Stearman Robert S, Dwyer-Nield Lori, Grady Michael C, Malkinson Alvin M, Geraci Mark W
Department of Medicine/Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA.
Cancer Res. 2008 Jan 1;68(1):34-43. doi: 10.1158/0008-5472.CAN-07-0988.
One area of intensive investigation is to understand complex cellular and signaling interactions in the tumor microenvironment. Using a novel, although straightforward, microarray approach, we defined a gene expression signature from the lung tumor microenvironment in the murine A/J-urethane model of human lung adenocarcinoma. The tumor microenvironment is reflected by the composition of the cell types present and alterations in mRNA levels, resulting in a "Field Effect" around the tumor. The genes composing the Field Effect expression signature include proteases and their inhibitors, inflammation markers, and immune signaling molecules. By several criteria, the Field Effect expression signature can be attributed to the macrophage lineage, suggesting a qualitative change in the expression pattern of tumor-associated macrophages (TAM) observed in lung tumors. The protein expression levels for a number of Field Effect genes were verified by Western blot analysis of lung homogenates, and for their expression in macrophages and parenchymal cells outside of the tumors by immunohistochemistry. In addition, the Field Effect expression signature was used to classify bronchoalveolar lavage (BAL) cells from tumor-bearing or age-matched control mice. Using a variety of statistical measures, the Field Effect expression signature correctly classified the BAL cells >94% of the time. Finally, the protein levels for several Field Effect genes were higher in cell-free BAL fluid, indicating they may be secreted by the TAMs. This work suggests that TAMs generate a unique gene expression signature within the tumor microenvironment, and this signature could potentially be used for identifying lung cancer from BAL cells and/or fluid.
一个深入研究的领域是了解肿瘤微环境中复杂的细胞和信号相互作用。我们采用了一种新颖且简单的微阵列方法，在人肺腺癌的小鼠A/J-乌拉坦模型中，从肺肿瘤微环境中定义了一个基因表达特征。肿瘤微环境由存在的细胞类型组成以及mRNA水平的改变所反映，在肿瘤周围产生一种“场效应”。构成场效应表达特征的基因包括蛋白酶及其抑制剂、炎症标志物和免疫信号分子。根据多个标准，场效应表达特征可归因于巨噬细胞谱系，这表明在肺肿瘤中观察到的肿瘤相关巨噬细胞（TAM）的表达模式发生了质的变化。通过对肺匀浆的蛋白质印迹分析以及通过免疫组织化学对肿瘤外巨噬细胞和实质细胞中的表达情况进行验证，确定了多个场效应基因的蛋白质表达水平。此外，场效应表达特征被用于对荷瘤小鼠或年龄匹配的对照小鼠的支气管肺泡灌洗（BAL）细胞进行分类。使用多种统计方法，场效应表达特征在超过94%的时间内能够正确地对BAL细胞进行分类。最后，几种场效应基因的蛋白质水平在无细胞BAL液中更高，表明它们可能由TAM分泌。这项工作表明，TAM在肿瘤微环境中产生独特的基因表达特征，并且这种特征有可能用于从BAL细胞和/或液体中识别肺癌。
