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
Affiliations
Rebecca A. Dagg
Children’s Cancer Research Unit, The Children’s Hospital at Westmead, University of Sydney, Westmead, NSW 2145, Australia
Hilda A. Pickett
Telomere Length Regulation Unit, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia
Axel A. Neumann
Cancer Research Unit, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia
Christine E. Napier
Cancer Research Unit, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia
Jeremy D. Henson
Cancer Cell Immortality Group, Adult Cancer Program, Prince of Wales Clinical School, University of New South Wales, Randwick, NSW 2052, Australia
Erdahl T. Teber
Bioinformatics Unit, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia
Jonathan W. Arthur
Bioinformatics Unit, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia
C. Patrick Reynolds
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
Jayne Murray
Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Australia, Randwick, NSW 2031, Australia
Michelle Haber
Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Australia, Randwick, NSW 2031, Australia
Alexander P. Sobinoff
Telomere Length Regulation Unit, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia
Loretta M.S. Lau
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
Roger R. Reddel
Cancer Research Unit, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia; Corresponding author
Summary: 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. : Dagg et al. find that a subset of highly malignant neuroblastomas (survival ∼50% despite intensive treatment) lack an effective telomere length maintenance mechanism. Their cells undergo continuous telomere shortening throughout >200 population doublings, challenging the concept that activation of a mechanism to prevent telomere shortening is essential for oncogenesis. Keywords: telomeres, ever-shorter telomeres, telomerase, alternative lengthening of telomeres, neuroblastoma
