Extensive Proliferation of Human Cancer Cells with Ever-Shorter Telomeres

Rebecca A Dagg; Hilda A Pickett; Axel A Neumann; Christine E Napier; Jeremy D Henson; Erdahl T Teber; Jonathan W Arthur; C Patrick Reynolds; Jayne Murray; Michelle Haber; Alexander P Sobinoff; Loretta M S Lau; Roger R Reddel

doi:10.1016/j.celrep.2017.05.087

Extensive Proliferation of Human Cancer Cells with Ever-Shorter Telomeres

Cell Rep. 2017 Jun 20;19(12):2544-2556. doi: 10.1016/j.celrep.2017.05.087.

Authors

Affiliations

¹ Children's Cancer Research Unit, The Children's Hospital at Westmead, University of Sydney, Westmead, NSW 2145, Australia.
² Telomere Length Regulation Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
³ Cancer Research Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
⁴ Cancer Cell Immortality Group, Adult Cancer Program, Prince of Wales Clinical School, University of New South Wales, Randwick, NSW 2052, Australia.
⁵ Bioinformatics Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
⁶ Cancer 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.
⁷ Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Australia, Randwick, NSW 2031, Australia.
⁸ Children'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.
⁹ Cancer Research Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia. Electronic address: rreddel@cmri.org.au.

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

Abstract

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.

Keywords: alternative lengthening of telomeres; ever-shorter telomeres; neuroblastoma; telomerase; telomeres.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cell Proliferation*
Enzyme Activation
Gene Amplification
Humans
N-Myc Proto-Oncogene Protein / genetics
Neuroblastoma / genetics
Neuroblastoma / pathology
Telomerase / metabolism
Telomere Shortening*

Substances

MYCN protein, human
N-Myc Proto-Oncogene Protein
Telomerase