Transgenic mice bearing the polyomavirus large T antigen directed by 2.1 kb of the Keratin 19 promoter develop bronchiolar papillary tumors with progression to lung adenocarcinomas

Abstract

Keratin 19 is an intermediate filament protein produced by cells of simple epithelia and basal cells of stratified epithelia of different organs. These cell types are associated with important human cancers. We have used the keratin 19 promoter to target the expression of the polyomavirus (Py) large T-antigen, an immortalizing oncogene known to bind to the tumor suppressor retinoblastoma gene product, to epithelial cells. Individuals of the transgenic mouse line K19PyLT-6 developed one or two nodules in one of their lungs. By histology, the nodules were papillary tumors that consisted of nonciliated epithelial cells of the terminal bronchioles. In addition, infiltrates emanating from the nodules were consistent with the development of pulmonary adenocarcinomas. In situ hybridization techniques demonstrated large T-antigen expression in the tumors. Primary cultures were established from a lung tumor dissected from a K19PyLT-6 transgenic mouse. These large T-antigen-expressing cell lines produced the keratin proteins reminiscent of the epithelial origin of the lung tumor. However, further molecular studies indicated that these cell lines did not express Clara cells or pneumocytes markers. s.c. injection of the cell lines into nontransgenic syngeneic mice produced tumors in 2 weeks that resembled malignant pulmonary adenocarcinomas. These animals, which display tumor progression in situ, and the cell lines derived thereof provide a useful system for the study of lung tumorigenesis.