TY - JOUR
T1 - The roles of telomerase in the generation of polyploidy during neoplastic cell growth
AU - Christodoulidou, Agni
AU - Raftopoulou, Christina
AU - Chiourea, Maria
AU - Papaioannou, George K.
AU - Hoshiyama, Hirotoshi
AU - Wright, Woodring E.
AU - Shay, Jerry W.
AU - Gagos, Sarantis
N1 - Funding Information:
Abbreviations: CIN, chromosomal instability in neoplasia; ALT, alternative lengthening of telomeres Address all correspondence to: Sarantis Gagos, PhD, Soranou Efessiou 4, Athens 11527, Greece. E-mail: sgagos@bioacademy.gr 1This work was supported by the Biomedical Research Foundation of the Academy of Athens (Athens, Greece), in an intramural funding for S.G., grant 05NON-EU-449 of the Greek Secretariat of Research of the Greek Ministry of Development, and the EU COST Action BM0703 “Cangenin.” The authors declare no competing financial interests. 2This article refers to supplementary materials, which are designated by Tables W1 and W2 and Figures W1 to W6 and are available online at www.neoplasia.com. Received 30 August 2012; Revised 30 November 2012; Accepted 3 December 2012 Copyright © 2013 Neoplasia Press, Inc. All rights reserved 1522-8002/13/$25.00 DOI 10.1593/neo.121398
Funding Information:
*Laboratory of Genetics and Gene Therapy, Center of Basic Research II, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; †Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX; ‡King Abdulaziz University, Center of Excellence in Genomic Medicince Research, Jeddah, Saudi Arabia
PY - 2013/2
Y1 - 2013/2
N2 - Polyploidy contributes to extensive intratumor genomic heterogeneity that characterizes advanced malignancies and is thought to limit the efficiency of current cancer therapies. It has been shown that telomere deprotection in p53-deficient mouse embryonic fibroblasts leads to high rates of polyploidization. We now show that tumor genome evolution through whole-genome duplication occurs in ~15% of the karyotyped human neoplasms and correlates with disease progression. In a panel of human cancer and transformed cell lines representing the two known types of genomic instability (chromosomal and microsatellite), as well as the two known pathways of telomere maintenance in cancer (telomerase activity and alternative lengthening of telomeres), telomere dysfunction-driven polyploidization occurred independently of the mutational status of p53. Depending on the preexisting context of telomere maintenance, telomerase activity and its major components, human telomerase reverse transcriptase (hTERT) and human telomerase RNA component (hTERC), exert both reverse transcriptase-related (canonical) and noncanonical functions to affect tumor genome evolution through suppression or induction of polyploidization. These new findings provide a more complete mechanistic understanding of cancer progression that may, in the future, lead to novel therapeutic interventions.
AB - Polyploidy contributes to extensive intratumor genomic heterogeneity that characterizes advanced malignancies and is thought to limit the efficiency of current cancer therapies. It has been shown that telomere deprotection in p53-deficient mouse embryonic fibroblasts leads to high rates of polyploidization. We now show that tumor genome evolution through whole-genome duplication occurs in ~15% of the karyotyped human neoplasms and correlates with disease progression. In a panel of human cancer and transformed cell lines representing the two known types of genomic instability (chromosomal and microsatellite), as well as the two known pathways of telomere maintenance in cancer (telomerase activity and alternative lengthening of telomeres), telomere dysfunction-driven polyploidization occurred independently of the mutational status of p53. Depending on the preexisting context of telomere maintenance, telomerase activity and its major components, human telomerase reverse transcriptase (hTERT) and human telomerase RNA component (hTERC), exert both reverse transcriptase-related (canonical) and noncanonical functions to affect tumor genome evolution through suppression or induction of polyploidization. These new findings provide a more complete mechanistic understanding of cancer progression that may, in the future, lead to novel therapeutic interventions.
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U2 - 10.1593/neo.121398
DO - 10.1593/neo.121398
M3 - Article
C2 - 23441130
AN - SCOPUS:84873499221
SN - 1522-8002
VL - 15
SP - 156
EP - 168
JO - Neoplasia (United States)
JF - Neoplasia (United States)
IS - 2
ER -