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 this enzyme represses human colon tumorigenesis and decreases lung tumor multiplicity in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-exposed A/J mice. The purpose of this investigation was to characterize the expression of cyclooxygenase-2 (COX-2) during tumor progression in the A/J mouse lung and to compare the results with expression in other cancer-susceptible and several cancer-resistant mouse strains. Analysis of normal A/J mouse lung showed that type II alveolar epithelial cells express high levels of COX-2 protein and mRNA, indicating that COX-2 is present constitutively in this tumor progenitor cell prior to any carcinogen exposure. Examination of lung-cancer-resistant (C3H/HeJ, C57BL/6J, DBA/2J) and other lung-cancer-susceptible (A/WySnJ, SWR/J) strains showed similar levels of COX-2 mRNA expression in the three susceptible strains and lower levels of expression in two of the resistant strains, indicating a possible correlation between COX-2 expression 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 and occasional absence of protein expression were also observed in A/J lung tumors, particularly in adenomas and adenocarcinomas, suggesting that COX-2 is not obligatory for maintenance of the malignant phenotype. In support of this conclusion, treatment of xenografted cell lines derived from malignant murine pulmonary tumors with COX-2 inhibitors produced only a slight repression of growth. However, the frequent expression of COX-2 in early lesions in the A/J mouse lung combined with the known reduction in tumor number in animals treated with COX-2 inhibitors prior to carcinogen exposure indicate 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.
Wardlaw
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Lovelace Respiratory Research Institute, PO Box 5890, Albuquerque, NM 87185, USA.
March
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TH
Belinsky
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SA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens; D002455:Cell Division / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004198:Disease Susceptibility; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis* / Q000378:metabolism / Q000494:pharmacology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D008565:Membrane Proteins; D051379:Mice; D008805:Mice, Inbred A; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009602:Nitrosamines; D011230:Precancerous Conditions / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000378:metabolism / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D013449:Sulfonamides / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D000096926:Benzenesulfonamides
D000970:Antineoplastic Agents; D002273:Carcinogens; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009602:Nitrosamines; D011392:Proline; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; D013859:Thiocarbamates; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C066229:prolinedithiocarbamate; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C496540:PTGS2 protein, human