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[Cancer Research 64, 9027-9034, December 15, 2004]
© 2004 American Association for Cancer Research

Regular Articles

Immortalization of Human Bronchial Epithelial Cells in the Absence of Viral Oncoproteins

Ruben D. Ramirez1,2,7, Shelley Sheridan1, Luc Girard1, Mitsuo Sato1, Young Kim9, Jon Pollack9, Michael Peyton1, Ying Zou5, Jonathan M. Kurie8, J. Michael DiMaio6, Sara Milchgrub4, Alice L. Smith1,4, Rhonda F. Souza2,7, Laura Gilbey5, Xi Zhang7, Kenia Gandia7, Melville B. Vaughan5, Woodring E. Wright5, Adi F. Gazdar1,4, Jerry W. Shay5 and John D. Minna1,2,3

1 Hamon Center for Therapeutic Oncology Research and Departments of 2 Internal Medicine, 3 Pharmacology, 4 Pathology, 5 Cell Biology, and 6 Cardiovascular and Thoracic Surgery, The University of Texas Southwestern Medical Center, Dallas, Texas; 7 Dallas Veterans Affairs Medical Center, Dallas, Texas; 8 Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; and 9 Department of Pathology, Stanford University Medical Center, Stanford, California

By expressing two genes (hTERT and Cdk4), we have developed a method to reproducibly generate continuously replicating human bronchial epithelial cell (HBEC) lines that provide a novel resource to study the molecular pathogenesis of lung cancer and the differentiation of bronchial epithelial cells. Twelve human bronchial epithelial biopsy specimens obtained from persons with and without lung cancer were placed into short-term culture and serially transfected with retroviral constructs containing cyclin-dependent kinase (Cdk) 4 and human telomerase reverse transcriptase (hTERT), resulting in continuously growing cultures. The order of introduction of Cdk4 and hTERT did not appear to be important; however, transfection of either gene alone did not result in immortalization. Although they could be cloned, the immortalized bronchial cells did not form colonies in soft agar or tumors in nude mice. The immortalized HBECs have epithelial morphology; express epithelial markers cytokeratins 7, 14, 17, and 19, the stem cell marker p63, and high levels of p16INK4a; and have an intact p53 checkpoint pathway. Cytogenetic analysis and array comparative genomic hybridization profiling show immortalized HBECs to have duplication of parts of chromosomes 5 and 20. Microarray gene expression profiling demonstrates that the Cdk4/hTERT-immortalized bronchial cell lines clustered together and with nonimmortalized bronchial cells, distinct from lung cancer cell lines. We also immortalized several parental cultures with viral oncoproteins human papilloma virus type 16 E6/E7 with and without hTERT, and these cells exhibited loss of the p53 checkpoint and significantly different gene expression profiles compared with Cdk4/hTERT-immortalized HBECs. These HBEC lines are a valuable new tool for studying of the pathogenesis of lung cancer.




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