Gottfried Eva, Faust Stefan, Fritsche Jana, Kunz-Schughart Leoni A, Andreesen Reinhard, Miyake Kensuke, Kreutz Marina
Dept. of Hematology and Oncology, University of Regensburg, Germany.
Immunobiology. 2003;207(5):351-9. doi: 10.1078/0171-2985-00246.
Most malignant tumors contain so-called tumor-associated macrophages (TAM) as a major component of their leukocytic infiltrate. To investigate the impact of the tumor microenvironment on activation and differentiation of macrophages, we established a 3-dimensional model system by culturing human monocytes within multicellular tumor spheroids. After 7 days, monocyte-derived TAM were isolated and analyzed for phenotypic alterations as compared to macrophages cultured without tumor cell contact. We found the known macrophage differentiation marker Carboxypeptidase M to be suppressed while CD14, HLA-DR, and CD16 were up-regulated. Using Differential Display, we identified several genes that were differentially expressed between TAM and control macrophages. Prolidase, a peptidase known to influence the chemoattraction of neutrophils and macrophage activity, was down-regulated in TAM. In contrast, the Toll-like receptor family-related molecules MD-1 and RP105 were up-regulated by tumor cell contact, both at the RNA and protein level. From our data we conclude that TAM represent a distict macrophage population characterized by low expression of differentiation-associated macrophage antigens but also by a constitutive state of activation.
大多数恶性肿瘤含有所谓的肿瘤相关巨噬细胞（TAM），作为其白细胞浸润的主要成分。为了研究肿瘤微环境对巨噬细胞激活和分化的影响，我们通过在多细胞肿瘤球体中培养人单核细胞建立了一个三维模型系统。7天后，分离出单核细胞衍生的TAM，并与未与肿瘤细胞接触培养的巨噬细胞相比，分析其表型改变。我们发现已知的巨噬细胞分化标志物羧肽酶M受到抑制，而CD14、HLA-DR和CD16上调。使用差异显示技术，我们鉴定了几个在TAM和对照巨噬细胞之间差异表达的基因。脯氨酰肽酶是一种已知影响中性粒细胞趋化性和巨噬细胞活性的肽酶，在TAM中下调。相反，Toll样受体家族相关分子MD-1和RP105在RNA和蛋白质水平上均因肿瘤细胞接触而上调。从我们的数据中我们得出结论，TAM代表了一个独特的巨噬细胞群体，其特征是分化相关巨噬细胞抗原表达低，但也处于组成性激活状态。
