Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
University of Edinburgh/Medical Research Council Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh, UK.
J Hepatol. 2015 Mar;62(3):607-16. doi: 10.1016/j.jhep.2014.10.029. Epub 2014 Oct 30.
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.
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.
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 cm3±0.36) after M2 macrophage injection compared with the control (0.39 cm3±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.
M2 macrophages contribute to poor prognosis in HCC and promote tumour invasiveness through CCL22-induced EMT.
在许多癌症中，已充分证明了交替活化（M2）巨噬细胞在肿瘤前表型中的作用，但在肝细胞癌（HCC）中除外。鉴于它们与慢性组织损伤以及增强的肿瘤侵袭和生长密切相关，我们旨在研究 M2 巨噬细胞对 HCC 的直接影响。
采用免疫组织化学和定量 PCR 方法检测 95 例 HCC 临床标本中的 M2 巨噬细胞。在体内和体外共培养系统中研究了 M2 巨噬细胞在 HCC 中的促肿瘤功能及其潜在的分子机制。
在临床研究中，高 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）水平表明预后不良，并且与 HCC 患者的肿瘤结节增多和静脉浸润相关。在原位模型中，与对照组（0.39 cm3±0.05）相比，M2 巨噬细胞注射后肝肿瘤体积增加了 3.26 倍（1.27 cm3±0.36）（p=0.032）。还发现治疗组的肺转移率增加。在体外，与 M2 巨噬细胞共培养可使 HCC 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）。MHCC97L 强烈诱导 M2 巨噬细胞衍生的 CCL22 增强肿瘤迁移能力，并与 HCC 患者的静脉浸润相关。在 MHCC97L 中发现，通过 Snail 激活的上皮-间质转化（EMT）通过 M2 巨噬细胞和 CCL22 得到促进。
M2 巨噬细胞导致 HCC 预后不良，并通过 CCL22 诱导的 EMT 促进肿瘤侵袭。
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