Increased expression of cyclooxygenase-2 in rat lung tumors induced by thetobacco-specific nitrosamine 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanone: The impact of a high-fat diet

Aberrant or excessive expression of cyclooxygenase (COX)-2 has been implica ted in the pathogenesis of many disease processes, including carcinogenesis . COX-2 expression was immunohistochemically examined in archival samples ( D. Hoffmann ct at., Canter Res., 53: 2758-2761, 1993) of lung neoplasms (ad enomas, adenorarcinomas, and adenosquamous carcinomas) induced by 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in male F344 rats that had been fed either a semipurified AIN-76A diet with high-fat (HF; 23.5% corn oil) or low-fat (LF; 5% corn oil) content, The intensity and extent of COX-2 pos itivity was graded from 0 (undetectable or negligible expression) to grades 1 (<30% expression), 2 (30-60% expression), 3 (60-90% expression), and 4 ( >90% expression), The scoring criteria were similar to those used with spec imens from human lung cancers (T, Hida et al., Cancer Res., 58: 3761-3764, 1998), In group 1 (NNK plus HF diet), adenomas, adenocarcinomas, and adenos quamous carcinomas were of mean grades 2, 3, and 4, respectively; in group 2 (NNK plus LF diet), the corresponding mean grades were 1, 1, and 3, Altho ugh control rats, given HF (group 3) or LF (group 4) diets but no NNK, deve loped spontaneous lung tumors, the expression of COX-2 was either negligibl e tone adenoma of grade 0 in group 3) or of a very low grade tone adenocarc inoma of grade 1 in group 4), In addition, the latency of the tumors in the peripheral lung in assays with NNK is significantly shorter in rats mainta ined on the HF diet than in those on LF diet. COX-2 expression was not evid ent in normal lung tissues. We report here for the first time that NNK indu ces increasingly higher levels of COX-2 expression with progressive stages of lung tumorigenesis when rats are fed the HF diet, The increase in COX-2 expression may be associated with the development of lung tumors induced by NNK. This well-defined animal model is valuable for studying modulation of COX-2 expression in lung carcinogenesis by various factors, including diet ary components.