K-ras mutations in lung tumors from NNK-treated mice with lipopolysaccharide-elicited lung inflammation.

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.