Glypican-3 参与招募 M2 极化的肿瘤相关巨噬细胞进入肝细胞癌。
Involvement of glypican-3 in the recruitment of M2-polarized tumor-associated macrophages in hepatocellular carcinoma.
机构信息
Safety Assessment Department, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
出版信息
Cancer Biol Ther. 2009 Dec;8(24):2329-38. doi: 10.4161/cbt.8.24.9985. Epub 2009 Dec 3.
Previously, we demonstrated that membrane expression of glypican-3 (GPC3) stimulates the recruitment of macrophages into human hepatocellular carcinoma (HCC) tissues. However, functional polarization of the macrophages and the chemoattractant factors related to the recruitment has yet to be determined. In this study, to clarify the polarization (M1 or M2) of the macrophages and provide a clue as to the factors involved in the recruitment, we used xenograft models of SK-HEP-1 and SK03 cell lines with undetectable and high-level membrane expression of GPC3, respectively and analyzed the expression profiles of the relevant genes in both xenografts mainly using microarray techniques. Clustering analyses with mouse genome arrays revealed that the SK-HEP-1 and SK03 xenografts showed different expression profiles for M2 macrophage-related genes but not for M1 macrophage-related genes. Many of the M2 macrophage-related genes were upregulated in the SK03 xenografts compared to the SK-HEP-1 xenografts. Additionally, most of the macrophages infiltrating into the SK03 xenografts were positive for M2 macrophage-specific markers. Regarding the chemoattractant factors, the microarray and quantitative real-time PCR analyses revealed that, of the genes reportedly related to macrophage recruitment, CCL5, CCL3 and CSF1 were significantly upregulated in the SK03 xenograft. These findings suggest that the macrophages recruited into GPC3-overexpressing (with membrane expression) HCC are M2-polarized ones and, more specifically, M2 tumor-associated macrophages which are known to promote tumor progression and metastasis, and CCL5, CCL3 and CSF1 are possible candidate genes for the recruitment of macrophages.
先前,我们证明了磷脂酰聚糖-3(GPC3)的膜表达可刺激巨噬细胞募集到人类肝细胞癌(HCC)组织中。然而,巨噬细胞的功能极化以及与募集相关的趋化因子因素尚待确定。在这项研究中,为了阐明巨噬细胞的极化(M1 或 M2),并为募集涉及的因素提供线索,我们使用了 SK-HEP-1 和 SK03 细胞系的异种移植模型,它们分别具有可检测和高水平的 GPC3 膜表达,并主要使用微阵列技术分析了两个异种移植物中的相关基因表达谱。使用小鼠基因组芯片进行聚类分析表明,SK-HEP-1 和 SK03 异种移植物显示出与 M2 巨噬细胞相关基因不同的表达谱,但与 M1 巨噬细胞相关基因无差异。与 SK-HEP-1 异种移植物相比,SK03 异种移植物中许多与 M2 巨噬细胞相关的基因上调。此外,浸润到 SK03 异种移植物中的大多数巨噬细胞呈 M2 巨噬细胞特异性标志物阳性。关于趋化因子因素,微阵列和定量实时 PCR 分析表明,在报道与巨噬细胞募集相关的基因中,CCL5、CCL3 和 CSF1 在 SK03 异种移植物中显著上调。这些发现表明,募集到 GPC3 过表达(膜表达)HCC 的巨噬细胞是 M2 极化的,更具体地说是 M2 肿瘤相关巨噬细胞,已知其促进肿瘤进展和转移,CCL5、CCL3 和 CSF1 可能是招募巨噬细胞的候选基因。