title: Neural tumor-initiating cells have distinct telomere maintenance and can be safely targeted for telomerase inhibition.
abstract: OBJECTIVE
  Cancer recurrence is one of the major setbacks in oncology. Maintaining telomeres is essential for sustaining the limitless replicative potential of such cancers. Because telomerase is thought to be active in all tumor cells and normal stem cells, telomerase inhibition may be nonspecific and have detrimental effects on tissue maintenance and development by affecting normal stem cell self-renewal.
  
  
  METHODS
  We examined telomerase activity, telomere maintenance, and stem cell maturation in tumor subpopulations from freshly resected gliomas, long-term, primary, neural tumor-initiating cells (TIC) and corresponding normal stem cell lines. We then tested the efficacy of the telomerase inhibitor Imetelstat on propagation and self-renewal capacity of TIC and normal stem cells in vitro and in vivo.
  
  
  RESULTS
  Telomerase was undetectable in the majority of tumor cells and specific to the TIC subpopulation that possessed critically short telomeres. In contrast, normal tissue stem cells had longer telomeres and undetectable telomerase activity and were insensitive to telomerase inhibition, which results in proliferation arrest, cell maturation, and DNA damage in neural TIC. Significant survival benefit and late tumor growth arrest of neuroblastoma TIC were observed in a xenograft model (P = 0.02). Furthermore, neural TIC exhibited irreversible loss of self-renewal and stem cell capabilities even after cessation of treatment in vitro and in vivo.
  
  
  CONCLUSIONS
  TIC exhaustion with telomerase inhibition and lack of telomerase dependency in normal stem cells add new dimensions to the telomere hypothesis and suggest that targeting TIC with telomerase inhibitors may represent a specific and safe therapeutic approach for tumors of neural origin.
authors.affiliation: The Arthur and Sonia Labatt Brain Tumor Research Centre, Cell Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Pedro
authors.initials: P
authors.lastname: Castelo-Branco
authors.forename: Cindy
authors.initials: C
authors.lastname: Zhang
authors.forename: Tatiana
authors.initials: T
authors.lastname: Lipman
authors.forename: Mayumi
authors.initials: M
authors.lastname: Fujitani
authors.forename: Loen
authors.initials: L
authors.lastname: Hansford
authors.forename: Ian
authors.initials: I
authors.lastname: Clarke
authors.forename: Calvin B
authors.initials: CB
authors.lastname: Harley
authors.forename: Robert
authors.initials: R
authors.lastname: Tressler
authors.forename: David
authors.initials: D
authors.lastname: Malkin
authors.forename: Erin
authors.initials: E
authors.lastname: Walker
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
authors.forename: Peter
authors.initials: P
authors.lastname: Dirks
authors.forename: Uri
authors.initials: U
authors.lastname: Tabori
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D005910:Glioma / Q000201:enzymology / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D009432:Neural Crest; D058953:Neural Stem Cells / Q000378:metabolism*; D009447:Neuroblastoma / Q000201:enzymology / Q000378:metabolism / Q000628:therapy*; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*
chemical_list: D019098:Telomerase