Transgenic mouse models were established to study
tumorigenesis of
bronchiolo-alveolar adenocarcinomas derived from alveolar type II pneumocytes (AT-II cells). Transgenic lines expressing the murine oncogene c- myc under the control of the lung-specific
surfactant protein C promoter developed multifocal bronchiolo-alveolar
hyperplasias,
adenomas and
carcinomas respectively, whereas transgenic lines expressing a secretable form of the
epidermal growth factor (IgEGF), a structural and functional homologue of
transforming growth factor alpha (
TGF alpha), developed
hyperplasias of the alveolar epithelium. Since the oncogenes c- myc and
TGF alpha are frequently overexpressed in human lung
bronchiolo-alveolar adenocarcinomas, these mouse lines are useful as models for human lung
bronchiolo-alveolar adenocarcinomas. The average life expectancies of hemizygous and homozygous c- myc transgenics were 14.25 months and 9.2 months, respectively, suggesting that a dosage effect of c- myc caused an accelerated
bronchiolo-alveolar adenocarcinoma formation. First analyses of double transgenics, hemizygous for both c- myc and IgEGF, show that these mice develop
bronchiolo-alveolar adenocarcinomas at the average age of 9 months, indicating that these oncogenes cooperate during the
lung cancer formation. Our results demonstrate that c- myc and
EGF are directly involved and cooperate with one another during formation of
bronchiolo-alveolar adenocarcinomas in the lung.