K-ras activation generates an inflammatory response in lung tumors - PubMed (original) (raw)
. 2006 Mar 30;25(14):2105-12.
doi: 10.1038/sj.onc.1209237.
A M Houghton, T J Mariani, S Perera, C B Kim, R Padera, G Tonon, K McNamara, L A Marconcini, A Hezel, N El-Bardeesy, R T Bronson, D Sugarbaker, R S Maser, S D Shapiro, K-K Wong
Affiliations
- PMID: 16288213
- DOI: 10.1038/sj.onc.1209237
K-ras activation generates an inflammatory response in lung tumors
H Ji et al. Oncogene. 2006.
Abstract
Activating mutations in K-ras are one of the most common genetic alterations in human lung cancer. To dissect the role of K-ras activation in bronchial epithelial cells during lung tumorigenesis, we created a model of lung adenocarcinoma by generating a conditional mutant mouse with both Clara cell secretory protein (CC10)-Cre recombinase and the Lox-Stop-Lox K-ras(G12D) alleles. The activation of K-ras mutant allele in CC10 positive cells resulted in a progressive phenotype characterized by cellular atypia, adenoma and ultimately adenocarcinoma. Surprisingly, K-ras activation in the bronchiolar epithelium is associated with a robust inflammatory response characterized by an abundant infiltration of alveolar macrophages and neutrophils. These mice displayed early mortality in the setting of this pulmonary inflammatory response with a median survival of 8 weeks. Bronchoalveolar lavage fluid from these mutant mice contained the MIP-2, KC, MCP-1 and LIX chemokines that increased significantly with age. Cell lines derived from these tumors directly produced MIP-2, LIX and KC. This model demonstrates that K-ras activation in the lung induces the elaboration of inflammatory chemokines and provides an excellent means to further study the complex interactions between inflammatory cells, chemokines and tumor progression.
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