Helm Ole, Held-Feindt Janka, Grage-Griebenow Evelin, Reiling Norbert, Ungefroren Hendrik, Vogel Ilka, Krüger Uwe, Becker Thomas, Ebsen Michael, Röcken Christoph, Kabelitz Dieter, Schäfer Heiner, Sebens Susanne
Institute for Experimental Medicine, Group Inflammatory Carcinogenesis, UK S-H Campus, Kiel, Germany.
Int J Cancer. 2014 Aug 15;135(4):843-61. doi: 10.1002/ijc.28736. Epub 2014 Feb 5.
Pancreatic ductal adenocarcinoma (PDAC) still ranking 4th in the order of fatal tumor diseases is characterized by a profound tumor stroma with high numbers of tumor-associated macrophages (TAMs). Driven by environmental factors, monocytes differentiate into M1- or M2-macrophages, the latter commonly regarded as being protumorigenic. Because a detailed analysis of TAMs in human PDAC development is still lacking, freshly isolated PDAC-derived TAMs were analyzed for their phenotype and impact on epithelial-mesenchymal-transition (EMT) of benign (H6c7) and malignant (Colo357) pancreatic ductal epithelial cells. TAMs exhibited characteristics of M1-macrophages (expression of HLA-DR, IL-1β, or TNF-α) and M2-macrophages (expression of CD163 and IL-10). In the presence of TAMs, H6c7, and Colo357 cells showed an elongated cell shape along with an increased expression of mesenchymal markers such as vimentin and reduced expression of epithelial E-cadherin. Similar to TAMs, in vitro generated M1- and M2-macrophages both mediated EMT in H6c7 and Colo357 cells. M1-macrophages acquired M2-characteristics during coculture that could be prevented by GM-CSF treatment. However, M1-macrophages still potently induced EMT in H6c7 and Colo357 cells although lacking M2-characteristics. Overall, these data demonstrate that TAMs exhibit anti- as well as proinflammatory properties that equally contribute to EMT induction in PDAC initiation and development.
胰腺导管腺癌（PDAC）在致命性肿瘤疾病中仍排名第四，其特征是具有大量肿瘤相关巨噬细胞（TAM）的深厚肿瘤基质。在环境因素的驱动下，单核细胞分化为M1或M2巨噬细胞，后者通常被认为具有促肿瘤作用。由于仍缺乏对人类PDAC发展中TAM的详细分析，因此对新鲜分离的PDAC来源的TAM进行了表型分析，以及它们对良性（H6c7）和恶性（Colo357）胰腺导管上皮细胞上皮-间质转化（EMT）的影响。TAM表现出M1巨噬细胞（HLA-DR、IL-1β或TNF-α的表达）和M2巨噬细胞（CD163和IL-10的表达）的特征。在TAM存在的情况下，H6c7和Colo357细胞呈现出细长的细胞形态，同时间充质标志物波形蛋白的表达增加，上皮E-钙黏蛋白的表达减少。与TAM类似，体外产生的M1和M2巨噬细胞均介导H6c7和Colo357细胞的EMT。M1巨噬细胞在共培养过程中获得了M2特征，这可以通过GM-CSF处理来预防。然而，尽管缺乏M2特征，M1巨噬细胞仍能有效诱导H6c7和Colo357细胞发生EMT。总体而言，这些数据表明，TAM具有抗炎和促炎特性，在PDAC的起始和发展过程中均对EMT诱导起到同等作用。
