的调节和功能。结果：中性粒细胞主要富集在 HCC 组织的瘤周基质中，其水平可以作为 HCC 患者生存不良的有力预测因子。促炎性 IL-17 是上皮细胞衍生的 CXC 趋化因子将中性粒细胞募集到 HCC 组织瘤周基质中的关键介质。累积的瘤周中性粒细胞是 HCC 组织中基质金属蛋白酶 9 的主要来源：这种分泌的蛋白质刺激肝癌细胞中的促血管生成活性。因此，肿瘤周围中性粒细胞的高浸润与肝癌患者肿瘤侵袭边缘的血管生成进展呈正相关。此外，我们发现选择性消耗中性粒细胞可有效抑制体内肿瘤血管生成和生长。结论：这些数据提供了支持中性粒细胞在人类肿瘤进展中关键作用的直接证据，并揭示了不同肿瘤环境中癌细胞和免疫细胞之间的微调协同作用，从而将炎症反应重新引导至肿瘤促进方向。 (C) 2010 年欧洲肝脏研究协会。由 Elsevier B.V. 出版。保留所有权利。
Background & Aims: Substantial evidence indicates that inflammation is a critical component of tumor progression. Hepatocellular carcinoma (HCC) is usually derived from inflamed cirrhotic liver with extensive leukocyte infiltration. Neutrophils are the common inflammatory infiltrate in tumors, but their nature and regulation in human cancers remain elusive.Methods: A total of 238 HCC patients were enrolled randomly. Immunohistochemistry and SuperArray Real-Time PCR were used to analyze the distribution and clinical relevance of neutrophils in different microanatomical areas. The regulation and function of neutrophils were assessed by both in vitro and in vivo studies.Results: Neutrophils were enriched predominantly in peritumoral stroma of HCC tissues and their levels could serve as a powerful predictor for poor survival in HCC patients. Proinflammatory IL-17 is a critical mediator of the recruitment of neutrophils into peritumoral stroma of HCC tissues by epithelial cell-derived CXC chemokines. The accumulated peritumoral neutrophils were the major source of matrix metalloproteinase-9 in HCC tissues: this secreted protein stimulated proangiogenic activity in hepatoma cells. Accordingly, high infiltration of peritumoral neutrophils was positively correlated with angiogenesis progression at tumor-invading edge of HCC patients. Furthermore, we found that selective depletion of neutrophils effectively inhibited tumor angiogenesis and growth, in vivo.Conclusions: 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 distinct tumor milieu, which reroutes the inflammatory response into a tumor-promoting direction. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.