ANALYSIS OF P21(WAF1 CIP1) EXPRESSION IN NORMAL, PREMALIGNANT, AND MALIGNANT-CELLS DURING THE DEVELOPMENT OF HUMAN LUNG ADENOCARCINOMA/

Our studies suggested that adenocarcinoma of the peripheral lung mostl y develops by several steps from atypical adenomatous hyperplasia thro ugh early adenocarcinoma to overt adenocarcinoma, and that some p53 ab normalities play an important role in this progression. In the present study, we examined by immunohistochemistry the expression of p53-indu cible cyclin-dependent kinase inhibitor p21(Waf1/Cip1) (p21) in the ce lls at various developmental stages of lung adenocarcinoma (32 lesions of adenomatous hyperplasia, 14 of early adenocarcinoma, 23 of well di fferentiated adenocarcinoma, and 17 of moderately or poorly differenti ated adenocarcinoma) in comparison with 19 reactive proliferative lesi ons and analyzed the relationship between p53 and p21 expression, Bron chioalveolar cells in the normal lung expressed very Little or no p21 and no p53 expression. In not only reactive but also neoplastic lesion s regardless of their developmental stage, the cells expressed p21 at various frequencies. The average labeling indices ranged from 5.4 to 1 3.8%, and there was no significant difference between any of these cat egories, The expression of p21, however, tended to be relatively low i n moderately and poorly differentiated adenocarcinomas (5.5%) compared to well differentiated adenocarcinomas (12.2%), and high-level p21 ex pressors (10% less than or equal to positive cells) were more frequent in the latter group (1 of 17 (6%) versus 8 of 23 (35%); P < 0.05), su ggesting that p21 expression is affected by the degree of differentiat ion of the neoplastic cells, Although the correlation was positive bet ween the expression of p21 and p53 in reactive lesions (r = 0.88; P < 0.001), none was found in neoplastic lesions at any step or grade (-0. 12 less than or equal to r less than or equal to 0.26), These results indicated that p21 expression depends upon p53 expression in reactive lung cells, whereas p21 expression is at least in part independent of that of p53 from the earliest to the most fully developed step of lung adenocarcinoma tumorigenesis, We concluded that disruption of the p53 -dependent cell cycle regulation is a very early event in the tumorige nesis of lung adenocarcinoma.