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K-ras mutations in lung tumors from NNK-treated mice with lipopolysaccharide-elicited lung inflammation
Phouthone Keohavong1, Beth Kahkonen, Edwina Kinchington
1Environmental and Occupational Health, University of Pittsburgh, 100 Technology Drive, Bridgeside Point, Pittsburgh, PA 15219-3130, USA. pho1@pitt.edu
Background:
Chronic lung inflammation has been associated with an increased risk of lung cancer. However, it is unclear whether such an event affects the incidence of mutations in the K-ras oncogene frequently found in lung tumors and suggested to be involved in lung tumorigenesis. This study investigated potential impacts of inflammation on the incidence of lung tumors and K-ras mutations using a mouse model.
Materials And Methods:
FVB/N mice were treated with lipopolysaccharide (LPS) for 16 weeks with or without co-treatment with 4-(methyl-nitrosoamino)-1-(3-pyridyl)-1-butanone (NNK) during the first 4 weeks.
Results:
There was a significant increase in lung inflammatory responses in mice treated with LPS and with LPS+NNK, compared with mice treated with NNK or with vehicle. The average number of lung tumors per mouse was 3.87 (between 1 and 6) and 0.73 (between 0 and 3) in mice treated with LPS+NNK and NNK alone, respectively (p<0.0001). No lung tumors were observed in mice treated with LPS or vehicle. A higher proportion of lung tumors from mice treated with LPS+NNK had K-ras mutations, compared with the mice treated with NNK alone (81.03% versus 45.45%, p<0.05).
Conclusion:
LPS-elicited chronic lung inflammation significantly increases the risk of NNK-mediated lung tumorigenesis in FVB/N mice through K-ras gene activation by point mutations.
