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Cited by 411Telomeres, Telomerase, and SenescenceCancer-related Molecular PathwaysGenetics, Aging, and Longevity in Model Organisms

Telomere dysfunction and tumour suppression: the senescence connection

Open access
Deng, Yibin, Chan, Suzanne S., Chang, Sandy·2008·Nature Reviews Cancer
DOI 10.1038/nrc2393PMC PMC3688269
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Abstract

Long-lived organisms such as humans have evolved several intrinsic tumour suppressor mechanisms to combat the slew of oncogenic somatic mutations that constantly arise in proliferating stem-cell compartments. One of these anticancer barriers is the telomere, a specialized nucleoprotein complex that caps the ends of eukaryotic chromosome. Impaired telomere function activates the canonical DNA damage response pathway that engages p53 to initiate apoptosis or replicative senescence. Here, we discuss how p53-dependent senescence induced by dysfunctional telomeres may be as potent as apoptosis in suppressing tumorigenesis in vivo.

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Written from the paper’s full text.

TL;DR

This review argues that dysfunctional telomeres activate a DNA damage response that engages p53-dependent apoptosis and replicative senescence, and that senescence can be as potent as apoptosis for suppressing tumorigenesis in vivo. Mouse models with short/dysfunctional telomeres show reduced tumor incidence and progression when p53 signaling is intact.

Key findings

  • Telomere dysfunction triggers a DDR through ATM/ATR, CHK1/CHK2, p53 and p21, leading to apoptosis or replicative senescence; dysfunctional telomeres form TIFs containing γ-H2AX, 53BP1, NBS1, MDC1 and CHK2.
  • In mouse cancer models, short dysfunctional telomeres suppress tumors when p53 is intact: G6 mTerc−/−;Ink4a−/− mice showed reduced tumor incidence from 64% to 31%; late-generation mTerc−/− mice produced 20-fold fewer skin tumors; late-generation mTerc−/− Eμ-myc mice had only 25% lymphoma incidence versus wild-type/early-generation mice developing B-cell lymphoma by 200 days.
  • p53-dependent apoptosis appears dispensable for spontaneous tumor suppression when senescence is activated: Bcl-2-overexpressing G5/6 mTerc−/− Eμ-myc bone marrow failed to produce tumors 100 days post-transplantation, with small encapsulated tumors showing a 3-fold decrease in mitotic index and positive SA-β-Gal, p16 and p15 staining.
  • In iG1 mTerc−/− p53R172P mice, which lack p53-dependent apoptosis but retain senescence, tumor formation was nearly completely suppressed: 0/23 tumors in p53P/+ and 1/9 in p53P/P mice, with robust SA-β-gal staining in multiple organs.

Methods

  • This is a Perspective/review synthesizing published experimental studies; no new primary data are reported.
  • Evidence comes largely from mouse models, including successive generations of telomerase knockout (mTerc−/−) mice, Eμ-myc lymphoma, p53 R172P knock-in, Ink4a−/−, ApcMin, hepatocellular carcinoma and skin carcinogenesis models, plus human cell lines and xenograft studies of telomerase inhibitors.
  • Main analysis compares tumor incidence, latency, survival, cytogenetic hallmarks of telomere dysfunction, DDR markers/TIFs, and senescence markers such as SA-β-gal, p16, p15, p21 and p53.

Limitations

  • Stated: anti-telomerase therapy requires an intact p53 pathway, but p53 is mutated in approximately 50% of human cancers; senescent tumor cells may secrete tumor-promoting products; and this therapy will not work in ALT tumors lacking functional telomerase.
  • Stated: the role of the p16Ink4a-RB pathway in the telomere DDR is unclear, and p21 loss in late-generation mTerc−/− mice did not increase chromosomal instability or tumorigenesis, suggesting redundancy or additional p53-dependent effects.
  • Evident: conclusions rely heavily on mouse models, with possible mouse–human differences in DDR wiring; the review also notes historical difficulty in reliably detecting senescent cells in vivo.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/nrc2393

Cites

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Statistics

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Claims the paper makes

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  • Premisenone given
    § Abstract

    In the setting of a competent p53 pathway, mouse models have shown that telomere shortening is tumor suppressive by promoting replicative senescence to inhibit tumor formation.

    “However, in the setting of a competent p53 pathway, mouse models have recently shown that telomere shortening is also tumor suppressive by promoting replicative senescence to inhibit tumor formation.”
    Quote in the paperSubstantial claim
  • Premisecitation
    § Abstract

    Replicative senescence is due largely to erosion of telomeres, the protective structures that cap the ends of eukaryotic chromosomes.

    “We now know that the endpoint of this proliferative limit, termed replicative senescence, is due largely to erosion of telomeres, protective structures that cap the end of all eukaryotic chromosomes.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349–352 (1998). source

      Not checked in the free run.

    • cites [4] Vaziri, H. & Benchimol, S. Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Curr. Biol. 8, 279–282 (1998). source

      Not checked in the free run.

  • Premisecitation
    § Abstract

    Dysfunctional telomeres activate upstream checkpoint PI3 kinases such as ATM or ATR.

    “Dysfunctional telomeres activate upstream checkpoint PI3 kinases, such as ATM (ataxia-telangiectasia mutated) or ATR (ataxia-telangiectasia and Rad3 related)22, 27-30”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [22] d'Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003). source

      Not checked in the free run.

    • cites [27] Guo, X. et al. Dysfunctional telomeres activate an ATM–ATR-dependent DNA damage response to suppress tumorigenesis. EMBO J. 26, 4709–4719 (2007). source

      Not checked in the free run.

    • cites [28] Churikov, D. & Price, C. M. Pot1 and cell cycle progression cooperate in telomere length regulation. Nature Struct. Mol. Biol. 15, 79–84 (2008). source

      Not checked in the free run.

  • Premisecitation
    § Abstract

    Telomere attrition contributes to tumorigenesis by promoting genome instability.

    “A large body of experimental evidence has demonstrated that telomere attrition contributes to tumorigenesis by promoting genome instability5.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Maser, R. S. & DePinho, R. A. Connecting chromosomes, crisis, and cancer. Science 297, 565–569 (2002). source

      Not checked in the free run.

  • Premisecitation
    § Abstract

    A total lifetime loss of approximately 2-4 kb in average telomere length has been observed in human cells.

    “A total lifetime loss of ~2-4 kb in average telomere length has been observed in human cells8-10.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [8] Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990). This report links increasing telomere attrition with increased cell divisions and advancing age, suggesting that telomere shortening may be the underlying mechanism of the Hayflick limit. source

      Not checked in the free run.

    • cites [9] Allsopp, R. C. et al. Telomere length predicts replicative capacity of human fibroblasts. Proc. Natl Acad. Sci. USA 89, 10114–10118 (1992). source

      Not checked in the free run.

    • cites [10] Harley, C. B. et al. Telomerase, cell immortality, and cancer. Cold Spring Harb. Symp. Quant. Biol. 59, 307–315 (1994). source

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  • May combine two claims. 38
  • Classified as probably not a substantial claim. 6
  • The quote only partly states this claim. 2

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    Premisecitation
    § Abstract

    Ectopic expression of telomerase in normal human somatic cells results in telomere elongation, abrogation of replicative senescence, a normal karyotype and cellular immortalization.

    “Activation of telomerase results in telomere elongation, abrogation of replicative senescence, a normal karyotype and cellular immortalization.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349–352 (1998). source

      Not checked in the free run.

    • cites [4] Vaziri, H. & Benchimol, S. Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Curr. Biol. 8, 279–282 (1998). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    Activated ATM/ATR phosphorylate CHK1 and CHK2, which phosphorylate p53; p53 phosphorylation displaces MDM2, liberating p53 from degradation and stimulating p21; p21 inhibits cell cycle progression by inhibiting cyclin-dependent kinases that phosphorylate and inactivate RB.

    “Once activated, these kinases phosphorylate downstream factors including CHK1 and CHK2 that in turn phosphorylates p5329. Phosphorylation of p53 results in the displacement of the murine double minute 2 (MDM2) protein, liberating p53 from degradation and stimulation of the expression of the cyclin-dependent kinase inhibitor p21. p21 inhibits cell cycle progression by inhibiting cyclin-dependent”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Gire, V., Roux, P., Wynford-Thomas, D., Brondello, J. M. & Dulic, V. DNA damage checkpoint kinase Chk2 triggers replicative senescence. EMBO J. 23, 2554–2563 (2004). source

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    Premisecitation
    § Abstract

    Fusions are the basis of genomic instability associated with telomere dysfunction, leading to anaphase bridging, breakage and repair; repetition leads to aneuploidy and further fusions, and loss of heterozygosity or gene amplification could result in tumorigenesis.

    “These fusions are the basis of genomic instability associated with telomere dysfunction as they lead to anaphase bridging, subsequent breakage and that requires further repair. Repetition of this fusion-bridge-breakage cycle leads to aneuploidy, further fusions and depending on how such DNA damage is resolved, it has been hypothesized that loss of heterozygosity or gene amplification could result”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] Maser, R. S. & DePinho, R. A. Connecting chromosomes, crisis, and cancer. Science 297, 565–569 (2002). source

      Not checked in the free run.

    • cites [21] DePinho, R. A. & Polyak, K. Cancer chromosomes in crisis. Nature Genet. 36, 932–934 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    Normal human diploid fibroblasts have an intrinsic proliferative limit; after 60-80 population doublings in culture they stop dividing and adopt a senescence phenotype.

    “After 60-80 population doublings in culture, HDFs stop dividing and adopt a phenotype characterized by large, flat cell size, a vacuolated morphology, inability to synthesize DNA, and the presence of the senescence-associated β-galactosidase (SA-β-gal) marker2.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961). A classic paper demonstrating that human cells have finite proliferative capacity in vitro (the 'Hayflick limit'). source

      Not checked in the free run.

    • cites [2] Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995). This paper reports on the SA-β-gal assay as a way to mark senescent cells. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    Mammalian telomeres associate with the shelterin complex of six core proteins: TRF1, TRF2, TIN2, POT1, TPP1 and RAP1.

    “Mammalian telomeres associate with the shelterin complex of six core proteins — telomeric-repeat binding factor 1 (TRF1), TRF2, TRF1 interacting protein 2 (TIN2), protection of telomeres 1 (POT1), the POT1 and TIN2 interacting protein TPP1 and the transcriptional repressor/activator protein RAP115, 16”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] de Lange, T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 19, 2100–2110 (2005). source

      Not checked in the free run.

    • cites [16] Liu, D., O'Connor, M. S., Qin, J. & Songyang, Z. Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins. J. Biol. Chem. 279, 51338–51342 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    Telomere length determines the proliferative lifespan of human diploid fibroblasts, and upregulation of telomerase activity restores proliferative capacity.

    “These results clearly demonstrate that telomere length determines the proliferative lifespan of HDFs, and that upregulation of telomerase activity (hence telomere length) restores proliferative capacity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    Both critically short telomeres and direct disruption of the shelterin structure can initiate telomere dysfunction, trigger a DNA damage response and chromosomal fusions.

    “These results suggest that both critically short telomeres and direct disruption of the shelterin structure can initiate telomere dysfunction, trigger a DDR and chromosomal fusions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    Human telomeres are only 8-12 kb or less at birth, so the lifetime attrition is significant and may elicit certain aspects of human aging phenotypes.

    “Considering that human telomeres are only 8-12 kb in length or less at birth, this degree of attrition is significant over the natural lifespan of humans, and may be responsible to elicit certain aspects of human aging phenotypes11.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Blasco, M. A. Telomere length, stem cells and aging. Nature Chem. Biol. 3, 640–649 (2007). source

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  • May combine two claims.

    Premisecitation
    § Abstract

    Telomeres that can no longer exert end-protective functions are dysfunctional, and these can arise from progressive telomere attrition or perturbation of shelterin components, resulting in inappropriate chromosomal end-to-end fusions through NHEJ or HR.

    “Telomeres that can no longer exert end-protective functions are said to be dysfunctional, and these telomeres could arise either from progressive telomere attrition, or when components of the shelterin complex are perturbed, resulting in inappropriate chromosomal end-to-end fusions through the non-homologous end joining (NHEJ) or homologous recombination (HR) DNA repair pathways 17.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Verdun, R. E. & Karlseder, J. Replication and protection of telomeres. Nature 447, 924–931 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    Telomerase expression is low or absent in most human somatic tissues, while it is robust in early proliferative progenitor germ and stem cells.

    “Telomerase expression is low or absent in most human somatic tissues6, while it is robust in early proliferative progenitor germ and stem cells 7, 8.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] Masutomi, K. et al. Telomerase maintains telomere structure in normal human cells. Cell 114, 241–253 (2003). source

      Not checked in the free run.

    • cites [7] Wright, W. E., Piatyszek, M. A., Rainey, W. E., Byrd, W. & Shay, J. W. Telomerase activity in human germline and embryonic tissues and cells. Dev. Genet. 18, 173–179 (1996). source

      Not checked in the free run.

    • cites [8] Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990). This report links increasing telomere attrition with increased cell divisions and advancing age, suggesting that telomere shortening may be the underlying mechanism of the Hayflick limit. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § Abstract

    Dysfunctional telomeres are recognized as DNA double-strand breaks that impinge upon p53 and/or pRB tumor suppressor pathways, inducing p21 and p16 Ink4a to initiate replicative senescence.

    “These results suggest that dysfunctional telomeres are recognized as DSBs that impinge upon p53 and/or pRB tumor suppressor pathways, to induce expression of their regulators p21 and p16 Ink4a to initiate replicative senescence24-26.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [24] Wright, W. E. & Shay, J. W. The two-stage mechanism controlling cellular senescence and immortalization. Exp. Gerontol. 27, 383–389 (1992). This paper documents that DNA damage checkpoint proteins such as p53 and RB are required for cells with shortened telomeres to undergo cellular senescence. Elimination of these proteins enables these cells to immortalize. source

      Not checked in the free run.

    • cites [25] Kamijo, T. et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91, 649–659 (1997). source

      Not checked in the free run.

    • cites [26] Sage, J., Miller, A. L., Perez-Mancera, P. A., Wysocki, J. M. & Jacks, T. Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature 424, 223–228 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    Human diploid fibroblasts that entered replicative senescence display molecular markers characteristic of cells bearing DNA double-strand breaks, suggesting dysfunctional telomeres elicit a potent DNA damage response.

    “Biochemical analyses revealed that HDFs that entered replicative senescence display molecular markers characteristic of cells bearing DNA double-strand breaks (DSBs), suggesting that dysfunctional telomeres elicit a potent DNA damage response (DDR)22.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] d'Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    Markers of the DNA damage response include phosphorylated γ-H2AX, 53BP1, NBS1, MDC1 and CHK2; many localize to dysfunctional telomeres to form TIFs, and their inactivation in senescent cells restores cell cycle progression into S-phase.

    “These markers of the DDR include phosphorylated γ-H2AX, 53BP1, NBS1, MDC1 and CHK2, among others. Many of these proteins localize directly to dysfunctional telomeres to form dysfunctional telomere-induced foci (TIFs), and their inactivation in senescent cells restores cell cycle progression into S-phase22, 23.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] d'Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003). source

      Not checked in the free run.

    • cites [23] Takai, H., Smogorzewska, A. & de Lange, T. DNA damage foci at dysfunctional telomeres. Curr. Biol. 13, 1549–1556 (2003). References 22 and 23 report that dysfunctional telomeres activate a DDR, resulting in the accumulation of DDR proteins at telomeres. Cells with dysfunctional telomeres enter into senescence by activating a p53-dependent checkpoint response. source

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  • May combine two claims.

    Premisecitation
    § Abstract

    The telomere 3′ single-stranded overhang can invade double-stranded telomeric tracts, displacing the homologous strand, forming a t-loop with a displacement loop at the invasion site.

    “Analysis of telomeres from a diverse array of organisms revealed that the telomere 3′ single-stranded overhang can invade the double-stranded telomeric tracts, displacing the homologous strand of the same telomere. Consequently, a telomere forms a lasso-like structure, termed the ‘t-loop’, with a displacement (D) loop at the invasion site12, 13”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Griffith, J. D. et al. Mammalian telomeres end in a large duplex loop. Cell 97, 503–514 (1999). source

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    • cites [13] de Lange, T. T-loops and the origin of telomeres. Nature Rev. Mol. Cell Biol. 5, 323–329 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    In late generation mTerc−/−, p21−/− mice, loss of p21 does not increase chromosomal instability nor tumorigenesis.

    “late generation mTerc−/−, p21−/− mice do not show increased chromosomal instability nor do they succumb to increased tumorigenesis61.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Choudhury, A. R. et al. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nature Genet. 39, 99–105 (2007). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation
    § Abstract

    The demonstration that dysfunctional telomeres could engage a senescence program to suppress tumorigenesis in vivo suggests possible future therapeutic applications.

    “The demonstration that dysfunctional telomeres could engage a senescence program to suppress tumorigenesis in vivo suggests possible future therapeutic applications63.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Harley, C. B. Telomerase and cancer therapeutics. Nature Rev. Cancer 8, 167–179 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    In mTerc−/−ApcMin mice, progression from micro to macroadenomas was inhibited in G6 animals, presumably due to activation of p53-dependent tumor suppressive pathways by dysfunctional telomeres.

    “These results suggest that progression from micro to macroadenomas was inhibited in G6 mTerc−/−ApcMin mice, presumably due to the activation of p53-dependent tumor suppressive pathways by dysfunctional telomeres.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    Replicative senescence and crisis provide potent barriers to tumor development, and proper telomere maintenance is an essential aspect of full malignant transformation.

    “Together, these observations support the view that replicative senescence and crisis provide potent barriers to tumor development and, by extension, that proper telomere maintenance is an essential aspect of full malignant transformation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    Treatment of G6-mTerc−/−;Ink4a−/− mice with short dysfunctional telomeres yielded a dramatic reduction in tumor incidence (from 64% to 31%) and much longer survival.

    “However, similar treatment of G6-mTerc−/−;Ink4a−/− mice with short dysfunctional telomeres yielded a dramatic reduction in tumor incidence (from 64% to 31%) and much longer survival49.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Greenberg, R. A. et al. Short dysfunctional telomeres impair tumorigenesis in the INK4aΔ2/3 cancer-prone mouse. Cell 97, 515–525 (1999). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    Telomere induced cellular senescence is capable of suppressing spontaneous tumorigenesis from mesenchymal tumors but is insufficient to suppress cancer formation of epithelial tissues such as the skin.

    “One explanation is that while telomere induced cellular senescence is capable of suppressing spontaneous tumorigenesis from mesenchymal tumors, it is insufficient to suppress cancer formation of epithelial tissues such as the skin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    Dysfunctional telomeres can also activate p53-dependent apoptosis, since mice bearing dysfunctional telomeres show increased apoptosis in proliferative cells.

    “In addition to promoting cell cycle arrest, dysfunctional telomeres can also activate p53-dependent apoptosis, since mice bearing dysfunctional telomeres show increased apoptosis in proliferative cells31-33.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [31] Lee, H. W. et al. Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569–574 (1998). source

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    • cites [32] Rudolph, K. L. et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96, 701–712 (1999). source

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    • cites [33] Rajaraman, S. et al. Telomere uncapping in progenitor cells with critical telomere shortening is coupled to S-phase progression in vivo. Proc. Natl Acad. Sci. USA 104, 17747–17752 (2007). source

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  • May combine two claims.

    Premisecitation
    § Abstract

    Removal of p53 function rescued many cellular defects despite critically short telomeres, including growth arrest in cell culture, testicular atrophy, intestinal and germ cell apoptosis.

    “Importantly, removal of p53 function rescued many of the cellular defects despite the presence of critically short telomeres, including growth arrest in cell culture, testicular atrophy, intestinal and germ cell apoptosis46.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Chin, L. et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527–538 (1999). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § Abstract

    Dysfunctional telomeres can activate a cellular senescence pathway to suppress tumorigenesis in the absence of apoptosis, while this pathway was not elicited in tumors with competent telomeres.

    “These results suggest that dysfunctional telomeres could activate a cellular senescence pathway to suppress tumorigenesis in the absence of apoptosis to suppress tumorigenesis, while this pathway was not elicited in the tumors with competent telomeres.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning
    § Abstract

    It is possible that p53-dependent but senescence- and apoptosis-independent effects of dysfunctional telomeres might account for some of the observed tumor suppression in vivo.

    “suggesting it is possible that p53-dependent but senescence- and apoptosis-independent effects of dysfunctional telomeres might account for some of the observed tumor suppression in vivo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    The telomerase deficient mouse lacks the critical RNA subunit mTerc, is viable, fertile and has no significant morphological abnormalities.

    “The telomerase deficient mouse lacks the critical RNA subunit mTerc, is viable, fertile and has no significant morphological abnormalities42.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Blasco, M. A. et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    Loss of p21 extended organismal lifespan and rescued cellular proliferative defects due to dysfunctional telomeres in late generation mTerc−/−, p21−/− mice.

    “Instead, loss of p21 extended organismal lifespan and rescued cellular proliferative defects due to dysfunctional telomeres, presumably due to reduced entry of proliferative cells into cellular senescence.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Choudhury, A. R. et al. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nature Genet. 39, 99–105 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    GRN163L is a modified oligonucleotide complementary to hTERC and a potent and specific telomerase antagonist.

    “GRN163L is a modified oligonucleotide complementary to hTERC and a potent and specific telomerase antagonist66.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Dikmen, Z. G. et al. In vivo inhibition of lung cancer by GRN163L: a novel human telomerase inhibitor. Cancer Res. 65, 7866–7873 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    Telomere dysfunction promotes the development of cancer in the setting of p53 deficiency, and an intact p53 pathway is important in tumor inhibition in the setting of telomere dysfunction.

    “Together, these findings demonstrate that telomere dysfunction promotes the development of cancer in the setting of p53 deficiency, and further reinforce the importance of an intact p53 pathway in tumor inhibition in the setting of telomere dysfunction.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Findings from mouse models of telomere dysfunction and cancer are informative about human tumor suppression and tumorigenesis.

  • May combine two claims.

    Premisecitation
    § Abstract

    Cells harboring the p53 R172P mutation are incapable of activating p53-dependent apoptosis, but the p53-dependent cellular senescence pathway is intact, as induction of telomere dysfunction through TRF2-DN led to reduced proliferation and senescent cells positive for SA-β-Gal.

    “Cells harboring this mutation (p53P/P) are incapable of activating p53-dependent apoptosis59, but the p53-dependent cellular senescence pathway is intact as induction of telomere dysfunction through overexpression of TRF2-DN in these cells led to dramatic reduction of cellular proliferation and the appearance of senescent cells that stain positive for SA-β-Gal58.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [58] Cosme-Blanco, W. et al. Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence. EMBO Rep. 8, 497–503 (2007). Using telomerase-knockout mouse models in a setting in which the apoptotic function of p53 is eliminated, references 57 and 58 document for the first time that activation of the cellular senescence programme could potently inhibit tumour initiation and progression in vivo. source

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    • cites [59] Liu, G. et al. Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice. Nature Genet. 36, 63–68 (2004). source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premiseown data
    § Abstract

    Transplantation of G5/6 mTerc−/−, Eμ-myc, Bcl-2 bone marrow failed to produce any tumors 100 days post-transplantation, while wild type and G1 produced palpable tumors within 6 weeks.

    “However, transplantation of G5/6 mTerc−/−, Eμ-myc, Bcl-2 bone marrow failed to produce any tumors 100 days post-transplantation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    TIF formation correlated with delocalization of POT1 and was antagonized by overexpression of POT1 or TRF2.

    “Interestingly, TIF formation correlated with delocalization of POT1 and was antagonized by overexpression of POT1 or TRF2.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Salvati, E. et al. Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect. J. Clin. Invest. 117, 3236–3247 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning
    § Abstract

    In vivo, progressive decline in telomere function correlated with increased tumor incidence and decreased survival.

    “Similar findings were observed in vivo, where the progressive decline in telomere function correlated with increased tumor incidence and decreased survival.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premiseown data
    § Abstract

    iG1 mTerc−/− p53P/+ and iG1 mTerc−/− p53P/P cells possessed a 6-8 fold increase in p-p arm fusions and a 3-fold increase in anaphase bridges, hallmarks of telomere dysfunction.

    “In contrast, iG1 mTerc−/− p53P/+ and iG1 mTerc−/− p53P/P cells possessed a 6-8 fold increase in p-p arm fusions and a 3-fold increase in the formation of anaphase bridges, both hallmarks of telomere dysfunction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    The upregulation of telomerase in most human cancers and its requirement for proliferation makes anti-telomerase compounds a potential means to induce telomere shortening and initiation of a senescence program in tumor cells.

    “The upregulation of telomerase in most human cancers and its requirement for proliferation makes anti-telomerase compounds a potential means to induce telomere shortening and initiation of a senescence program in tumor cells64.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Shay, J. W. & Keith, W. N. Targeting telomerase for cancer therapeutics. Br. J. Cancer 98, 677–683 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    p53 loss results in a permissive environment that favors proliferation and survival of genomically damaged cells and eventual progression to cancer.

    “Therefore, it is not surprising that p53 loss results in a permissive environment that favors proliferation and survival of genomically damaged cells and the eventual progression to cancer.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    Crisis serves as the second checkpoint in tumor suppression and is characterized by multiple chromosomal fusions.

    “Crisis serves as the second checkpoint in tumor suppression and is characterized by multiple chromosomal fusions36.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Counter, C. M. et al. Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J. 11, 1921–1929 (1992). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    Treatment of HT1080 fibrosarcoma cell lines with BIBR1532 results in progressive telomere shortening, induction of a senescence phenotype and inhibition of tumor growth when transplanted into recipient mice.

    “treatment of HT1080 fibrosarcoma cell lines with the telomerase inhibitor BIBR1532 results in progressive telomere shortening, induction of a senescence phenotype and inhibition of tumor growth when transplanted into recipient mice65.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Damm, K. et al. A highly selective telomerase inhibitor limiting human cancer cell proliferation. EMBO J. 20, 6958–6968 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    GRN163L effectively inhibits telomerase activity of various human cancer cell lines, resulting in progressive telomere shortening and induction of cellular senescence to suppress tumor cell growth in vitro.

    “GRN163L effectively inhibits telomerase activity of various human cancer cell lines67-70, resulting in progressive telomere shortening and induction of cellular senescence to suppress tumor cell growth in vitro.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [67] Djojosubroto, M. W. et al. Telomerase antagonists GRN163 and GRN163L inhibit tumor growth and increase chemosensitivity of human hepatoma. Hepatology 42, 1127–1136 (2005). source

      Not checked in the free run.

    • cites [68] Hochreiter, A. E. et al. Telomerase template antagonist GRN163L disrupts telomere maintenance, tumor growth, and metastasis of breast cancer. Clin. Cancer Res. 12, 3184–3192 (2006). source

      Not checked in the free run.

    • cites [69] Jackson, S. R. et al. Antiadhesive effects of GRN163L — an oligonucleotide N3′→P5′ thio-phosphoramidate targeting telomerase. Cancer Res. 67, 1121–1129 (2007). source

      Not checked in the free run.

    • cites [70] Ozawa, T. et al. Antitumor effects of specific telomerase inhibitor GRN163 in human glioblastoma xenografts. Neuro Oncol. 6, 218–226 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    In p53-competent mouse models of hepatocellular carcinoma, dysfunctional telomeres initiated tumor growth but limited tumor size by activating apoptosis.

    “Similar results were observed in p53-competent mouse models of hepatocellular carcinoma, in which dysfunctional telomeres served to initiate tumor growth, but also limited the size of these tumors (progression) by activating apoptosis53.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Farazi, P. A. et al. Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma. Cancer Res. 63, 5021–5027 (2003).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    Virally transformed human cells that eliminate p53 and/or pRB function can escape crisis at very low frequencies and invariably adopt telomere-maintenance programs: 80-90% of human tumors possess some telomerase activity, while the remainder maintain telomeres via ALT.

    “Virally transformed human cells that eliminate p53 and/or pRB function can escape crisis at very low frequencies, and invariably adopt telomere-maintenance programs: 80-90% of human tumors possess some telomerase activity, while the remainder maintain telomeres via a recombination-mediated process termed ALT (for Alternative Lengthening of Telomeres)37-40.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [37] Shay, J. W., Van Der Haegen, B. A., Ying, Y. & Wright, W. E. The frequency of immortalization of human fibroblasts and mammary epithelial cells transfected with SV40 large T-antigen. Exp. Cell Res. 209, 45–52 (1993). source

      Not checked in the free run.

    • cites [38] Kim, N. W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2015 (1994). source

      Not checked in the free run.

    • cites [39] Bryan, T. M., Englezou, A., Dalla-Pozza, L., Dunham, M. A. & Reddel, R. R. Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nature Med. 3, 1271–1274 (1997). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S4 (based). The quote only partly states this claim.

    Interpretationnone given
    § Abstract

    In carcinomas, activation of both senescence and apoptotic pathways are required to enforce tumor suppression.

    “In carcinomas, perhaps activation of both senescence and apoptotic pathways are required to enforce tumor suppression.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Conclusions

    Tumor cells rendered senescent would yield secretory products that might itself be tumor promoting.

    “One must also be concerned about the possibility that tumor cells rendered senescent would yield secretory products that might itself be tumor promoting77.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Krtolica, A., Parrinello, S., Lockett, S., Desprez, P. Y. & Campisi, J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc. Natl Acad. Sci. USA 98, 12072–12077 (2001). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given
    § Conclusions

    This therapy will not work in ALT tumors which lack functional telomerase.

    “Finally, this therapy will not work in ALT tumors which lack functional telomerase.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Conclusions

    Both telomere dysfunction and the DDR are activated at the earliest stages in many human carcinomas.

    “Recent observations indicate that both telomere dysfunction73, 74 and the DDR75, 76 are activated at the earliest stages in many human carcinomas.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [73] Chin, K. et al. In situ analyses of genome instability in breast cancer. Nature Genet. 36, 984–988 (2004). source

      Not checked in the free run.

    • cites [74] Meeker, A. K. et al. Telomere length abnormalities occur early in the initiation of epithelial carcinogenesis. Clin. Cancer Res. 10, 3317–3326 (2004). source

      Not checked in the free run.

    • cites [75] Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864–870 (2005). source

      Not checked in the free run.

    • cites [76] Gorgoulis, V. G. et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907–913 (2005). source

      Not checked in the free run.

44 of 44

  • The paper relies on this without support.

    Long-lived organisms such as humans have evolved intrinsic tumor suppressor mechanisms to combat oncogenic somatic mutations that arise in proliferating stem cell compartments.

    “Long lived organisms such as humans have evolved several intrinsic tumor suppressor mechanisms to combat the slew of oncogenic somatic mutations that constantly arise in proliferating stem cell compartments.”

  • The paper relies on this without support.

    Findings from mouse models of telomere dysfunction and cancer are informative about human tumor suppression and tumorigenesis.

    “late generation mTerc−/− p53+/− mice emerged with a tumor spectrum that strikingly resembled those of aged humans: carcinomas of the skin, breast, and intestine with cytogenetic hallmarks of telomere dysfunction emerged as the largest group of tumors47.”

  • The paper relies on this without support.

    p53 is mutated in approximately 50% of all human cancers.

    “p53 is mutated in approximately 50% of all human cancers.”

  • The paper relies on this without support.

    The G-rich strand of telomeric DNA can fold into a 4-stranded G-quadruplex (G4), whose stabilization perturbs telomere function.

    “The G-rich strand of telomeric DNA can fold into a 4-stranded G-quadruplex (G4), whose stabilization perturbs telomere function.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Most mouse studies have found short telomeres to protect against cancer rather than promote it.

    “although in most mouse studies, short telomeres have been found to be cancer-protective rather than cancer-promoting80.”

    From The telomere syndromes (2012) · cites this paper as [80]

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Authors
Deng, Y., Chan, S. S., & Chang, S.
Affiliations
The University of Texas MD Anderson Cancer Center (US)
Corresponding author
Chang, Sandy
ORCID
Venue
Nature Reviews Cancer
Publisher
Springer Science and Business Media LLC
Published
2008-06
Volume
8
Issue
6
Pages
450-458
ISSN
  • 1474-175X (ISSN-L)
  • 1474-1768
DOI
10.1038/nrc2393
PMC
PMC3688269
OpenAlex
W2036639619
Semantic Scholar
75f734a34472ae400620f2bd295550ba3267f262
Cited by
411
References
98
Citations by year
2026: 9 · 2025: 10 · 2024: 9 · 2023: 9 · 2022: 11 · 2021: 16 · 2020: 13 · 2019: 22 · 2018: 18 · 2017: 28 · 2016: 18 · 2015: 31 · 2014: 22 · 2013: 31 · 2012: 30
FWCI
4.85
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature reviews. Cancer (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Abraham J. and Phyllis Katz Foundation
  • National Institutes of Health
  • National Institute on Aging (R01AG028888)
  • National Cancer Institute (K01CA124461, R01CA129037)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
telomere dysfunction, replicative senescence, tumor suppression, apoptosis, DNA damage response, telomeres, carcinogenesis, stem cells
MeSH terms
Animals, DNA Damage, Humans, Neoplasms, Tumor Suppressor Protein p53, Retinoblastoma Protein, Telomere, Cellular Senescence, Apoptosis, Telomerase, Cyclin-Dependent Kinase Inhibitor p21

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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

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