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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.
Cancer Res. 2006 Apr 01; 66(7):3584-92.CR

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+Show Affiliations

Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16585183

Citation

Brachner, Andreas, et al. "Telomerase- and Alternative Telomere Lengthening-independent Telomere Stabilization in a Metastasis-derived Human Non-small Cell Lung Cancer Cell Line: Effect of Ectopic HTERT." Cancer Research, vol. 66, no. 7, 2006, pp. 3584-92.
Brachner A, Sasgary S, Pirker C, et al. Telomerase- and alternative telomere lengthening-independent telomere stabilization in a metastasis-derived human non-small cell lung cancer cell line: effect of ectopic hTERT. Cancer Res. 2006;66(7):3584-92.
Brachner, A., Sasgary, S., Pirker, C., Rodgarkia, C., Mikula, M., Mikulits, W., Bergmeister, H., Setinek, U., Wieser, M., Chin, S. F., Caldas, C., Micksche, M., Cerni, C., & Berger, W. (2006). Telomerase- and alternative telomere lengthening-independent telomere stabilization in a metastasis-derived human non-small cell lung cancer cell line: effect of ectopic hTERT. Cancer Research, 66(7), 3584-92.
Brachner A, et al. Telomerase- and Alternative Telomere Lengthening-independent Telomere Stabilization in a Metastasis-derived Human Non-small Cell Lung Cancer Cell Line: Effect of Ectopic HTERT. Cancer Res. 2006 Apr 1;66(7):3584-92. PubMed PMID: 16585183.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Telomerase- and alternative telomere lengthening-independent telomere stabilization in a metastasis-derived human non-small cell lung cancer cell line: effect of ectopic hTERT. AU - Brachner,Andreas, AU - Sasgary,Soleman, AU - Pirker,Christine, AU - Rodgarkia,Chantal, AU - Mikula,Mario, AU - Mikulits,Wolfgang, AU - Bergmeister,Helga, AU - Setinek,Ulrike, AU - Wieser,Matthias, AU - Chin,Suet-Feung, AU - Caldas,Carlos, AU - Micksche,Michael, AU - Cerni,Christa, AU - Berger,Walter, PY - 2006/4/6/pubmed PY - 2006/5/23/medline PY - 2006/4/6/entrez SP - 3584 EP - 92 JF - Cancer research JO - Cancer Res. VL - 66 IS - 7 N2 - 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. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/16585183/Telomerase__and_alternative_telomere_lengthening_independent_telomere_stabilization_in_a_metastasis_derived_human_non_small_cell_lung_cancer_cell_line:_effect_of_ectopic_hTERT_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=16585183 DB - PRIME DP - Unbound Medicine ER -