Multiple cells-of-origin of mutant K-Ras-induced mouse lung adenocarcinoma.
- Author(s)
- Sutherland, KD; Song, JY; Kwon, MC; Proost, N; Zevenhoven, J; Berns, A;
- Details
- Publication Year 2014-04-01,Volume 111,Issue #13,Page 4952-7
- Journal Title
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type
- Journal Article
- 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.
- Research Division(s)
- Stem Cells And Cancer
- PubMed ID
- 24586047
- Publisher's Version
- https://doi.org/10.1073/pnas.1319963111
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2016-01-25 09:00:35
Last Modified: 2016-01-25 09:02:31