THE ALVEOLAR TYPE-II CELL IS A PLURIPOTENTIAL STEM-CELL IN THE GENESIS OF HUMAN ADENOCARCINOMAS AND SQUAMOUS-CELL CARCINOMAS

Studies in a canine bronchogenic carcinoma model indicate that alveola r type II cells may differentiate from carcinogen-exposed epithelium o f larger bronchi and generate adenocarcinomas with bronchioloalveolar and other growth patterns. In this study, we investigated whether type II cells are one of the major proliferating cells (=stem cells) in th e genesis of two major subsets of bronchogenic carcinoma in humans. Ad enocarcinomas (17 bronchioloalveolar; 3 papillary; and 10 other) and s quamous cell carcinomas (n=27) as well as (pre)neoplastic lesions in a djacent bronchi and bronchioles were examined for the presence of type II cell markers and cellular proliferation markers (PCNA; Ki-67) usin g light and electron microscopy and immunohistochemistry. Distinctive features of type II cells, which do not depend upon the degree of cell maturity, are the approximately cuboid shape, large and roundish nucl eus, cytoplasmic staining for surfactant protein A (SP-A), and presenc e of multilamellar bodies or their precursory forms. Cells with this p henotype were found in early progressive (i.e., dysplastic, in situ, m icroinvasive) lesions in conducting airways and in all the carcinomas investigated, although with a much greater abundance among glandular l esions compared to squamous lesions. The most consistent sites of type II cells were the basal and adjacent epithelial layers. Nuclear PCNA (Ki-67) expression usually predominated in the same region. None of th e lesions displayed specific Clara cell features. Our findings strongl y suggest that the type LI cell is a pluripotential stem cell in human lung carcinogenesis. Based on our findings in humans and dogs, we pos tulate that type II tumor stem cells may originate from one of two sou rces: (1) normal bronchial epithelium (by an oncofetal mechanism of di fferentiation); and (2) normal alveolar type II cells.