Wardlaw S A, March T H, Belinsky S A
Lovelace Respiratory Research Institute, PO Box 5890, Albuquerque, NM 87185, USA.
Carcinogenesis. 2000 Jul;21(7):1371-7.
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.
环氧化酶-2（COX-2）在高比例的人类结肠肿瘤、肺腺癌和其他癌症中呈过表达。抑制这种酶可抑制人类结肠肿瘤发生，并减少4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮暴露的A/J小鼠的肺肿瘤数量。本研究的目的是表征A/J小鼠肺肿瘤进展过程中环氧化酶-2（COX-2）的表达，并将结果与其他癌症易感和几种癌症抗性小鼠品系的表达进行比较。对正常A/J小鼠肺的分析表明，II型肺泡上皮细胞表达高水平的COX-2蛋白和mRNA，表明在任何致癌物暴露之前，COX-2在这种肿瘤祖细胞中组成性存在。对肺癌抗性（C3H/HeJ、C57BL/6J、DBA/2J）和其他肺癌易感（A/WySnJ、SWR/J）品系的检查表明，三种易感品系中COX-2 mRNA表达水平相似，而两种抗性品系中表达水平较低，表明II型细胞中COX-2表达与肺癌易感性之间可能存在相关性。在A/J肺肿瘤发育的所有阶段均观察到COX-2蛋白表达。在A/J肺肿瘤中也观察到蛋白表达的变化和偶尔缺失，特别是在腺瘤和腺癌中，这表明COX-2对于维持恶性表型不是必需的。支持这一结论 的是，用COX-2抑制剂处理源自恶性小鼠肺肿瘤的异种移植细胞系仅产生轻微的生长抑制。然而，COX-2在A/J小鼠肺早期病变中的频繁表达，加上在致癌物暴露前用COX-2抑制剂处理的动物中肿瘤数量已知减少，表明COX-2可能是肺癌化学预防的一个有前景的靶点。此外，肺癌敏感小鼠的正常肿瘤祖细胞中高水平的COX-2表达表明COX-2可能在肺癌易感性中起作用。
