title: Identification of cancer initiating cells in K-Ras driven lung adenocarcinoma.
abstract: Ubiquitous expression of a resident K-Ras(G12V) oncogene in adult mice revealed that most tissues are resistant to K-Ras oncogenic signals. Indeed, K-Ras(G12V) expression only induced overt tumors in lungs. To identify these transformation-permissive cells, we induced K-Ras(G12V) expression in a very limited number of adult lung cells (0.2%) and monitored their fate by X-Gal staining, a surrogate marker coexpressed with the K-Ras(G12V) oncoprotein. Four weeks later, 30% of these cells had proliferated to form small clusters. However, only SPC(+) alveolar type II (ATII) cells were able to form hyperplastic lesions, some of which progressed to adenomas and adenocarcinomas. In contrast, induction of K-Ras(G12V) expression in lung cells by intratracheal infection with adenoviral-Cre particles generated hyperplasias in all regions except the proximal airways. Bronchiolar and bronchioalveolar duct junction hyperplasias were primarily made of CC10(+) Clara cells. Some of them progressed to form benign adenomas. However, only alveolar hyperplasias, exclusively made up of SPC(+) ATII cells, progressed to yield malignant adenocarcinomas. Adenoviral infection induced inflammatory infiltrates primarily made of T and B cells. This inflammatory response was essential for the development of K-Ras(G12V)-driven bronchiolar hyperplasias and adenomas, but not for the generation of SPC(+) ATII lesions. Finally, activation of K-Ras(G12V) during embryonic development under the control of a Sca1 promoter yielded CC10(+), but not SPC(+), hyperplasias, and adenomas. These results, taken together, illustrate that different types of lung cells can generate benign lesions in response to K-Ras oncogenic signals. However, in adult mice, only SPC(+) ATII cells were able to yield malignant adenocarcinomas.
authors.affiliation: Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, 28029 Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Mainardi
authors.forename: Nieves
authors.initials: N
authors.lastname: Mijimolle
authors.forename: Sarah
authors.initials: S
authors.lastname: Francoz
authors.forename: Carolina
authors.initials: C
authors.lastname: Vicente-Dueñas
authors.forename: Isidro
authors.initials: I
authors.lastname: Sánchez-García
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbacid
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D000256:Adenoviridae / Q000378:metabolism; D000483:Alleles; D000818:Animals; D055745:Bronchioles / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D049109:Cell Proliferation; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D007249:Inflammation; D008168:Lung / Q000166:cytology*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009857:Oncogenes; D011401:Promoter Regions, Genetic; D011650:Pulmonary Alveoli / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D018631:ras Proteins
keywords: genetically engineered mouse model; inflammation; lung stem cells; non-small cell lung cancer