Abstract
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.
Highlights
Non-small cell lung cancer (NSCLC) accounts for,85% of lung cancers and most patients present with advanced disease [1]
To regulate gene activity in type II cells, we generated two mouse lines by (1) introducing CreER into the endogenous mouse SPC (Sftpc; surfactant associated protein C) locus via gene targeting [29] and (2) introducing rtTA into an SPC-containing bacterial artificial chromosome (BAC) for producing transgenic mice. This is based on the finding that SPC constitutes the major peptide in type II cells and is not present in other lung cell types [30] except the Significant proliferation of type II cells (SPC+)CC10+ bronchioalveolar stem cells (BASCs) at the bronchioalveolar duct junction (BADJ)
Our findings suggest that alveolar tumors induced by Kras/p53 perturbation were derived from alveolar type II cells and not BASCs
Summary
Non-small cell lung cancer (NSCLC) accounts for ,85% of lung cancers and most patients present with advanced disease [1]. Improvements in prognosis have been modest, with an overall 5-year survival rate of only 10–15% This is in sharp contrast to the drastically improved 5-year survival rates in patients afflicted by many other types of solid tumors such as breast or prostate cancer. These achievements are due to early diagnosis and effective treatment. This highlights an urgent need for basic research to identify the cells from which lung cancer originates and uncover the molecular basis of tumor development in order to design new therapies [5,6,7,8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
