title: Multiple cells-of-origin of mutant K-Ras-induced mouse lung adenocarcinoma.
abstract: Much controversy surrounds the cell-of-origin of mutant K-Ras (K-RasG12D)-induced lung adenocarcinoma. To shed light on this issue, we have used technology that enables us to conditionally target K-RasG12D expression in Surfactant Protein C (SPC)(+) alveolar type 2 cells and in Clara cell antigen 10 (CC10)(+) Clara cells by use of cell-type-restricted recombinant Adeno-Cre viruses. Experiments were performed both in the presence and absence of the tumor suppressor gene p53, enabling us to assess what effect the cell-of-origin and the introduced genetic lesions have on the phenotypic characteristics of the resulting adenocarcinomas. We conclude that both SPC-expressing alveolar type 2 cells and CC10-expressing Clara cells have the ability to initiate malignant transformation following the introduction of these genetic alterations. The lungs of K-Ras(lox-Stop-lox-G12D/+) and K-Ras(lox-Stop-lox-G12D/+);tumor suppressor gene Trp53(F/F) mice infected with Adeno5-SPC-Cre and Adeno5-CC10-Cre viruses displayed differences in their tumor spectrum, indicating distinct cellular routes of tumor initiation. Moreover, using a multicolor Cre reporter line, we demonstrate that the resulting tumors arise from a clonal expansion of switched cells. Taken together, these results indicate that there are multiple cellular paths to K-RasG12D-induced adenocarcinoma and that the initiating cell influences the histopathological phenotype of the tumors that arise.
authors.affiliation: Division of Molecular Genetics, Centre for Biomedical Genetics, and Department of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Kate D
authors.initials: KD
authors.lastname: Sutherland
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Song
authors.forename: Min Chul
authors.initials: MC
authors.lastname: Kwon
authors.forename: Natalie
authors.initials: N
authors.lastname: Proost
authors.forename: John
authors.initials: J
authors.lastname: Zevenhoven
authors.forename: Anton
authors.initials: A
authors.lastname: Berns
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D002999:Clone Cells; D018450:Disease Progression; D005822:Genetic Vectors; D007150:Immunohistochemistry; D019426:Integrases / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D011230:Precancerous Conditions / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011995:Recombination, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014598:Uteroglobin / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; C556390:Scgb1a1 protein, mouse; D016159:Tumor Suppressor Protein p53; D014598:Uteroglobin; C045073:Cre recombinase; D019426:Integrases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: BASCs; NSCLC; bronchioalveolar stem cells; non small cell lung cancer