Apoptotic activity is increased in parallel with the metaplasia–dysplasia–carcinoma sequence of the bronchial epithelium

Abstract

Summary A high level of apoptotic activity and an independence of apoptosis from the expression of p53 and bcl-2 have been observed in non-small-cell lung carcinoma. We examined 44 samples of normal, metaplastic and premalignant (i.e. mild, moderate and severe dysplasias and carcinoma in situ) bronchial epithelia to evaluate whether differences in the apoptotic activity could already be seen in the stages preceding squamous cell carcinoma of the lung (SQCLC). Apoptotic cells and bodies were visualized by 3′ end labelling. The expression of p53 and members of the bcl-2 gene family, such as bcl-2, bax and mcl-1, were determined immunohistochemically with specific antibodies. The relative number of apoptotic cells and bodies [apoptotic index (AI%)] was already increased threefold as the normal bronchial epithelium changed to squamous metaplasia, and the AIs of the dysplastic lesions were about four times higher than those of the normal epithelium. Apoptosis was significantly associated with cell proliferation, as determined by proliferating cell nuclear antigen (PCNA) immunohistochemistry. However, the extent of apoptosis did not correlate with the expression of p53, bcl-2, bax and mcl-1. We conclude that, in the metaplasia-dysplasia-carcinoma sequence in the lung, the elevation of the AI% is an early event associated with cell proliferation activity, but is independent of the expression of p53, bcl-2, mcl-1 and bax.

Expression of Bax and Apoptosis-Related Proteins in Human Esophageal Squamous Cell Carcinoma Including Dysplasia

“…However, studies on the relationship between Bax immunoreactivity and AI in preneoplastic lesions are rare (21,23). In bronchial dysplasia, no correlation was found between expression of Bax protein and apoptotic activity (21). Interestingly, in the present study, in dysplasia, the AI in Bax-positive lesions was significantly higher than that in Bax-negative lesions, whereas there was no significant correlation between Bax expression and AI in cancerous regions.…”

“…Then, Krajewski et al reported that loss of Bax immunostaining was strongly associated with tumor progression and with shorter survival of patients with metastatic breast adenocarcinoma (20). In contrast, no association between expres-sion of Bax and increase of apoptosis was reported by another group (16,21). Thus, the nature of the correlation between apoptosis and Bax expression in vivo has remained controversial.…”

“…Krajewski et al reported that loss of Bax immunopositivity was strongly associated with tumor progression and shorter survival of patients with metastatic breast adenocarcinoma (20). On the other hand, there have been a number of recent studies finding no significant difference between Bax protein immunoreactivity and AI in either oral and oropharyngeal cancers or bronchial SCCs (16,21).…”

“…Several reports have described extent of AI in preneoplastic lesions in various types of tissue. However, studies on the relationship between Bax immunoreactivity and AI in preneoplastic lesions are rare (21,23). In bronchial dysplasia, no correlation was found between expression of Bax protein and apoptotic activity (21).…”

Expression of Minichromosome Maintenance 2 (MCM2), Ki-67, and Cell-Cycle-Related Molecules, and Apoptosis in the Normal-Dysplasia-Carcinoma Sequence of the Oral Mucosa

“…Moreover, the LI of the P21 and P27 cyclin-dependent kinase inhibitors obviously decreased in the SCCs compared to the dysplasias, the value being significantly different in P21, possibly implying a rather static nature and existence of the cell-cycle-dependent apoptosis in oral dysplasias. Similarly, Ishida et al [17], Birchall et al [18] and Tormanen et al [19] have demonstrated a higher apoptotic activity in premalignant gastric lesions, in dysplasias of the oral cavity, and in dysplasias of bronchial epithelia compared to corresponding invasive carcinomas.…”