Development of an experimental model for human tracheobronchial carcinogenesis and a new method for early detection of tumor progression of malignant cell lines derived from human lung cancer using de-epithelialized rat tracheas xenotransplanted into nude

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Normal human tracheobronchial epithelial cells obtained by tissue culture from nine donors were used to repopulate de-epithelialized rat tracheas. After reconstruction of rat tracheas transplanted into nude mice, beeswax pellets contained 100ug 7, 12-dimethylbenz[a]anthracene (DMBA) were inserted into those lumina. Epithelial cells from DMBA-treated tracheas were subculturable., whereas epithelial cells from most untreated tracheas were not subculturable. After in vivo treatment with DMBA, those cells did not terminally differentiate even in medium containing 8% serum. Karyotypes from these cells showed considerable aneuploidy. Although these cells did not survive for more than 10 subcultures (42 weeks), this was considerably longer-than the survival of control cells. Because of their longer survival, resistance to serum-induced terminal differentlation and chromosome alterations, they were considered to be phenotypically altered or partially transformed cells produced by in vivo treatment of human cells with a chemical carcinogen.The human lung tumor-derived three adenocarcinoma cell lines which were established in this project were also inoculated into de-epithelialized rat tracheas, and xenotransplanted into nude mice. At early stage of cell proliferations, three different cell types which were bronchial surface epithelium-like, clara cell-like, and goblet cell-like were observed and three preneoplastic lesions which were tubular, papillar, and cribriform progressions were also observed respectively.In this "In Vivo Culture System", the process of human tracheobronchial carcinogenesis and very early stage of cancer progression in tracheobrochial epithelium will be possively observed in our further study. These investigations will also make it possible earlyer and more accurate detection of tracheobronchial carcinoma clinically.