Published ahead of print on July 17, 2008, doi:10.1165/rcmb.2008-0147OC
© 2009 American Thoracic Society DOI: 10.1165/rcmb.2008-0147OC Overexpression of Sprouty 2 in Mouse Lung Epithelium Inhibits Urethane-Induced Tumorigenesis1 Division of Pulmonary and Critical Care Medicine, Case Western Reserve University, University Hospitals of Cleveland, and Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio; and 2 Division of Pulmonary Sciences and Critical Care Medicine, Denver Veterans Affairs Medical Center, University of Colorado Cancer Center, and University of Colorado Health Sciences Center, Denver, Colorado Correspondence and requests for reprints should be addressed to York E. Miller, M.D., Pulmonary 111A, Denver Veterans Affairs Medical Center, Denver, CO 80220. E-mail: york.miller{at}uchsc.edu Members of the Sprouty family encode novel proteins that are thought to function primarily as intracellular antagonists of the Ras-signaling pathway. Increased Ras signaling is a critical characteristic of human lung adenocarcinoma, the most common type of non–small cell lung cancer. Sprouty 2 is expressed in the lung epithelium, the tissue layer from which lung cancers arise. We hypothesized that overexpression of Sprouty 2 in the distal lung epithelium would inhibit lung tumorigenesis. To test the hypothesis, the consequences of overexpressing Sprouty 2 in the distal lung epithelium on urethane-induced mouse lung tumorigenesis were determined. Urethane is a chemical carcinogen found in tobacco smoke that causes activating mutations in Kras and induces lung tumors in mice. Sprouty 2–overexpressor mice developed significantly fewer lung tumors compared with their littermate controls (13.2 ± 1.1 versus 18.1 ± 1.3, P = 0.006). Tumor diameter was also significantly smaller in Sprouty 2 overexpressors (0.85 mm ± 0.03 versus 0.95 mm ± 0.02, P = 0.005). Sprouty 2 overexpression did not alter Kras mutational frequencies in urethane-induced tumors, suggesting that the tumor-suppressing effect of Sprouty 2 overexpression acts at a stage after Kras mutation, perhaps by interfering with receptor tyrosine kinase–induced signaling. These results demonstrate that Sprouty 2 overexpression inhibited both tumor initiation and subsequent tumor growth.
Key Words: Sprouty • lung cancer • mouse • chemoprevention • Ras
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