Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes.
To investigate the role of an activated K-Ras gene in the initiation and maintenance of lung adenocarcinomas, we developed transgenic mice that express murine K-Ras4b(G12D) under the control of doxycycline in type II pneumocytes. Focal proliferative lesions of alveolar type II pneumocytes were observed as early as seven days after induction with doxycycline; after two months of induction, the lungs contained adenomas and adenocarcinomas, with focal invasion of the pleura at later stages. Removal of doxycycline caused a rapid fall in levels of mutant K-Ras RNA and concomitant apoptotic regression of both the early proliferative lesions and the tumors. Tumor burden was dramatically decreased by three days after withdrawal, and tumors were undetectable after one month. When similar experiments were performed with animals deficient in either the p53 gene or the Ink4A/Arf locus, tumors arose more quickly (within one month of exposure to doxycycline) and displayed more obvious histological features of malignancy; nevertheless, these tumors also regressed rapidly when the inducer was removed, implying that continued production of mutant K-Ras is necessary to maintain the viability of tumor cells in the absence as well as the presence of tumor suppressor genes. We also show that the appearance and regression of these pulmonary tumors can be readily monitored in anesthetized transgenic animals by magnetic resonance imaging.
Fisher
G H
GH
Varmus Laboratory, National Cancer Institute, Division of Basic Sciences, National Institutes of Health, Bethesda, Maryland 20892, USA.
Wellen
S L
SL
Klimstra
D
D
Lenczowski
J M
JM
Tichelaar
J W
JW
Lizak
M J
MJ
Whitsett
J A
JA
Koretsky
A
A
Varmus
H E
HE
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D001973:Bromodeoxyuridine; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D011905:Genes, ras / Q000235:genetics*; D005838:Genotype; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D009364:Neoplasm Recurrence, Local; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013752:Tetracycline / Q000494:pharmacology; D019076:Transgenes / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D016159:Tumor Suppressor Protein p53; D013752:Tetracycline; D001973:Bromodeoxyuridine