Abstract
3504
Tumor associated macrophages (TAM) accumulate during the development of chemically-induced primary pulmonary adenocarcinomas. Particular TAM phenotypes may contribute to establishing a tolerant microenvironment that nurtures rather than inhibits tumor growth. Macrophages classically activated by IFN-γ plus LPS use arginine preferentially to increase NO production via expression of inducible nitric oxide synthase (iNOS). Additionally prostaglandin E2 (PGE2) is produced but not prostacyclin (PGI2). IL-4 plus IL-13 activate macrophages to use arginine in an alternative way by upregulating arginase I, which decreases NO production as well as synthesis of PGE2. Macrophages are a major source of the PGE2 that suppresses the adaptive immune response during inflammation to encourage tumor growth. In contrast, PGI2 antagonizes lung tumorigenesis in mice. Immunohistochemical analysis of TAM during urethane-induced tumor progression in A/J mice displays a temporally regulated activation switch in the TAM population. Peritumoral macrophages immunostain for arginase in benign adenomas but not in malignant adenocarcinomas. In contrast, macrophages display a limited iNOS staining in adenomas that increases in adenocarcinomas. By immunoblotting, iNOS expression was significantly elevated at both time points in normal appearing tissue adjacent to the tumors as compared to age matched control lungs. Arginase I expression was significantly higher in uninvolved tissue in benign tumor-bearing mice than in control animals, but expression in carcinoma bearing mice was reduced, consistent with what was observed by immunohistochemistry. We have begun experiments on the mouse pulmonary macrophage MH-S cell line that can be manipulated by cytokine exposure in vitro to exhibit classical or alternative activation. This provides a model for studying PGE2 and PGI2 production in co-culture experiments with normal and neoplastic lung epithelial cells. Understanding the mechanisms by which inflammatory and epithelial cells interact to encourage lung tumor growth will help distinguish among the behavioral differences of normal, benign, and neoplastic lung cells and thereby allow experimental modulation of tumor progression. Analysis of the differential PGE2 and PGI2 production by tumor associated stromal cells during progression may provide new therapeutic targets. (Supported by CA33497 and CA96133)
[Proc Amer Assoc Cancer Res, Volume 47, 2006]