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Cited by 469Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsTGF-β signaling in diseases

Inside and out: the activities of senescence in cancer

Open access
Pérez-Mancera, Pedro A., Young, Andrew R. J., Narita, Masashi·2014·Nature Reviews Cancer
DOI 10.1038/nrc3773
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Abstract

The core aspect of the senescent phenotype is a stable state of cell cycle arrest. However, this is a disguise that conceals a highly active metabolic cell state with diverse functionality. Both the cell-autonomous and the non-cell-autonomous activities of senescent cells create spatiotemporally dynamic and context-dependent tissue reactions. For example, the senescence-associated secretory phenotype (SASP) provokes not only tumour-suppressive but also tumour-promoting responses. Senescence is now increasingly considered to be an integrated and widespread component that is potentially important for tumour development, tumour suppression and the response to therapy.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that senescence is more than a stable proliferative arrest: senescent cells remain metabolically active and communicate with their surroundings through secreted factors. It surveys how these cell-intrinsic and cell-extrinsic activities can suppress or promote cancer depending on context, with implications for therapy.

Key findings

  • Senescence is heterogeneous and usually involves p53 and RB pathways, alongside telomere shortening/DNA damage responses, autophagy, metabolic shifts, altered secretion, and epigenetic regulation; multiple markers are needed for confident identification.
  • In oncogene-induced and therapy-induced senescence, mitochondrial oxidative phosphorylation can be hyperactive. PDH activity rises in BRAF-V600E- or RAS-G12V-driven senescence; reducing PDH blocks BRAF-V600E senescence, while activating PDH is sufficient to induce senescence in normal cells. In human melanoma, roughly 10% of tumours had above-average PGC1α expression, and MITF/PGC1α-expressing melanoma cells were more resistant to oxidative stress and associated with poor prognosis.
  • Autophagy is activated during senescence and can support SASP components such as IL-6 and IL-8, but its role varies by context; blocking autophagy can delay senescence, cause cell death, or exacerbate senescence depending on the model.
  • The SASP can reinforce or spread senescence, recruit innate and adaptive immune cells to clear senescent cells, or promote tumorigenesis. Examples include NK-cell-mediated clearance via NKG2D–RAE1 and CD4+ T-cell-dependent senescence surveillance; stromal senescence can limit fibrosis and hepatocellular carcinoma in some models but promote hepatocellular carcinoma in an obesity/deoxycholic acid model.

Methods

  • Narrative review; no primary experimental design, dataset, or statistical analysis is reported.
  • The paper synthesizes published in vitro, mouse-model, and human tumour studies across pre-neoplasia, therapy-induced senescence, metabolism, autophagy, SASP, immune clearance, stromal senescence, and cytokine-mediated senescence.
  • Data or sample: Not stated in the paper (no new data collected).

Limitations

  • The paper states that many mechanisms remain unclear and context-dependent, including why mitochondrial dysfunction versus hyperactive respiration is observed, why stromal SASP effects differ between models, and how autophagy acts differently across tissues; further study is needed.
  • Evident from the text: as a review, it does not describe a systematic search or quantitative synthesis, and its conclusions depend on heterogeneous models and contexts.
  • Evident from the text: several sections contain editorial queries and incomplete figure/table formatting, which limits clarity but does not alter the scientific claims summarized.

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

Integrity signals

Registry

Crossref · 10.1038/nrc3773

Cites

167 of 167 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 151 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Senescent cells can exhibit hyperactive mitochondrial respiration in some contexts.

    “senescent cells can exhibit hyperactive mitochondrial respiration (oxidative phosphorylation ) in some contexts.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [41] Kaplon, J. et al. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 498, 109–112 (2013). This study established the metabolic profile of OIS cells, identifying active PDH with increased mitochondrial respiration during OIS. source

      Not checked in the free run.

    • cites [42] Kondoh, H. et al. Glycolytic enzymes can modulate cellular life span. Cancer Res. 65, 177–185 (2005). source

      Not checked in the free run.

    • cites [43] Dörr, J. R. et al. Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature 501, 421–425 (2013). This study shows that in a TIS model, the SASP, which provokes endoplasmic reticulum stress, is associated with increased glucose use, hyperactive mitochondrial respiration, and autophagy activation, and that TIS cells are sensitive to blocking glucose use or autophagy, which causes endoplasmic reticulum-related apoptosis. source

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  • Premisecitation

    Tumour cells typically preferentially use glycolysis even in the presence of oxygen.

    “In contrast to tumour cells, which typically preferentially use glycolysis in the presence of oxygen to generate energy”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Koppenol, W. H., Bounds, P. L. & Dang, C. V. Otto Warburg's contributions to current concepts of cancer metabolism. Nature Rev. Cancer 11, 325–337 (2011). source

      Not checked in the free run.

  • Premisenone given

    Senescent cells remain metabolically active.

    “Senescent cells are metabolically active.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Human melanoma has two distinct subgroups: a conventional glycolytic group and a group with high oxidative phosphorylation rates.

    “recent studies have identified two distinct sub-groups in human melanoma: a conventional glycolytic group and a group characterised by high rates of oxidative phosphorylation 47,48 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [47] Haq, R. et al. Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF. Cancer Cell 23, 302–315 (2013). source

      Not checked in the free run.

    • cites [48] Vazquez, F. et al. PGC1α expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell 23, 287–301 (2013). source

      Not checked in the free run.

  • Premisecitation

    Senescence has been identified in several premalignant tumours in humans and mice.

    “a series of studies [22][23][24][25][26] identified senescence in several premalignant tumours, both in humans and mice.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [22] Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005). source

      Not checked in the free run.

    • cites [23] Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005). source

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    • cites [24] Collado, M. et al. Tumour biology: Senescence in premalignant tumours. Nature 436, 642–642 (2005). source

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  • Classified as probably not a substantial claim. 8
  • May combine two claims. 37
  • The quote only partly states this claim. 3

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    Senescence is a stable cell-cycle arrest state that can be induced in normal and tumour cells by various stresses.

    “Induction of senescence, a stable state of cell cycle arrest, was originally described in normal cells, but it can also be induced in tumour cells in response to various stresses.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    Senescent cells can be cleared from lesions in some contexts, similar to apoptotic cells.

    “the long-term fate of senescent cells, which, similar to apoptotic cells, can be cleared from lesions in some contexts.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In Eμ-Myc; Bcl2 lymphomas, cells became senescent and mice had better prognosis than Eμ-Myc; Trp53-/- mice, although the Bcl2 lymphomas eventually progressed.

    “However, the prognosis of these mice was significantly better than the Eµ-Myc; Trp53 -/-mice because the cells in the Eµ-Myc; Bcl2 lymphomas became senescent, although the Eµ-Myc; Bcl2 lymphomas also eventually progressed.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Schmitt, C. A. et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109, 335–346 (2002). This was the first study showing that chemotherapy-induced tumour senescence contributed to improved survival in mice, in an apoptosis defective context. source

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    Premisecitation

    HRAS-G12V-induced senescent HDFs exhibit reduced lipid synthesis and increased fatty acid oxidation, leading to enhanced mitochondrial oxygen consumption.

    “Quijano et al. 53 showed that HRAS-G12V-induced senescent HDFs exhibit reduced lipid synthesis and increased fatty acid (FA) oxidation, leading to enhanced mitochondrial oxygen consumption.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Quijano, C. et al. Oncogene-induced senescence results in marked metabolic and bioenergetic alterations. Cell Cycle 11, 1383–1392 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Senescence has a heterogeneous phenotype in terms of cellular markers, and multiple markers are required to define it confidently.

    “Senescence has a heterogeneous phenotype in terms of cellular markers: multiple markers are required to define senescence with confidence.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Telomere shortening, persistent DNA damage response, autophagy, metabolic alterations, altered protein secretion, and epigenetic gene regulation are senescence effector programs.

    “These include telomere shortening and a persistent DNA damage response, autophagy and other metabolic alterations, altered protein secretion, and epigenetic gene regulation [2][3][4] .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [2] D'adda Di Fagagna, F. Living on a break: cellular senescence as a DNA-damage response. Nature Rev. Cancer 8, 512–522 (2008). source

      Not checked in the free run.

    • cites [3] Kuilman, T., Michaloglou, C., Mooi, W. J. & Peeper, D. S. The essence of senescence. Genes Dev. 24, 2463–2479 (2010). source

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    • cites [4] Salama, R., Sadaie, M., Hoare, M. & Narita, M. Cellular senescence and its effector programs. Genes Dev. 28, 99–114 (2014). source

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  • May combine two claims.

    Premisecitation

    SASP can reinforce or induce senescence.

    “including reinforcing or inducing senescence”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [91] Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008). source

      Not checked in the free run.

    • cites [92] Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008). References 91 and 92 describe the crucial role of pro-inflammatory cytokines and their receptors in senescence. source

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    • cites [105] Coppé, J.-P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. Plos Biol. 6, 2853–2868 (2008). source

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    Premisecitation

    ME1 and ME2 expression is repressed by p53, and MEs negatively regulate p53, so ME depletion activates p53 and induces senescence.

    “ME1 and ME2 expression is repressed by p53 and the MEs negatively regulate p53, thus depletion of the MEs results in p53 activation in a feed forward manner, thereby inducing senescence 50 (FIG.1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Jiang, P., Du, W., Mancuso, A., Wellen, K. E. & Yang, X. Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature 493, 689–693 (2013). This study shows that malic enzymes and p53 reciprocally repress each other and that depletion of ME1 or ME2 induces senescence in both normal and tumour cells. source

      Not checked in the free run.

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    Premisecitation

    Autophagy is dynamically activated during OIS and facilitates synthesis of IL-6 and IL-8, major SASP components.

    “Autophagy is dynamically activated during OIS and facilitates the synthesis of interleukin 6 (IL-6) and IL-8, major components of the SASP 58,59 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [58] Narita, M. et al. Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science 332, 966–970 (2011). source

      Not checked in the free run.

    • cites [59] Young, A. R. J. et al. Autophagy mediates the mitotic senescence transition. Genes Dev. 23, 798–803 (2009). This study shows that autophagy is activated during senescence and that the inhibition of autophagy delays the onset of senescence and the SASP. source

      Not checked in the free run.

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    Premisecitation

    Activation of PDH in mutant BRAF-driven human melanoma cells blocks tumorigenesis and sensitises them to the BRAF inhibitor PLX4720.

    “activation of PDH in mutant BRAF-driven human melanoma cells not only blocks tumorigenesis but also sensitises them to the BRAF inhibitor PLX4720 (an analogue of vemurafenib), eliminating treatment-resistant cell populations 41 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Kaplon, J. et al. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 498, 109–112 (2013). This study established the metabolic profile of OIS cells, identifying active PDH with increased mitochondrial respiration during OIS. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Senescence typically depends on the p53 and RB pathways, with additional regulation by other effector programs.

    “Senescence typically depends on the p53 and RB pathways, but other effector programs confer additional layers of regulation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In KrasG12D-driven pancreatic tumorigenesis, autophagy-deficient mice show transient accumulation of early PanIN with increased apoptosis, and lesions never progress to late PanIN or PDA.

    “In this model, autophagy deficient mice exhibit a marked but transient accumulation of early PanIN accompanied by increased rates of apoptotic cell death, and these lesions never progress to late stage PanINs or PDA 87 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] Rosenfeldt, M. T. et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature 504, 296–300 (2014). source

      Not checked in the free run.

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    Premisecitation

    Some SASP components reinforce senescence in already primed cells and induce senescence in normal neighbouring cells in a paracrine manner.

    “some SASP components not only reinforce the senescence response in cells that are already primed for senescence, but also induce senescence in normal neighbouring cells in a paracrine fashion 93,106”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [93] Acosta, J. C. et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nature Cell Biol. 15, 978–990 (2013). This study identified the inflammasome as a critical regulator of the SASP. source

      Not checked in the free run.

    • cites [106] Hubackova, S. et al. IL1- and TGFβ-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine 'bystander senescence'. Aging 4, 932–951 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In an Eμ-Myc lymphoma model, p53-induced apoptosis of lymphoma cells activates macrophages to secrete TGFβ1, which induces senescence in lymphoma cells.

    “In an Eµ-Myc lymphoma model, p53induced apoptosis of lymphoma cells led to the activation of macrophages to secrete TGFß1, which in turn induced senescence in lymphoma cells 36”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Reimann, M. et al. Tumor stroma-derived TGF-b limits Myc-Driven lymphomagenesisvia Suv39h1-dependent senescence. Cancer Cell 17, 262–272 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Senescence in some forms of tissue damage involves spatiotemporal control of secreted protein levels and SASP content, which modulates the senescence phenotype and dynamically regulates tissue integrity, contributing to lesion resolution.

    “These data indicate that senescence in the context of some forms of tissue damage involves the spatio-temporal control of secreted protein levels as well as the content of SASP, which in turn modulates the senescence phenotype and dynamically regulates the surrounding tissue integrity; eventually contributing to the resolution of the lesion.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Treatment with Tag-TH1 cells induces proliferation arrest in tumours and improves survival in RIP-Tag2 mice.

    “Treatment of mice with Tag-T H 1 cells in this model induces a cell proliferation arrest in the tumors and improves the survival of these mice 128”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] Müller-Hermelink, N. et al. TNFR1 signaling and IFN-γ signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis. Cancer Cell 13, 507–518 (2008). source

      Not checked in the free run.

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    Premisecitation

    Adult-onset activation of Kras-G12V in pancreatic acinar cells results in a low frequency of PanIN and resistance to transformation, partly through oncogene-induced senescence.

    “pancreatic acinar cells, in which Kras-G12V is activated during adulthood, exhibit a low frequency of PanIN development and resistance to transformation, at least in part due to OIS 118”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [118] Guerra, C. et al. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell 19, 728–739 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a CCl4-induced mouse liver fibrosis model, activated hepatic stellate cells become senescent and display a SASP including extracellular matrix degrading enzymes and proinflammatory cytokines.

    “activated HSCs become senescent, exhibiting a typical SASP, including the expression of extracellular matrix degrading enzymes and proinflammatory cytokines.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [94] Lujambio, A. et al. Non-cell-autonomous tumor suppression by p53. Cell 153, 449–460 (2013). source

      Not checked in the free run.

    • cites [120] Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008). This was the first study to show that HSC senescence controls fibrosis through the SASP. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tag binds RB and p53 but attenuates rather than fully inactivates them, allowing RIP-Tag2 mice to show progressive tumorigenesis with only a small fraction of islets developing invasive pancreatic cancer.

    “Although Tag binds both RB and p53, it attenuates, rather than fully inactivates, their activity, thus their residual activities allow the RIP-Tag2 mice to exhibit progressive tumorigenesis with only a small portion of islets developing invasive pancreatic cancer 127,129”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [127] Bergers, G., Javaherian, K., Lo, K. M., Folkman, J. & Hanahan, D. Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 284, 808–812 (1999). source

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    • cites [129] Casanovas, O., Hager, J. H., Chun, M. G. H. & Hanahan, D. Incomplete inhibition of the Rb tumor suppressor pathway in the context of inactivated p53 is sufficient for pancreatic islet tumorigenesis. Oncogene 24, 6597–6604 (2005). source

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    Premisecitation

    Autophagy deficiency suppresses KrasG12D-driven lung cancer development even without Trp53, presumably partly due to mitochondrial dysfunction.

    “in contrast to the pancreas model, autophagy deficiency (by autophagy related 7 (Atg7) knockout) suppresses Kras G12D -driven lung cancer development even in the absence of Trp53; presumably this is partially due to mitochondrial dysfunction.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Guo, J. Y. et al. Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes Dev. 27, 1447–1461 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    CCN1 can promote myofibroblast senescence associated with antifibrotic gene expression in skin, suggesting CCN1-mediated stromal senescence may participate in wound healing.

    “CCN1 can also promote myofibroblast senescence, which is associated with the expression of antifibrotic genes in the skin, thus CCN1 mediated stromal senescence might be involved in wound healing 123”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Jun, J.-I. & Lau, L. F. The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nature Cell Biol. 12, 676–685 (2010). source

      Not checked in the free run.

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    Premisecitation

    The senescence phenotype in this model depends on the p16-RB pathway, with residual RB activity sufficient for senescence induction.

    “The senescence phenotype is dependent on the p16-RB pathway, thus unlike the aforementioned Tag-driven hepatoma model, the residual RB activity seems to be sufficient for senescence induction in this model 129”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [129] Casanovas, O., Hager, J. H., Chun, M. G. H. & Hanahan, D. Incomplete inhibition of the Rb tumor suppressor pathway in the context of inactivated p53 is sufficient for pancreatic islet tumorigenesis. Oncogene 24, 6597–6604 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Human melanocytic naevi remain non-proliferative for decades without becoming malignant melanoma, showing that senescence arrest can be tumour suppressive without obvious senescence surveillance.

    “human melanocytic naevi (an OIS model), remain non-proliferative for decades without transformation into malignant melanoma 25”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005). This is a seminal study that identified OIS of human melanocytic naevi. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-6 and IL-8 can facilitate senescence in a cell-autonomous fashion, amplifying the phenotype.

    “these same factors can facilitate senescence in a cell-autonomous fashion, thus amplifying the phenotype 91,92,105”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [91] Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008). source

      Not checked in the free run.

    • cites [92] Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008). References 91 and 92 describe the crucial role of pro-inflammatory cytokines and their receptors in senescence. source

      Not checked in the free run.

    • cites [105] Coppé, J.-P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. Plos Biol. 6, 2853–2868 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Re-expression of endogenous p53 induced senescence and elimination of senescent tumour cells was mediated by innate immune cells including macrophages, neutrophils, and NK cells, in mice lacking adaptive immune system.

    “Re-expression of endogenous p53 induced senescence and the elimination of the senescent tumour cells was mediated by innate immune cells, including macrophages, neutrophils and natural killer (NK) cells, albeit in mice lacking an adaptive immune system.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007). This was the first study to show that the innate immune response eliminates the senescent cells induced in tumours in mice. source

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  • May combine two claims.

    Premisecitation

    Episodic pancreatitis induced by caerulein inhibits the OIS program and facilitates malignant transformation in the Kras-G12V pancreatic model.

    “episodic pancreatitis induced by caerulein, a decapeptide analog of the gastrointestinal peptide hormone cholecystokinin, inhibited the OIS program, thus facilitating malignant transformation in this model 118”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [118] Guerra, C. et al. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell 19, 728–739 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Depletion of MYC in a mouse subcutaneous T-ALL model results in sustained tumour regression associated with senescence and apoptosis, where adaptive immune response involving CD4+ T cells is required for senescence induction and sustained regression, but not apoptosis induction.

    “the depletion of MYC in a mouse subcutaneous transplantation model of T cell acute lymphoblastic lymphoma (T-ALL), which carries tetracycline regulated MYC transgene, results in sustained tumour regression associated with senescence and apoptosis, where an adaptive immune response (involving CD4 + T cells in particular) was required for senescence induction and sustained tumour regression, but not”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [116] Rakhra, K. et al. CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer Cell 18, 485–498 (2010). source

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    Premisecitation

    The SASP of senescent activated HSCs attracts innate immune cells that eliminate these cells and help resolve fibrosis.

    “The SASP also attracts innate immune cells that in turn eliminate the senescent HSCs and facilitate the resolution of fibrosis 94,120”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [94] Lujambio, A. et al. Non-cell-autonomous tumor suppression by p53. Cell 153, 449–460 (2013). source

      Not checked in the free run.

    • cites [120] Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008). This was the first study to show that HSC senescence controls fibrosis through the SASP. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TAA-expressing islets treated with Tag-TH1 cells remain functional and appear to be in tumour dormancy.

    “The TAA-expressing islets treated with Tag-T H 1 cells are functional (i.e. they produce insulin), thus appeared to be in a state of tumour dormancy 128”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] Müller-Hermelink, N. et al. TNFR1 signaling and IFN-γ signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis. Cancer Cell 13, 507–518 (2008). source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    In LSL-Kras G12V ; RERTn +/ERT mice, Cdk4 ablation suppresses development of non-small cell lung carcinoma.

    “| | LSL-Kras G12V ; RERTn +/ERT | Cdk4 ablation | development | 158 | | | |”
    • Also stated in: § Additional information · plain
      “| | | | | | Suppression of non-small cell lung carcinoma | | |”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [158] Puyol, M. et al. A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell 18, 63–73 (2010). source

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

    Premisecitation

    Michaloglou et al. 2005 identified OIS of human melanocytic naevi.

    “This is a seminal study that identified OIS of human melanocytic naevi.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005). This is a seminal study that identified OIS of human melanocytic naevi. source

      Not checked in the free run.

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

    Premisecitation

    Serrano et al. 1997 established the concept of oncogene-induced senescence (OIS).

    “This seminal paper established the concept of OIS.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997). This seminal paper established the concept of OIS. source

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  • May combine two claims.

    Premisecitation

    Embryonic cell senescence is p21-dependent but not p53-dependent, is accompanied by the SASP, and these cells are eliminated by macrophages.

    “Embryonic cell senescence is p21, but not p53, dependent, is accompanied by the SASP, and these cells are eliminated by macrophages 149,150”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [149] Muñoz-Espín, D. et al. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118 (2013). source

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    • cites [150] Storer, M. et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155, 1119–1130 (2013). source

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    Premisecitation

    In LSL-Kras G12V ; RERTn +/ERT mice, the CDK4 inhibitor PD0332991 suppresses development of non-small cell lung carcinoma.

    “| CDK4 inhibitor | LSL-Kras G12V ; RERTn +/ERT | PD0332991 | development | 158 | | | |”
    • Also stated in: § Additional information · plain
      “| | | | | | Suppression of non-small cell lung carcinoma | | |”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [158] Puyol, M. et al. A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell 18, 63–73 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Partial induction of senescence in tumours could eradicate or exacerbate the tumours.

    “The partial induction of senescence in tumours could eradicate or exacerbate the tumours 110,113”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [110] Jackson, J. G. et al. p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer. Cancer Cell 21, 793–806 (2012). source

      Not checked in the free run.

    • cites [113] Iannello, A., Thompson, T. W., Ardolino, M., Lowe, S. W. & Raulet, D. H. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J. Exp. Med. 210, 2057–2069 (2013). This study suggests that NK cells that are recruited to the tumour lesion by the SASP of senescent tumour cells may also kill non-senescent tumour cells. source

      Not checked in the free run.

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

    Premisecitation

    Kaplon et al. 2013 characterized the metabolomics of OIS cells and found active PDH and elevated mitochondrial respiration during OIS.

    “This study established the metabolomics profile of OIS cells, identifying active PDH with increased mitochondrial respiration during OIS.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Kaplon, J. et al. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 498, 109–112 (2013). This study established the metabolic profile of OIS cells, identifying active PDH with increased mitochondrial respiration during OIS. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice, age-dependent accumulation of p16-positive cells in tissue stem cell or progenitor cell compartments contributes to tissue degeneration, and p16 depletion attenuates some age-dependent phenotypes.

    “age-dependent accumulation of p16-positive cells in tissue stem cell or progenitor cell compartments contributes to tissue degeneration, and p16 depletion attenuates some age-dependent phenotypes [145][146][147]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145][146][147]

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Senescent cells are resistant to apoptosis or mitotic catastrophe upon chemotherapy; if senescent tumour cells are not eliminated, sustained pro-tumorigenic cytokines can lead to worse outcome.

    “Much like dormant cells, senescent cells are resistant to apoptosis or mitotic catastrophe upon chemotherapy, thus if senescent tumour cells are not eliminated, the sustained expression of pro-tumorigenic cytokines can lead to a worse outcome 110”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [110] Jackson, J. G. et al. p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer. Cancer Cell 21, 793–806 (2012). source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    In human lung and prostate cancer xenografts, the SKP2 inhibitor SKP2 Inhibitor#25 inhibits tumour growth.

    “| SKP2 inhibitor | xenografts | | | SKP2 Inhibitor#25 | Tumour growth inhibition | 159 |”
    • Also stated in: § Additional information · plain
      “| | Human lung and prostate cancer | | | | | | |”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [159] Chan, C.-H. et al. Pharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression. Cell 154, 556–568 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The majority of prostate cancer patients at presentation have lost one allele of PTEN while maintaining intact TP53; TP53 mutations and complete loss of PTEN are both associated with advanced stage prostate cancer.

    “the majority of prostate cancer patients at presentation have lost one allele of PTEN while maintaining intact TP53; whereas TP53 mutations and the complete loss of PTEN are both associated with advanced stage prostate cancer 153,154”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [153] Schlomm, T. et al. Clinical significance of p53 alterations in surgically treated prostate cancers. Mod. Pathol. 21, 1371–1378 (2008). source

      Not checked in the free run.

    • cites [154] Song, M. S., Salmena, L. & Pandolfi, P. P. The functions and regulation of the PTEN tumour suppressor. Nature Rev. Mol. Cell. Biol. 13, 283–296 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pten heterozygosity promotes tumour initiation and proliferation in the prostate, but complete loss of Pten can oppose prostate tumorigenesis by triggering a powerful p53-dependent cellular senescence response.

    “Pten heterozygosity promotes tumour initiation and proliferation in the prostate, but paradoxically, the complete loss of Pten can oppose prostate tumorigenesis by triggering a powerful p53-dependent cellular senescence response 38”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Nardella, C., Clohessy, J. G., Alimonti, A. & Pandolfi, P. P. Pro-senescence therapy for cancer treatment. Nature Rev. Cancer 11, 503–511 (2011). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

    Premisecitation

    In a haematopoietic system model, suppressing MYC causes lymphoma regression.

    “| | haematopoietic system | MYC suppression | lymphoma | 116 | | | |”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [116] Rakhra, K. et al. CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer Cell 18, 485–498 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elimination of p16-expressing cells does not facilitate tumorigenesis in this model, unlike p16 ablation.

    “unlike p16-ablation, elimination of p16-expressing cells does not facilitate tumorigenesis in this model.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    NK cells that the SASP of senescent tumour cells attracts to the tumour may also destroy non-senescent tumour cells.

    “This study suggests that NK cells recruited to the tumour lesion by the SASP of senescent tumour cells may also kill non-senescent tumour cells.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Iannello, A., Thompson, T. W., Ardolino, M., Lowe, S. W. & Raulet, D. H. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J. Exp. Med. 210, 2057–2069 (2013). This study suggests that NK cells that are recruited to the tumour lesion by the SASP of senescent tumour cells may also kill non-senescent tumour cells. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a TIS model, the SASP provokes ER stress and is associated with increased glucose use, hyperactive mitochondrial respiration, and autophagy activation.

    “This study shows that in a TIS model the SASP, which provokes endoplasmic reticulum (ER) stress, is associated with increased glucose use, hyperactive mitochondrial respiration, and autophagy activation”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Dörr, J. R. et al. Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature 501, 421–425 (2013). This study shows that in a TIS model, the SASP, which provokes endoplasmic reticulum stress, is associated with increased glucose use, hyperactive mitochondrial respiration, and autophagy activation, and that TIS cells are sensitive to blocking glucose use or autophagy, which causes endoplasmic reticulum-related apoptosis. source

      Not checked in the free run.

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

    Premisecitation

    Malic enzymes and p53 mutually repress one another.

    “This study shows that Malic enzymes (MEs) and p53 reciprocally repress each other”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Jiang, P., Du, W., Mancuso, A., Wellen, K. E. & Yang, X. Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature 493, 689–693 (2013). This study shows that malic enzymes and p53 reciprocally repress each other and that depletion of ME1 or ME2 induces senescence in both normal and tumour cells. source

      Not checked in the free run.

46 of 46

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?

  • Senescent cells secrete inflammatory proteins, growth factors, and metalloproteases that constitute the SASP.

    “In fact, senescent cells secrete an array of inflammatory proteins, growth factors, and metalloproteases that collectively constitute the SASP (senescence-associated secretory phenotype).”

    From Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway (2017) · cites this paper as Pérez-Mancera et al., 2014

  • Deleterious consequences from ineffective clearance of senescent cells and their over-accumulation in tissues can promote age-related diseases and cancer.

    “However, the deleterious consequences that result from ineffective clearance of senescent cells and their over-accumulation in tissues can promote age-related diseases and cancer.2,26–30”

    From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [30]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Lung cancer model has two different KRAS mutations

    Minor

    The same discussion identifies the autophagy-inhibition lung model as KRAS-G12V-driven and then as KRAS-G12D-driven. These are different mutations, so the model is described inconsistently.

1 of 1

Cites

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Related

Authors
Pérez-Mancera, P. A., Young, A. R. J., & Narita, M.
Affiliations
University of Cambridge (GB)
Corresponding author
Narita, Masashi
ORCID
Venue
Nature Reviews Cancer
Publisher
Springer Science and Business Media LLC
Published
2014-07-17
Volume
14
Issue
8
Pages
547-558
ISSN
  • 1474-175X (ISSN-L)
  • 1474-1768
DOI
10.1038/nrc3773
OpenAlex
W1963704214
Semantic Scholar
34d61b9672e8adfeea27bec14cd0bfbd47df2729
Cited by
462
References
161
Citations by year
2026: 9 · 2025: 26 · 2024: 32 · 2023: 35 · 2022: 41 · 2021: 39 · 2020: 34 · 2019: 41 · 2018: 48 · 2017: 58 · 2016: 55 · 2015: 39 · 2014: 5
FWCI
6.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature reviews. Cancer (publishedVersion)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion)
Funders
Cancer Research UK (15890)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
cellular senescence, senescence-associated secretory phenotype, carcinogenesis, tumor progression, tumor suppression, tumor promotion, cell cycle arrest, non-cell-autonomous effects, cancer therapy response
MeSH terms
Animals, Humans, Neoplasms, Precancerous Conditions, Signal Transduction, Cellular Senescence, Tumor Microenvironment

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

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