A novel murine carcinogen-induced model recapitulates the progression and heterogeneity of human lung adenocarcinoma.

Abstract

Autochthonous murine models of lung adenocarcinoma, both genetically engineered and carcinogen-induced, show a different pattern of morphological progression when compared to human lung cancer. These models lack the accumulation of collagen in the alveolar wall and invasion of the underlying stroma, instead spreading to the air spaces as adenomas, a rare entity not associated with malignant transformation in human lungs. We developed new models of lung adenocarcinoma that more closely resemble the progression and heterogeneity of human lung cancer. These models are based on the administration of tobacco carcinogens, nicotine-derived nitrosamine ketone and benzo(a)pyrene, plus a single dose of bleomycin to induce lung fibrosis. We tested different protocols of carcinogen/bleomycin exposure in mice with lung-specific knockout of the tumor suppressor P53 induced by intranasal administration of an adenoviral vector encoding Cre recombinase. We found that these new models recapitulate more reliably the pattern of progression and the morphological heterogeneity of human lung adenocarcinoma.