Loss of p53 in craf-induced transgenic lung adenoma leads to tumor acceleration and phenotypic switch.
One of the most frequent malignancies in humans is lung adenocarcinoma.To develop novel diagnostic and therapeutic approaches for the management of this disease, animal models are required. We have used transgenic mice with lung-targeted expression of the CRaf kinase to evaluate genes altered frequently in human lung adenocarcinoma for their effect on tumor progression. Here we report that loss of p53 dramatically accelerates tumor development and induces a phenotypic switch in the target cell from cuboid to a nonciliated columnar morphology. Coexpression of lung epithelial cell markers surfactant protein C and Clara cell antigen suggests that tumor cell dedifferentiation could be involved in this process. The effect of p53 is specific, because loss of one of its target genes, p21(CIP1/WAF1), did not have this effect on cell phenotype although tumor latency was also reduced significantly. Neither loss of p53 nor p21 stimulated acquisition of the metastasis program beyond the stage of bronchiolar extension. This mouse model for pulmonary adenoma and adenocarcinoma should be very helpful for a better understanding of pathogenesis and treatment of this most deadly human cancer.
Institut für Medizinische Strahlenkunde und Zellforschung (MSZ), Bayerische Julius-Maximilians-Universität, D-97078 Würzburg, Germany.
Lev M
LM
Fedorov
Thomas
T
Papadopoulos
Oleg Y
OY
Tyrsin
Thomas
T
Twardzik
Rudolf
R
Götz
Ulf R
UR
Rapp
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000236:Adenoma / Q000235:genetics* / Q000473:pathology*; D000483:Alleles; D000818:Animals; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D017353:Gene Deletion; D005812:Genes, Switch / Q000235:genetics*; D016158:Genes, p53 / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019908:Proto-Oncogene Proteins c-raf