Alveolar type II cells possess the capability of initiating lung tumor development

Identifying cells of tumor origin is a fundamental question in tumor biology. Answers to this central question will not only advance our understanding of tumor initiation and progression but also have important therapeutic implications. In this study, we aimed to uncover the cells of origin of lung...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2012-12, Vol.7 (12), p.e53817
Main Authors: Lin, Chuwen, Song, Hai, Huang, Cecilia, Yao, Erica, Gacayan, Rhodora, Xu, Shan-Mei, Chuang, Pao-Tien
Format: Article
Language:English
Subjects:
Adenocarcinoma
Adenocarcinoma - genetics
Adenocarcinoma - pathology
Alveoli
Analysis
Animal models
Animals
Artificial chromosomes
Biology
Cancer
Cell Line, Tumor
Cell Transformation, Neoplastic - pathology
Cells, Cultured
Development and progression
Drug resistance
Embryos
Epidermal growth factors
Genes, p53 - physiology
Genes, ras - physiology
Health aspects
Humans
K-Ras protein
Laboratories
Lung cancer
Lung diseases
Lung Neoplasms - genetics
Lung Neoplasms - pathology
Medical prognosis
Mice
Mice, Transgenic
Molecular modelling
Mutation
Mutation - physiology
Neoplastic Stem Cells - pathology
Non-small cell lung cancer
Non-small cell lung carcinoma
p53 Protein
Physiology
Protein C
Pulmonary Alveoli - pathology
Rodents
Signaling
Stem cell transplantation
Stem cells
Surface active agents
Surfactants
Tumor proteins
Tumor removal
Tumor suppressor genes
Tumors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Identifying cells of tumor origin is a fundamental question in tumor biology. Answers to this central question will not only advance our understanding of tumor initiation and progression but also have important therapeutic implications. In this study, we aimed to uncover the cells of origin of lung adenocarcinoma, a major subtype of non-small cell lung cancer. To this end, we developed new mouse models of lung adenocarcinoma that enabled selective manipulation of gene activity in surfactant associated protein C (SPC)-expressing cells, including alveolar type II cells and bronchioalveolar stem cells (BASCs) that reside at the bronchioalveolar duct junction (BADJ). Our findings showed that activation of oncogenic Kras alone or in combination with the removal of the tumor suppressor p53 in SPC⁺ cells resulted in development of alveolar tumors. Similarly, sustained EGF signaling in SPC⁺ cells led to alveolar tumors. By contrast, BASCs failed to proliferate or produce tumors under these conditions. Importantly, in a mouse strain in which Kras/p53 activity was selectively altered in type II cells but not BASCs, alveolar tumors developed while BADJs retained normal architecture. These results confirm and extend previous findings and support a model in which lung adenocarcinoma can initiate in alveolar type II cells. Our results establish the foundation for elucidating the molecular mechanisms by which lung cancer initiates and progresses in a specific lung cell type.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0053817