Lung cancer is the leading global cause of
cancer-related deaths. Although smoking cessation is the best preventive action, nearly 50% of all
lung cancer diagnoses occur in people who have already quit smoking. Research into treatment options for these high-risk patients has been constrained to rodent models of chemical
carcinogenesis, which are time-consuming, expensive, and require large numbers of animals. Here we show that embedding precision-cut lung slices within an engineered
hydrogel and exposing this tissue to a
carcinogen from cigarette
smoke creates an in vitro model of
lung cancer premalignancy.
Hydrogel formulations were selected to promote early
lung cancer cellular phenotypes and extend PCLS viability up to six weeks. In this study,
hydrogel-embedded lung slices were exposed to the cigarette
smoke derived
carcinogen vinyl carbamate, which induces
adenocarcinoma in mice. At six weeks, analysis of proliferation, gene expression, histology, tissue stiffness, and cellular content revealed that
vinyl carbamate induced the formation of premalignant lesions with a mixed
adenoma/squamous phenotype. Two putative
chemoprevention agents were able to freely diffuse through the
hydrogel and induce tissue-level changes. The design parameters selected using murine tissue were validated with
hydrogel-embedded human PCLS and results showed increased proliferation and premalignant lesion gene expression patterns. This tissue-engineered model of human
lung cancer premalignancy is the starting point for more sophisticated ex vivo models and a foundation for the study of
carcinogenesis and
chemoprevention strategies.