Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2014 Apr 1;111(13):4952-7. doi: 10.1073/pnas.1319963111. Epub 2014 Feb 28.

Multiple cells-of-origin of mutant K-Ras-induced mouse lung adenocarcinoma.

Author information

1
Division of Molecular Genetics, Centre for Biomedical Genetics, and Department of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.

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.

KEYWORDS:

BASCs; NSCLC; bronchioalveolar stem cells; non small cell lung cancer

Comment in

PMID:
24586047
PMCID:
PMC3977239
DOI:
10.1073/pnas.1319963111
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center