Cyclooxygenase-2 expression is abundant in alveolar type II cells in lung cancer-sensitive mouse strains and in premalignant lesions

Overexpression of cyclooxygenase-2 (COX-2) is seen in a high percentage of human colon tumors, lung adenocarcinomas and other cancers. Inhibition of t his enzyme represses human colon tumorigenesis and decreases lung tumor mul tiplicity in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-exposed NJ mice . The purpose of this investigation was to characterize the expression of c yclooxygenase-2 (COX-2) during tumor progression in the A/J mouse lung and to compare the results with expression in other cancer-susceptible and seve ral cancer-resistant mouse strains, Analysis of normal NJ mouse lung showed that type PI alveolar epithelial cells express high levels of COX-2 protei n and mRNA, indicating that COX-2 is present constitutively in this tumor p rogenitor cell prior to any carcinogen exposure. Examination of lung-cancer -resistant (C3H/HeJ, C57BL/6J, DBNA/2J) and other lung-cancer-susceptible ( A/WySnJ, SWR/J) strains showed similar levels of COX-2 mRNA expression in t he three susceptible strains and lower levels of expression in two of the r esistant strains, indicating a possible correlation between COX-2 expressio n in type II cells and lung cancer susceptibility. COX-2 protein expression was observed in A/J lung tumors at all stages of development. Variation an d occasional absence of protein expression were also observed in A/J lung t umors, particularly in adenomas and adenocarcinomas, suggesting that COX-2 is not obligatory for maintenance of the malignant phenotype, Tn support of this conclusion, treatment of xenografted cell lines derived from malignan t murine pulmonary tumors with COX-2 inhibitors produced only a slight repr ession of growth. However, the frequent expression of COX-2 in early lesion s in the A/J mouse lung combined with the known reduction in tumor number i n animals treated with COX-2 inhibitors prior to carcinogen exposure indica te that COX-2 could be a promising target for lung cancer chemoprevention. In addition, high levels of COX-2 expression in the normal tumor-progenitor cells of lung-cancer-sensitive mice indicate that COX-2 may play a role in lung cancer susceptibility.