Carcinogenesis Advance Access published online on February 17, 2008
Carcinogenesis, doi:10.1093/carcin/bgn050
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Telomere dysfunction promotes genome instability and metastatic potential in a K-ras p53 mouse model of lung cancer
1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115
2 Center for Applied Cancer Science of the Belfer Institute for Innovative Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02115
3 Children's Hospital Stem Cell Program, Department of Genetics, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02115
4 Department of Pathology, Harvard Medical School, Boston, MA 02115
5 Department of Pathology and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390
6 Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, MA 02114
7 Department of Genetics and Medicine, Harvard Medical School, Boston, MA 02115
8 Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115
Correspondence: Kwok-Kin Wong, M.D., Ph.D., Department of Medical Oncology, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, D810, Boston, MA 02115, 617-632-6084, (Kwong1{at}partners.org)
Current mouse models of lung cancer recapitulate signature genetic lesions and some phenotypic features of human lung cancer. However, because mice have long telomeres, models to date do not recapitulate aspects of lung carcinogenesis—telomere attrition and the genomic instability that ensues—believed to serve as key mechanisms driving lung tumor initiation and progression. To explore the contributions of telomere dysfunction to lung cancer progression, we combined a telomerase catalytic subunit (mTerc) mutation with the well-characterized K-rasG12D mouse lung cancer model. K-rasG12D mTerc-/- mice with telomere dysfunction but intact p53 exhibited increased lung epithelial apoptosis, delayed tumor formation, and increased lifespan relative to K-rasG12D mTerc+/- mice with intact telomere function. This demonstrates that by itself, telomere dysfunction acts in a tumor suppressive mechanism. Introduction of a heterozygous p53 mutation exerted a marked histopathological, biological and genomic impact. K-rasG12D mTerc-/- p53+/- mice developed aggressive tumors with more chromosomal instabilities and high metastatic potential, leading to decreased overall survival. Thus, we have generated a murine model that more faithfully recapitulates key aspects of the human disease. Furthermore, these findings clearly demonstrate (in an in vivo model system) the dual nature of telomere shortening as both a tumor suppressive and tumor promoting mechanism in lung cancer, dependent on p53 status
Received December 20, 2007; revised February 4, 2008; accepted February 9, 2008.