The alveolar type II cell is a pluripotential stem cell in the genesis of human adenocarcinomas and squamous cell carcinomas

Abstract

Studies in a canine bronchogenic carcinoma model indicate that alveolar type 11 cells may differentiate from carcinogen-exposed epithelium of larger bronchi and generate adenocarcinomas with bronchioloalveolar and other growth patterns. In this study, we investigated whether type 11 cells are one of the major proliferating cells (=stem cells) in the genesis of two major subsets of bronchogenic carcinoma in humans. Adenocarcinomas (17 bronchioloalveolar; 3 papillary; and 10 other) and squamous cell carcinomas (n=27) as well as (pre)neoplastic lesions in adjacent bronchi and bronchioles were examined for the presence of type 11 cell markers and cellular proliferation markers (PCNA; Ki-67) using light and electron microscopy and immunohistochemistry. Distinctive features of type 11 cells, which do not depend upon the degree of cell maturity, are the approximately cuboid shape, large and roundish nucleus, cytoplasmic staining for surfactant protein A (SP-A), and presence of multilamellar bodies or their precursory forms. Cells with this phenotype were found in early progressive (i.e., dysplastic, in situ, microinvasive) lesions in conducting airways and in al1 the carcinomas investigated, although with a much greater abundance among glandular lesions compared to squamous lesions. The most consistent sites of type 11 cells were the basal and adjacent epithelial layers. Nuclear PCNA (Ki-67) expression usually predominated in the same region. None of the lesions displayed specific Clara cell features. Our findings strongly suggest that the type 11 cell is a pluripotential stem cell in human lung carcinogenesis. Based on our findings in humans and dogs, we postulate that type 11 tumor stem cells may originate from one of two sources: (1) normal bronchial epithelium (by an oncofetal mechanism of differentiation); and (2) normal alveolar type 11 cells.