title: Conditional expression of oncogenic C-RAF in mouse pulmonary epithelial cells reveals differential tumorigenesis and induction of autophagy leading to tumor regression.
abstract: Here we describe a novel conditional mouse lung tumor model for investigation of the pathogenesis of human lung cancer. On the basis of the frequent involvement of the Ras-RAF-MEK-ERK signaling pathway in human non-small cell lung carcinoma (NSCLC), we have explored the target cell availability, reversibility, and cell type specificity of transformation by oncogenic C-RAF. Targeting expression to alveolar type II cells or to Clara cells, the two likely precursors of human NSCLC, revealed differential tumorigenicity between these cells. Whereas expression of oncogenic C-RAF in alveolar type II cells readily induced multifocal macroscopic lung tumors independent of the developmental state, few tumors with type II pneumocytes features and incomplete penetrance were found when targeted to Clara cells. Induced tumors did not progress and were strictly dependent on the initiating oncogene. Deinduction of mice resulted in tumor regression due to autophagy rather than apoptosis. Induction of autophagic cell death in regressing lung tumors suggests the use of autophagy enhancers as a treatment choice for patients with NSCLC.
authors: Department of Molecular Biology, Max Planck Institute of Biochemistry, Martinsried, Germany. fceteci@biochem.mpg.de
authors: Fatih
authors: F
authors: Ceteci
authors: Jiajia
authors: J
authors: Xu
authors: Semra
authors: S
authors: Ceteci
authors: Emanuele
authors: E
authors: Zanucco
authors: Chitra
authors: C
authors: Thakur
authors: Ulf R
authors: UR
authors: Rapp
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology*; D014162:Transfection; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D019908:Proto-Oncogene Proteins c-raf