Development of pulmonary bronchiolo-alveolar adenocarcinomas in transgenic mice overexpressing murine c-myc and epidermal growth factor in alveolar type II pneumocytes.
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.
Center for Medical Biotechnology, Fraunhofer Institute for Toxicology and Aerosol Research, Nikolai-Fuchs-Str. 1, 30625 Hannover, Germany.
A
A
Ehrhardt
T
T
Bartels
A
A
Geick
R
R
Klocke
D
D
Paul
R
R
Halter
D000230:Adenocarcinoma / Q000235:genetics*; D000818:Animals; D001984:Bronchial Neoplasms / Q000235:genetics*; D003001:Cloning, Molecular; D004815:Epidermal Growth Factor / Q000235:genetics*; D015870:Gene Expression; D016259:Genes, myc; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology
D004815:Epidermal Growth Factor