Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma
Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma
复制标题
DOI：
10.1016/j.jhep.2014.10.029
复制
发表时间：
2015-03-01
影响因子：
25.7
通讯作者：
Man, Kwan
中科院分区：
文献类型：
--
作者：
Yeung, Oscar W. H.;Lo, Chung-Mau;Man, Kwan
背景与目的：除肝细胞癌外，在许多肿瘤中，交替激活的(M2)巨噬细胞对肿瘤前表型的作用已有充分的文献报道。鉴于M2巨噬细胞与慢性组织损伤及肿瘤侵袭和生长的密切关系，本研究旨在探讨M2巨噬细胞对肝癌的直接作用。方法：采用免疫组织化学和定量聚合酶链式反应对95例肝癌组织中M2巨噬细胞进行定量。结果：在临床研究中，M2特异性CD163(风险比=2.693；p=0.043)和清道夫受体A(风险比=3.563；p=0.044)水平高提示肝癌患者预后不良，并与肿瘤结节增多和静脉浸润相关。在原位模型中，注射M2巨噬细胞后，肝脏肿瘤体积增加了3.26倍(1.27 cm(3)+/-0.36)，与对照组(0.39 cm(3)+/-0.05)相比(p=0.032)。治疗组的肺转移率也有所增加。在体外，与M2巨噬细胞共培养使肝癌细胞(MHCC97L)的数量和迁移事件分别增加1.3倍和3.2倍(p<；0.05)。在MHCC97L的强烈诱导下，M2巨噬细胞来源的CCL22被证实能增强肿瘤的迁移能力，并与肝细胞癌患者的静脉浸润相关。M2巨噬细胞和CCL22可促进MHCC97L细胞上皮-间充质转化(EMT)过程中Snail的激活，促进EMT的发生。结论：M2巨噬细胞可通过CCL22诱导的EMT促进肝癌的侵袭性，导致预后不良。(C)2014年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background & Aims: The roles of alternatively activated (M2) macrophages on pro-tumour phenotypes have been well documented in many cancers except hepatocellular carcinoma (HCC). Considering their close relationship with chronic tissue injuries as well as enhanced tumour invasiveness and growth, we aimed to investigate the direct effects of M2 macrophages on HCC.Methods: M2 macrophages in 95 HCC clinical specimens were quantified using immunohistochemistry and quantitative PCR. The pro-tumour functions and the underlying molecular mechanisms of M2 macrophages in HCC were investigated in vivo and in an in vitro co-culture system.Results: In the clinical study, high M2-specific CD163 (hazard ratio = 2.693; p = 0.043) and scavenger receptor A (hazard ratio = 3.563; p = 0.044) levels indicated poor prognosis and correlated with increased tumour nodules and venous infiltration in HCC patients. In an orthotopic model, the liver tumour volume was increased 3.26-fold (1.27 cm(3) +/- 0.36) after M2 macrophage injection compared with the control (0.39 cm(3) +/- 0.05) (p = 0.032). An increased rate of lung metastasis was also found in the treatment group. In vitro, co-cultivation with M2 macrophages elevated the number of HCC cells (MHCC97L) and migration events by 1.3-fold and 3.2-fold, respectively (p < 0.05). Strongly induced by MHCC97L, M2 macrophage-derived CCL22 was proven to enhance tumour migration capacities and correlate with venous infiltration in HCC patients. Increased epithelial-mesenchymal transition (EMT) via Snail activation in MHCC97L was found to be promoted by M2 macrophages and CCL22.Conclusions: M2 macrophages contribute to poor prognosis in HCC and promote tumour invasiveness through CCL22-induced EMT. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.