The CCR2+ Macrophage Subset Promotes Pathogenic Angiogenesis for Tumor Vascularization in Fibrotic Livers
The CCR2+ Macrophage Subset Promotes Pathogenic Angiogenesis for Tumor Vascularization in Fibrotic Livers
复制标题
CCR2+巨噬细胞亚群促进纤维化肝脏肿瘤血管形成的致病性血管生成
DOI：
10.1016/j.jcmgh.2018.10.007
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发表时间：
2019-01-01
影响因子：
7.2
通讯作者：
Tacke, Frank
中科院分区：
文献类型：
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作者：
Bartneck, Matthias;Schrammen, Peter L.;Tacke, Frank
背景与目的：肝细胞癌（HCC）通常发生在纤维化或硬化的肝脏中，其特征在于致病性血管生成。髓系免疫细胞，特别是肿瘤相关巨噬细胞（TAMS），可能代表HCC的潜在新治疗靶点，补充目前的消融或免疫治疗。然而，TAM亚群在肝癌发生中的详细功能仍不清楚。方法：TAM亚群进行了深入分析，在人类HCC样本和联合纤维化HCC小鼠模型，建立了腹腔注射二乙基亚硝胺出生后和重复四氯化碳（CCl 4）治疗16周。在荧光激活细胞分选仪（fluorescence-activated cell sorter，transcriptomics）对TAM亚群进行综合分型的基础上，用趋化因子抑制剂评价CCR 2（+）TAM的功能。通过对比增强的微计算机断层扫描和histologic.RESULTS：我们发现，人类CCR 2（+）TAM积累在高度血管化的HCC边缘，并表达炎症标志物S100 A9，而CD 163（+）免疫抑制TAM积累在HCC中心。在纤维化-癌症小鼠模型中，我们鉴定了3种主要的肝髓样细胞群，它们具有不同的信使RNA谱，其中CCR 2（+）TAM特别显示出激活的炎症和血管生成途径。抑制CCR 2（+）TAM的浸润，在纤维化HCC模型中使用的药理趋化因子CCL 2拮抗剂显着降低致病性血管形成和肝血容量，以及衰减tumor volume.CONCLUSIONS：在人类患者和小鼠的HCC微环境的特点是功能不同的巨噬细胞群体，其中CCR 2（+）炎性TAM子集具有促血管生成的特性。了解慢性炎症肝脏中髓样细胞亚群的功能分化可能为调节肝脏巨噬细胞以抑制肿瘤促进的致病性血管生成提供新的机会。
BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) typically arises in fibrotic or cirrhotic livers, which are characterized by pathogenic angiogenesis. Myeloid immune cells, specifically tumor-associated macrophages (TAMS), may represent potential novel therapeutic targets in HCC, complementing current ablative or immune therapies. However, the detailed functions of TAM subsets in hepatocarcinogenesis have remained obscure.METHODS: TAM subsets were analyzed in-depth in human HCC samples and a combined fibrosis-HCC mouse model, established by i.p. injection with diethylnitrosamine after birth and repetitive carbon tetrachloride (CCl4) treatment for 16 weeks. Based on comprehensively phenotyping TAM subsets (fluorescence-activated cell sorter, transcriptomics) in mice, the function of CCR2(+) TAM was assessed by a pharmacologic chemokine inhibitor. Angiogenesis was evaluated by contrast-enhanced micro-computed tomography and histology.RESULTS: We show that human CCR2(+) TAM accumulate at the highly vascularized HCC border and express the inflammatory marker S100A9, whereas CD163(+) immune-suppressive TAM accrue in the HCC center. In the fibrosis-cancer mouse model, we identified 3 major hepatic myeloid cell populations with distinct messenger RNA profiles, of which CCR2(+) TAM particularly showed activated inflammatory and angiogenic pathways. Inhibiting CCR2(+) TAM infiltration using a pharmacologic chemokine CCL2 antagonist in the fibrosis-HCC model significantly reduced pathogenic vascularization and hepatic blood volume, alongside attenuated tumor volume.CONCLUSIONS: The HCC microenvironment in human patients and mice is characterized by functionally distinct macrophage populations, of which the CCR2(+) inflammatory TAM subset has pro-angiogenic properties. Understanding the functional differentiation of myeloid cell subsets in chronically inflamed liver may provide novel opportunities for modulating hepatic macrophages to inhibit tumor-promoting pathogenic angiogenesis.