THE ROLE OF GP130 CYTOKINES IL-6 AND OSM ON TUMOR DEVELOPMENT IN MOUSE MODELS FOR LUNG ADENOCARCINOMA

Abstract

<p>Lung cancer is the leading cause of cancer related deaths in both the US and Canada and efforts still need to be made towards understanding the disease. The role of inflammation in the promotion of cancer development represents a newer avenue of research. The glycoprotein (gp)-130 cytokine interleukin-6 (IL-6) has a well established role in promoting inflammation and recent evidence suggests roles in development of certain tumors in animal models. Less is known of the related family member oncostatin M (OSM) and the functions of either IL-6 or OSM in lung cancer development is not known. Based on the hypothesis that these cytokines promote lung cancer development, IL-6 and OSM were overexpressed in the lungs of two separate mouse models for lung cancer utilizing adenovirus vectors encoding IL-6 or OSM. The first mouse model utilized a Cre-conditional oncogene KRAS G12D (developed by Tyler Jacks) in which endotracheal administration of adenovirus (Ad)-encoded Cre-recombinase resulted in increases in lung densities in a dose-dependent fashion over a period of 6 weeks that were measurable by CT scanning and histology. Increases in cytokines IL-6 and kertinocyte chemoattractant (KC) were detectable in the bronchoalveolar lavage (BAL) by week 4, as well as marked increases in alveolar macrophage numbers. Macrophages were also shown as a possible target for Cre-mediated recombination and mutant KRAS expression. Administration of either AdIL-6 or AdOSM as well as AdCre resulted in a trend toward increases in tumor burden with AdOSM based on experiments terminated at 4 weeks. The second mouse model involved endotracheal administration of the lewis lung carcinoma (LLC) cell line, which after 7 days resulted in detectable tumor burden. Administration of either AdIL-6 or AdOSM and LLC cells simultaneously was shown to increase tumor burden relative to AdDl70 co-administration. These results suggest a possible role of IL-6 or OSM in promoting lung tumor development in animal models and may ultimately reveal gp130 cytokines IL-6 or OSM as a possible therapeutic target for the treatment of lung cancer.</p>