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Telomerase- and Alternative Telomere Lengthening–Independent Telomere Stabilization in a Metastasis-Derived Human Non–Small Cell Lung Cancer Cell Line: Effect of Ectopic hTERT

Andreas Brachner¹, Soleman Sasgary¹, Christine Pirker¹, Chantal Rodgarkia¹, Mario Mikula¹, Wolfgang Mikulits¹, Helga Bergmeister², Ulrike Setinek³, Matthias Wieser¹, Suet-Feung Chin⁴, Carlos Caldas⁴, Michael Micksche¹, Christa Cerni^1, and Walter Berger¹

¹ Department of Medicine I, Institute of Cancer Research, and ² Institute of Biomedical Research, Medical University of Vienna; ³ Institute for Pathology and Bacteriology, Otto Wagner Hospital Baumgartner Höhe, Vienna, Austria and ⁴ Cancer Genomics Program, Department of Oncology, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, United Kingdom

Requests for reprints: Walter Berger, Department of Medicine I, Institute of Cancer Research, Medical University Vienna, Borschkegasse 8a, A-1090 Wien, Austria. Phone: 43-1-4277-65245; Fax: 43-1-4277-9651; E-mail: walter.berger{at}meduniwien.ac.at.

In the majority of human malignancies, maintenance of telomeres is achieved by reactivation of telomerase, whereas a smaller fraction uses an alternative telomere lengthening (ALT) mechanism. Here, we used 16 non–small cell lung cancer (NSCLC) cell lines to investigate telomere stabilization mechanisms and their effect on tumor aggressiveness. Three of 16 NSCLC cell lines (VL-9, SK-LU-1, and VL-7) lacked telomerase activity, correlating with significantly reduced tumorigenicity in vitro and in vivo. Of the three telomerase-negative cell lines, only SK-LU-1 displayed characteristics of an ALT mechanism (i.e., highly heterogeneous telomeres and ALT-associated promyelocytic leukemia bodies). VL-9 cells gained telomerase during in vitro propagation, indicating incomplete immortalization in vivo. In contrast, NSCLC metastasis-derived VL-7 cells remained telomerase and ALT negative up to high passage numbers and following transplantation in severe combined immunodeficient mice. Telomeres of VL-7 cells were homogenously short, and chromosomal instability (CIN) was comparable with most telomerase-positive cell lines. This indicates the presence of an efficient telomere stabilization mechanism different from telomerase and ALT in VL-7 cells. To test the effect of ectopic telomerase reverse transcriptase (hTERT) in these unique ALT- and telomerase-negative tumor backgrounds, hTERT was transfected into VL-7 cells. The activation of telomerase led to an excessively rapid gain of telomeric sequences resulting in very long (14 kb), uniform telomeres. Additionally, hTERT expression induced a more aggressive growth behavior in vitro and in vivo without altering the level of CIN. These data provide further evidence for a direct oncogenic activity of hTERT not based on the inhibition of CIN. (Cancer Res 2006; 66(7): 3584-92)