Neural Tumor-Initiating Cells Have Distinct Telomere Maintenance and Can be Safely Targeted for Telomerase Inhibition

Pedro Castelo-Branco, Cindy Zhang, Tatiana Lipman, Mayumi Fujitani, Loen Hansford, Ian Clarke, Calvin Harley, Robert Tressler, David Malkin, Erin Walker, David Kaplan, Peter Dirks, Uri Tabori

Research output: Contribution to journalArticle

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Abstract

Purpose: 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
Original languageEnglish
Pages (from-to)111-121
Number of pages11
JournalClinical Cancer Research
Volume17
Issue number1
DOIs
Publication statusPublished - 2011
Externally publishedYes

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Neoplastic Stem Cells
Telomerase
Telomere
Maintenance
Stem Cells
Neoplasms
Withholding Treatment
Neuroblastoma
Heterografts
Glioma
DNA Damage
Cell Proliferation
Recurrence
Cell Line

Cite this

Castelo-Branco, P., Zhang, C., Lipman, T., Fujitani, M., Hansford, L., Clarke, I., ... Tabori, U. (2011). Neural Tumor-Initiating Cells Have Distinct Telomere Maintenance and Can be Safely Targeted for Telomerase Inhibition. Clinical Cancer Research, 17(1), 111-121. https://doi.org/10.1158/1078-0432.CCR-10-2075
Castelo-Branco, Pedro ; Zhang, Cindy ; Lipman, Tatiana ; Fujitani, Mayumi ; Hansford, Loen ; Clarke, Ian ; Harley, Calvin ; Tressler, Robert ; Malkin, David ; Walker, Erin ; Kaplan, David ; Dirks, Peter ; Tabori, Uri. / Neural Tumor-Initiating Cells Have Distinct Telomere Maintenance and Can be Safely Targeted for Telomerase Inhibition. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 1. pp. 111-121.
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abstract = "Purpose: 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",
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Castelo-Branco, P, Zhang, C, Lipman, T, Fujitani, M, Hansford, L, Clarke, I, Harley, C, Tressler, R, Malkin, D, Walker, E, Kaplan, D, Dirks, P & Tabori, U 2011, 'Neural Tumor-Initiating Cells Have Distinct Telomere Maintenance and Can be Safely Targeted for Telomerase Inhibition', Clinical Cancer Research, vol. 17, no. 1, pp. 111-121. https://doi.org/10.1158/1078-0432.CCR-10-2075

Neural Tumor-Initiating Cells Have Distinct Telomere Maintenance and Can be Safely Targeted for Telomerase Inhibition. / Castelo-Branco, Pedro; Zhang, Cindy; Lipman, Tatiana; Fujitani, Mayumi; Hansford, Loen; Clarke, Ian; Harley, Calvin; Tressler, Robert; Malkin, David; Walker, Erin; Kaplan, David; Dirks, Peter; Tabori, Uri.

In: Clinical Cancer Research, Vol. 17, No. 1, 2011, p. 111-121.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Neural Tumor-Initiating Cells Have Distinct Telomere Maintenance and Can be Safely Targeted for Telomerase Inhibition

AU - Castelo-Branco, Pedro

AU - Zhang, Cindy

AU - Lipman, Tatiana

AU - Fujitani, Mayumi

AU - Hansford, Loen

AU - Clarke, Ian

AU - Harley, Calvin

AU - Tressler, Robert

AU - Malkin, David

AU - Walker, Erin

AU - Kaplan, David

AU - Dirks, Peter

AU - Tabori, Uri

PY - 2011

Y1 - 2011

N2 - Purpose: 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

AB - Purpose: 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

U2 - 10.1158/1078-0432.CCR-10-2075

DO - 10.1158/1078-0432.CCR-10-2075

M3 - Article

VL - 17

SP - 111

EP - 121

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 1

ER -