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Sprouty 2 Gene in Mouse Lung Tumorigenesis* FREE TO VIEW

George Minowada, MD; York E. Miller
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*From the University Hospitals of Cleveland, Case Western Reserve University; Denver VAMC; University of Colorado Health Sciences Center.

Correspondence to: George Minowada, MD, Division of Pulmonary and Critical Care Medicine, Case Western Reserve University School of Medicine, University Hospitals of Cleveland, 2109 Adelbert Rd, BRB 10th Floor, Rm 1025, Cleveland, OH 44106; e-mail: gxm45@pop.cwru.edu

Chest. 2004;125(5_suppl):111S. doi:10.1378/chest.125.5_suppl.111S
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Members of the Sprouty (Spry) gene family encode novel proteins that function as intracellular antagonists of the Ras signaling pathway. Loss of Spry function would be predicted to enhance Ras signaling.

Several mechanisms appear to increase Ras signaling in the most common type of human lung cancer, non-small cell lung cancer (NSCLC). Epidermal growth factor receptor members and/or one of their ligands are expressed in most NSCLCs. Similarly, fibroblast growth factor 2 is expressed in many NSCLCs, if not most. Alternatively, 15 to 20% of NSCLCs have activating mutations in the KRAS gene. It remains unclear what role Ras signaling may play in the pathogenesis of NSCLC, but at least one consequence appears to be increased proliferation. In a mouse model of lung cancer, the chemical carcinogen urethane causes activating mutations in K-ras and induces lung tumors. Thus, perturbations that would be predicted to enhance Ras signaling appear to play a key role in the pathogenesis of some types of NSCLC. Such perturbations also appear to be markers of a more biologically aggressive cancer since patients with these tumors do worse.

Of the four members of the Spry family of genes, Spry 2 is expressed in the lung epithelium, the cell type from which NSCLC arises. We hypothesized that the Ras signaling antagonist Spry 2, which is expressed in the lung epithelium, modulates susceptibility to and/or the biological behavior of lung cancer. To begin to test this hypothesis, we have compared urethane-induced lung tumor development in Spry 2 lung-specific overexpressing mice (13 mice) with their littermate controls (14 mice). Consistent with the hypothesis, the mean tumor multiplicity and diameter were lower in the overexpressor mice (13.5 vs 18.7 tumors per mouse, respectively; 0.78 vs 0.86 μm per tumor, respectively).

Abbreviations: NSCLC = non-small cell lung cancer; Spry = Sprouty




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