Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 1, Pages 255-260Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1320383110
Keywords
inflammation; genetically engineered mouse model; non-small cell lung cancer; lung stem cells
Categories
Funding
- European Research Council [ERC-AG/250297-RAS AHEAD]
- EU-Framework Programme [LSHG-CT-2007-037665/CHEMORES, HEALTH-F2-2010-259770/LUNGTARGET, HEALTH-2010-260791/EUROCANPLATFORM]
- Spanish Ministry of Economy and Competitiveness [SAF2011-30173]
- Autonomous Community of Madrid [S2011/BDM-2470/ONCOCYCLE]
- National Institutes of Health [R01 CA109335-04A1]
- Spanish Ministry of Economy and Competitivenes [SAF2012-32810]
- Fundacion La Caixa
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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.
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