Telomerase- and alternative telomere lengthening-independent telomere stabilization in a metastasis-derived human non-small cell lung cancer cell line: effect of ectopic hTERT.

Abstract

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 homogeneously 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 ( approximately 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.

• Authors: Andreas Brachner, Soleman Sasgary, Christine Pirker, Chantal Rodgarkia, Mario Mikula, Wolfgang Mikulits, Helga Bergmeister, Ulrike Setinek, Matthias Wieser, Suet-Feung Chin, Carlos Caldas, Michael Micksche, Christa Cerni, Walter Berger
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 7 Pg. 3584-92 (Apr 01 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16585183 (Publication Type: Journal Article)

Chemical References

• DNA-Binding Proteins
• Telomerase

Topics

• Animals
• Carcinoma, Non-Small-Cell Lung (enzymology, genetics, pathology)
• Cell Growth Processes (genetics)
• Cell Line, Tumor
• DNA-Binding Proteins (biosynthesis, genetics, pharmacology, physiology)
• HeLa Cells
• Humans
• Lung Neoplasms (enzymology, genetics, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mice, SCID
• Telomerase (biosynthesis, deficiency, genetics, metabolism, pharmacology, physiology)
• Telomere
• Transfection