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K-ras activation generates an inflammatory response in lung tumors

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-rasG12D 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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Acknowledgements

We are grateful to Dr Matthew L Meyerson for sharing his unpublished K-ras mutational data set. KKW is supported by NIH Grant K08AG 2400401, the Sidney Kimmel Foundation for Cancer Research and the Joan Scarangello Foundation to Conquer Lung Cancer. This work was also supported by NIH Grant R01 HL70321 (SDS).

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Correspondence to K-K Wong.

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Ji, H., Houghton, A., Mariani, T. et al. K-ras activation generates an inflammatory response in lung tumors. Oncogene 25, 2105–2112 (2006). https://doi.org/10.1038/sj.onc.1209237

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