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A Macrophage Gene Expression Signature Defines a Field Effect in the Lung Tumor Microenvironment

Departments of ¹ Medicine/Pulmonary Sciences and Critical Care Medicine, and ² Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, Colorado

Requests for reprints: Robert S. Stearman, Box C272, Room BB 3B10, 4200 East Ninth Avenue, Denver, CO 80262. Phone: 303-315-2317; Fax: 303-315-5632; E-mail: Robert.Stearman{at}uchsc.edu.

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. [Cancer Res 2008;68(1):34–43]