期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：13
页码：4952-4957
DOI：10.1073/pnas.1319963111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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-Raslox-Stop-lox-G12D/+ and K-Raslox-Stop-lox-G12D/+;tumor suppressor gene Trp53F/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.
关键词：non small cell lung cancer ; NSCLC ; bronchioalveolar stem cells ; BASCs
