Multiple pulmonary adenomas in the lung of transgenic mice overexpressing the RON receptor tyrosine kinase. Recepteur d'origine nantais.
The receptor tyrosine kinase RON (recepteur d'origine nantais), a member of the MET proto-oncogene family, has been implicated in the pathogenesis of certain epithelial cancers including lung adenocarcinomas. To determine the oncogenic potential of RON, transgenic mice were generated using the surfactant protein C promoter to express human wild-type RON in the distal lung epithelial cells. The mice were born normal without morphological defects in the lung, however, multiple lung adenomas with distinct morphology and growth pattern were observed. Tumors appeared as a single mass in the lung around 2 months of age and gradually developed into multiple nodules throughout the lung. Most of the tumors were characterized as cuboidal epithelial cells with type II cell phenotypes. They grew along the alveolar walls and projected into the alveolar septa. A transition from pre-malignant adenomas to adenocarcinomas was observed. The RON transgene is highly expressed and constitutively activated in the tumors as evident by immunohistochemical staining and western blot analyses. Moreover, we found that Ras expression was dramatically increased in the majority of tumors. However, no mutation in the 'hot spots' of the K-Ras or p53 gene was observed, although limited genomic instability occurs in individual tumors. Taken together, this is a mouse lung tumor model with unique biological characteristics. The model may provide an opportunity to study the role of RON in lung tumors and to elucidate the mechanisms underlying this distinct lung tumor.
Chen
Yi-Qing
YQ
Department of Medicine, University of Colorado School of Medicine, CU Cancer Center, and Denver Health Medical Center, Denver, CO 80204, USA.
Zhou
Yong-Qing
YQ
Fu
Lu-Hong
LH
Wang
Dong
D
Wang
Ming-Hai
MH
D000230:Adenocarcinoma / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D000236:Adenoma / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D003433:Crosses, Genetic; D018450:Disease Progression; D004847:Epithelial Cells / Q000473:pathology; D005813:Genes, Synthetic; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D037721:Pulmonary Surfactant-Associated Protein C; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases