Carcinogenesis Advance Access published online on May 9, 2003
Carcinogenesis, doi:10.1093/carcin/bgg076
© 2003 by Oxford University Press
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CANCER BIOLOGY
1 Department of Pathology, University of Washington, Seattle, WA
* Corresponding author. E-mail: petersr{at}u.washington.edu.
Received 6 September 2002
; revised 25 March 2003
; accepted 25 April 2003
As there has been no previous information on the consequences of telomerase expression in genetically altered, mortal cells derived from premalignant tissue, we sought to determine the effect of hTERT [human catalytic subunit of telomerase reverse transcriptase] transduction of premalignant cell strains from Barrett's esophagus that do not contain telomerase activity and possess a finite lifespan. Primary cultures of Barrett's esophageal epithelium transduced with a retrovirus containing hTERT were characterized by growth factor requirements, cytogenetics and flow cytometry. Expression of telomerase lengthened telomeres and greatly extended the lifespan of hTERT transduced (hTERT+) Barrett's esophagus cells. Growth factor dependency of the hTERT+ cultures remained largely similar to the parental cultures, although there was a modest increase in the ability to grow in agar. Chromosomal instability, measured by both karyotypic and FISH [Fluorescence in situ hybridization] analyses, was reduced but not abrogated by hTERT transduction, suggesting that telomerase expression can enhance genomic stability. However, the persistence of residual instability gave rise to new clonal and nonclonal genetic variants, and in one hTERT+ culture a new DNA aneuploid population was observed, the only time such a ploidy shift has been seen in Barrett's cell strains in vitro. These in vitro observations are analogous to the clinical progression to aneuploidy that often precedes cancer in Barrett's esophagus, and suggest that reactivation of telomerase may be permissive for continued genetic evolution to cancer. Long-lived Barrett's Esophagus epithelial cultures should provide a useful in vitro model for studies of neoplastic evolution and chemopreventive therapies.
Extended lifespan of Barrett's esophagus epithelium transduced with the human telomerase catalytic subunit: a useful in vitro model
2 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA
3 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Medicine, University of Washington, Seattle, WA; Department of Genetics, University of Washington, Seattle, WA
4 Department of Pediatrics, University of Washington, Seattle, WA
5 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
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