Extensive Proliferation of Human Cancer Cells with Ever-Shorter Telomeres.

Author: Dagg RA1, Pickett HA2, Neumann AA3, Napier CE3, Henson JD4, Teber ET5, Arthur JW5, Reynolds CP6, Murray J7, Haber M7, Sobinoff AP2, Lau LMS8, Reddel RR9
Affiliation:
1Children's Cancer Research Unit, The Children's Hospital at Westmead, University of Sydney, Westmead, NSW 2145, Australia.
2Telomere Length Regulation Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
3Cancer Research Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
4Cancer Cell Immortality Group, Adult Cancer Program, Prince of Wales Clinical School, University of New South Wales, Randwick, NSW 2052, Australia.
5Bioinformatics Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
6Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
7Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Australia, Randwick, NSW 2031, Australia.
8Children's Cancer Research Unit, The Children's Hospital at Westmead, University of Sydney, Westmead, NSW 2145, Australia; Cancer Research Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
9Cancer Research Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia. Electronic address: rreddel@cmri.org.au.
Conference/Journal: Cell Rep.
Date published: 2017 Jun 20
Other: Volume ID: 19 , Issue ID: 12 , Pages: 2544-2556 , Special Notes: doi: 10.1016/j.celrep.2017.05.087. , Word Count: 173


Acquisition of replicative immortality is currently regarded as essential for malignant transformation. This is achieved by activating a telomere lengthening mechanism (TLM), either telomerase or alternative lengthening of telomeres, to counter normal telomere attrition. However, a substantial proportion of some cancer types, including glioblastomas, liposarcomas, retinoblastomas, and osteosarcomas, are reportedly TLM-negative. As serial samples of human tumors cannot usually be obtained to monitor telomere length changes, it has previously been impossible to determine whether tumors are truly TLM-deficient, there is a previously unrecognized TLM, or the assay results are false-negative. Here, we show that a subset of high-risk neuroblastomas (with ∼50% 5-year mortality) lacked significant TLM activity. Cancer cells derived from these highly aggressive tumors initially had long telomeres and proliferated for >200 population doublings with ever-shorter telomeres. This indicates that prevention of telomere shortening is not always required for oncogenesis, which has implications for inhibiting TLMs for cancer therapy.

Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

KEYWORDS: alternative lengthening of telomeres; ever-shorter telomeres; neuroblastoma; telomerase; telomeres

PMID: 28636942 DOI: 10.1016/j.celrep.2017.05.087

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