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Cited by 183Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsTGF-β signaling in diseases

Paracrine roles of cellular senescence in promoting tumourigenesis

Open access
Gonzalez-Meljem, Jose Mario, Apps, John Richard, Fraser, Helen Christina, Martinez-Barbera, Juan Pedro·2018·British Journal of Cancer
DOI 10.1038/s41416-018-0066-1PMC PMC5959857
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Abstract

Senescent cells activate genetic programmes that irreversibly inhibit cellular proliferation, but also endow these cells with distinctive metabolic and signalling phenotypes. Although senescence has historically been considered a protective mechanism against tumourigenesis, the activities of senescent cells are increasingly being associated with age-related diseases, including cancer. An important feature of senescent cells is the secretion of a vast array of pro-inflammatory cytokines, chemokines, and growth factors collectively known as the senescence-associated secretory phenotype (SASP). Recent research has shown that SASP paracrine signalling can mediate several pro-tumourigenic effects, such as enhancing malignant phenotypes and promoting tumour initiation. In this review, we summarise the paracrine activities of senescent cells and their role in tumourigenesis through direct effects on growth and proliferation of tumour cells, tumour angiogenesis, invasion and metastasis, cellular reprogramming and emergence of tumour-initiating cells, and tumour interactions with the local immune environment. The evidence described here suggests cellular senescence acts as a double-edged sword in cancer pathogenesis, which demands further attention in order to support the use of senolytic or SASP-modulating compounds for cancer treatment.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that senescent cells, through the senescence-associated secretory phenotype (SASP), can act in a paracrine manner to promote multiple pro-tumourigenic processes, challenging the view of senescence as purely tumour-suppressive. It concludes that senescence is a double-edged sword in cancer and highlights senolytic or SASP-modulating compounds as potential therapeutic strategies.

Key findings

  • SASP factors can directly promote tumour cell growth and proliferation: co-culture or co-injection of senescent fibroblasts increased tumourigenicity in xenograft models, including primary breast cancer tissues; AREG blockade reduced senescent-fibroblast-conditioned-media-induced growth of benign prostate epithelial cells; and deletion of IL1β reduced IL6 and CXCL1 expression and the number and size of liver tumours in an obesity-associated liver cancer model.
  • Senescent cells can promote angiogenesis, invasion, and metastasis: conditioned media from senescent cells induced EMT in non-aggressive breast cancer, mesothelioma, and melanoma cell lines; MMP2 and MMP3 secreted by senescent cells enhanced invasive properties; IL6 promoted tumour-supportive angiogenesis in a Ras-driven tumour model; and co-injection of senescent fibroblasts or peritoneal mesothelial cells with cancer cells increased tumour angiogenesis in xenografts.
  • SASP can inhibit differentiation and promote tumour-initiating/stem-like phenotypes: keratinocytes exposed to senescent-cell medium expressed tumour stem cell marker CD44; co-culture with senescent myeloma cells promoted cancer stem-like cells; mesothelioma SASP produced a highly clonogenic subpopulation with enhanced tumour formation in mice; and IL6 or CCL2 induced tumourigenic potential in melanoma cells in a STAT3-dependent manner with NANOG, SOX2, and OCT4 expression.
  • Senescent cells modulate local immunity in opposing ways: they can promote immune clearance via CCL2-mediated NK-T cell attraction, and p53 restoration in murine liver carcinomas triggered innate immune infiltration and complete tumour regression; however, senescent stromal cells and IL6 can increase suppressive myeloid cells, inhibit anti-tumour T-cell responses, and enhance tumour growth.

Methods

  • Narrative review of published literature, not a primary experimental study.
  • Synthesizes in vitro and in vivo evidence on paracrine effects of senescent cells and SASP components across tumour growth, angiogenesis/invasion/metastasis, cellular reprogramming/tumour-initiating cells, and immune interactions.
  • Main analysis is conceptual organization into four paracrine activity domains, with a table of example senolytic and SASP-modulating compounds; no systematic search strategy or quantitative meta-analysis is stated.

Limitations

  • The paper states that the relationship between senescence, tumourigenesis, and the immune system is complex and remains incompletely understood, and that further research is required to clarify factors controlling pro- and anti-tumour surveillance activities.
  • The paper states that its subdivisions of senescence-associated activities are mainly conceptual, because senescent cells exert compounded effects and current experimental approaches cannot easily distinguish these activities, especially in vivo.
  • Evident from the text: as a narrative review, it does not report a systematic literature search, quantitative effect sizes, or formal risk-of-bias assessment.

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

Integrity signals

Registry

Crossref · 10.1038/s41416-018-0066-1

Cites

86 of 86 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 110 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    Cellular senescence acts as a double-edged sword in cancer pathogenesis.

    “The evidence described here suggests cellular senescence acts as a double-edged sword in cancer pathogenesis, which demands further attention in order to support the use of senolytic or SASP-modulating compounds for cancer treatment.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The pro-tumourigenic paracrine effects of senescent cells observed in in vitro and mouse models are representative of human cancer pathogenesis.
  • Premisecitation

    Co-culture of senescent fibroblasts, induced by various stimuli, can promote the growth and proliferation of benign, pre-malignant, and malignant cells from a range of tumour types.

    “Co-culture of senescent fibroblasts, induced by various stimuli (e.g. radiation, DNA damage, replicative exhaustion), can promote the growth and proliferation of benign, pre-malignant, and malignant cells from a range of tumour types.9,12,26,41–44”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [9] Takasugi, M. et al. Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2. Nat. Commun. 8, 15729 (2017). source

      Not checked in the free run.

    • cites [12] Coppe, 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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    • cites [26] 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

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    • cites [41] Parrinello, S., Coppe, J. P., Krtolica, A. & Campisi, J. Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J. Cell Sci. 118(Pt 3), 485–496 (2005). source

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    • cites [42] Dilley, T. K., Bowden, G. T. & Chen, Q. M. Novel mechanisms of sublethal oxidant toxicity: induction of premature senescence in human fibroblasts confers tumor promoter activity. Exp. Cell Res. 290, 38–48 (2003). source

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    • cites [43] Liu, D. & Hornsby, P. J. Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. Cancer Res. 67, 3117–3126 (2007). source

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    • cites [44] Tsai, K. K., Chuang, E. Y., Little, J. B. & Yuan, Z. M. Cellular mechanisms for low-dose ionizing radiation-induced perturbation of the breast tissue microenvironment. Cancer Res. 65, 6734–6744 (2005). source

      Not checked in the free run.

  • Interpretationnone given

    SASP paracrine signalling can mediate pro-tumourigenic effects, such as enhancing malignant phenotypes and promoting tumour initiation.

    “Recent research has shown that SASP paracrine signalling can mediate several pro-tumourigenic effects, such as enhancing malignant phenotypes and promoting tumour initiation.”
    Quote in the paperSubstantial claim
  • Premisecitation

    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”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [2] Munoz-Espin, D. & Serrano, M. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496 (2014). source

      Not checked in the free run.

    • cites [26] 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.

    • cites [27] Campisi, J. Aging, cellular senescence, and cancer. Annu Rev. Physiol. 75, 685–705 (2013). source

      Not checked in the free run.

    • cites [28] Lecot, P., Alimirah, F., Desprez, P. Y., Campisi, J. & Wiley, C. Context-dependent effects of cellular senescence in cancer development. Br. J. Cancer 114, 1180–1184 (2016). source

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    • cites [29] Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008). source

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    • cites [30] Perez-Mancera, P. A., Young, A. R. & Narita, M. Inside and out: the activities of senescence in cancer. Nat. Rev. Cancer 14, 547–558 (2014). source

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  • Premisecitation

    Dysregulation or inappropriate activation of senescence contributes to tumour progression and malignancy.

    “There is mounting evidence that dysregulation or inappropriate activation of senescence contributes to tumour progression and malignancy.5,7,17”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [5] Rodier, F. & Campisi, J. Four faces of cellular senescence. J. Cell Biol. 192, 547–556 (2011). source

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    • cites [7] Coppe, J. P., Desprez, P. Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev. Pathol. 5, 99–118 (2010). source

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    • cites [17] Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J. & Kirkland, J. L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J. Clin. Invest. 123, 966–972 (2013). source

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  • May combine two claims. 19
  • Classified as probably not a substantial claim. 3

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    Premisecitation

    The composition and intensity of the SASP response can be affected by the senescence-inducing mechanism, cell type, and time since senescence initiation, indicating that there is no singular SASP.

    “The composition and intensity of the SASP response can be affected by several factors including the senescence-inducing mechanism, cell type, and the amount of time passed since senescence initiation, indicating that there is no singular SASP.12–17”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [12] Coppe, 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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    • cites [13] Maciel-Baron, L. A. et al. Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli. Age 38, 26 (2016). source

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    • cites [14] Coppe, J. P. et al. Tumor suppressor and agingbiomarkerp16(INK4a) induces cellular senescence without the associated inflammatory secretory phenotype. J. Biol. Chem. 286, 36396–36403 (2011). source

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    • cites [15] Kipling, D. et al. A transcriptomic analysis of the EK1.Br strain of human fibroblastoid keratocytes: the effects of growth, quiescence and senescence. Exp. Eye Res. 88, 277–285 (2009). source

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    • cites [16] Hoare, M. et al. NOTCH1 mediates a switch between two distinct secretomes during senescence. Nat. Cell Biol. 18, 979–992 (2016). source

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    • cites [17] Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J. & Kirkland, J. L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J. Clin. Invest. 123, 966–972 (2013). source

      Not checked in the free run.

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

    Premisecitation

    The SASP is involved in valuable physiological processes such as promoting tissue repair, fine-tuning development of embryonic structures, and stimulating immune surveillance.

    “Furthermore, the SASP is involved in valuable physiological processes such as promoting tissue repair,18–20 fine-tuning the development of embryonic structures,21–23 and stimulating immune surveillance.24,25”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [18] Jun, J. I. & Lau, L. F. The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat. Cell Biol. 12, 676–685 (2010). source

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    • cites [19] Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell. 31, 722–733 (2014). source

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    • cites [20] Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008). source

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    • cites [21] 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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    • cites [22] Munoz-Espin, D. et al. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118 (2013). source

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    • cites [23] Davaapil, H., Brockes, J. P. & Yun, M. H. Conserved and novel functions of programmed cellular senescence during vertebrate development. Development 144, 106–114 (2017). source

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    • cites [24] Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007). source

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    • cites [25] Lujambio, A. To clear, or not to clear (senescent cells)? That is the question. Bioessays 38(Suppl. 1), S56–S64 (2016). source

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  • May combine two claims.

    Premisecitation

    Activation of the senescence programme leads to cellular and molecular changes such as proliferation arrest, chromatin remodelling, elevated expression of cell cycle inhibitors, activation of a DNA damage response, enlargement of the lysosomal compartment, and activation of SASP.

    “Activation of the senescence programme leads to cellular and molecular changes such as proliferation arrest, chromatin remodelling, elevated expression of cell cycle inhibitors (such as p16INK4A or p21CIP1), activation of a DNA damage response, enlargement of the lysosomal compartment, and activation of a senescence-associated secretory phenotype (SASP).5,6”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] Rodier, F. & Campisi, J. Four faces of cellular senescence. J. Cell Biol. 192, 547–556 (2011). source

      Not checked in the free run.

    • cites [6] van Deursen, J. M. The role of senescent cells in ageing. Nature 509, 439–446 (2014). source

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

    Premisenone given

    Senescence serves as a response to stress, with inducing stimuli including chemotherapeutic, radiation and oxidative stress.

    “Senescence serves as a response to stress, and several inducing stimuli have now been identified including chemotherapeutic, radiation and oxidative stress, amongst others (Fig. 1).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Senescent cells can be found in both benign and malignant tumours.

    “Supporting this notion, the burden of senescent cells in tissues increases significantly with age in mice, primates, and humans,27 and they can be found in both benign and malignant tumours.31–35”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [31] Collado, M. et al. Tumour biology: senescence in premalignant tumours. Nature 436, 642 (2005). source

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    • cites [32] Haugstetter, A. M. et al. Cellular senescence predicts treatment outcome in metastasised colorectal cancer. Br. J. Cancer 103, 505–509 (2010). source

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    • cites [33] Vizioli, M. G. et al. Evidence of oncogene-induced senescence in thyroid carcinogenesis. Endocr. Relat. Cancer 18, 743–757 (2011). source

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    • cites [34] Reimann, M. et al. Tumor stroma-derived TGF-beta limits myc-driven lymphomagenesis via Suv39h1-dependent senescence. Cancer Cell. 17, 262–272 (2010). source

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    • cites [35] Roberson, R. S., Kussick, S. J., Vallieres, E., Chen, S. Y. & Wu, D. Y. Escape from therapy-induced accelerated cellular senescence in p53-null lung cancer cells and in human lung cancers. Cancer Res. 65, 2795–2803 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescence was traditionally considered an innate anti-cancer mechanism as it can eliminate damaged cells, and activation in cells harbouring oncogenic mutations serves as a tumour suppressor mechanism.

    “Senescence was traditionally considered an innate anti-cancer mechanism as it can serve to eliminate damaged cells,3,5 whereby activation of the senescence programme in cells harbouring oncogenic mutations serves as a tumour suppressor mechanism, preventing the expansion of these mutated cells and progression into malignancies.3,5”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] He, S. & Sharpless, N. E. Senescence in health and disease. Cell 169, 1000–1011 (2017). source

      Not checked in the free run.

    • cites [5] Rodier, F. & Campisi, J. Four faces of cellular senescence. J. Cell Biol. 192, 547–556 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Genetic or chemical ablation of senescent cells in mouse models delays the onset of age-related disorders, including cancer, leading to increased life-spans and promoting tissue rejuvenation in late life.

    “Importantly, genetic or chemical ablation of senescent cells in mouse models delays the onset of age-related disorders, including cancer, leading to increased life-spans and promoting tissue rejuvenation in late life.36–38”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [36] Chang, J. et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83 (2016). source

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    • cites [37] Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011). source

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    • cites [38] Baker, D. J. et al. Naturallyoccurringp16(Ink4a)-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016). source

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  • May combine two claims.

    Premisecitation

    Senescent cells can contribute to the acquisition of invasive and metastatic properties of cancer cells, as well as the induction of tumour-associated angiogenesis.

    “Senescent cells can contribute to the acquisition of invasive and metastatic properties of cancer cells, as well as the induction of tumour-associated angiogenesis.7,39”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Coppe, J. P., Desprez, P. Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev. Pathol. 5, 99–118 (2010). source

      Not checked in the free run.

    • cites [39] Alspach, E., Fu, Y. & Stewart, S. A. Senescence and the pro-tumorigenic stroma. Crit. Rev. Oncog. 18, 549–558 (2013). source

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  • May combine two claims.

    Premisecitation

    The SASP is able to inhibit differentiation both in vitro and in vivo, while in some cases leads to acquisition of stem cell characteristics.

    “Interestingly, the SASP is able to inhibit differentiation both in vitro and in vivo, while in some cases leads to acquisition of stem cell characteristics.41,44,54,55,64–66”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [41] Parrinello, S., Coppe, J. P., Krtolica, A. & Campisi, J. Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J. Cell Sci. 118(Pt 3), 485–496 (2005). source

      Not checked in the free run.

    • cites [44] Tsai, K. K., Chuang, E. Y., Little, J. B. & Yuan, Z. M. Cellular mechanisms for low-dose ionizing radiation-induced perturbation of the breast tissue microenvironment. Cancer Res. 65, 6734–6744 (2005). source

      Not checked in the free run.

    • cites [54] Ohanna, M. et al. Secretome from senescent melanoma engages the STAT3 pathway to favor reprogramming of naive melanoma towards a tumor-initiating cell phenotype. Oncotarget 4, 2212–2224 (2013). source

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    • cites [55] Canino, C. et al. SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells. Oncogene 31, 3148–3163 (2012). source

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    • cites [64] Cahu, J., Bustany, S. & Sola, B. Senescence-associated secretory phenotype favors the emergence of cancer stem-like cells. Cell Death Dis. 3, e446 (2012). source

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    • cites [65] Ritschka, B. et al. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev. 31, 172–183 (2017). source

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    • cites [66] Mosteiro, L. et al. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science 354, (2016). source

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  • May combine two claims.

    Premisecitation

    Exposure of keratinocytes to the culture medium from senescent cells promotes expression of tumour stem cell markers, such as CD44, and leads to a greater regenerative capacity in vivo.

    “Exposure of keratinocytes to the culture medium from senescent cells promotes expression of tumour stem cell markers, such as CD44, and leads to a greater regenerative capacity in vivo. 65”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Ritschka, B. et al. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev. 31, 172–183 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL6 has cell-adhesion disrupting actions, which is an important component of invasion.

    “In addition, individual SASP components can contribute to induce EMT phenotypes; IL6, for example, has been shown to have cell-adhesion disrupting actions, which is an important component of invasion.56”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Tamm, I., Kikuchi, T., Cardinale, I. & Krueger, J. G. Cell-adhesion-disrupting action of interleukin 6 in human ductal breast carcinoma cells. Proc. Natl Acad. Sci. USA 91, 3329–3333 (1994). source

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  • May combine two claims.

    Premisecitation

    A large number of proangiogenic factors are secreted by senescent cells, whereas angiostatic molecules have not been found to be secreted.

    “A large number of proangiogenic factors are also known to be secreted by senescent cells, whereas angiostatic molecules have not been found to be secreted.27,60”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Campisi, J. Aging, cellular senescence, and cancer. Annu Rev. Physiol. 75, 685–705 (2013). source

      Not checked in the free run.

    • cites [60] Oubaha, M. et al. Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy. Sci. Transl. Med. 8, 362ra144 (2016). source

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  • May combine two claims.

    Interpretationreasoning

    The SASP can promote cancer cell growth, challenging the view that senescence is primordially a beneficial process involved in preventing cancer progression.

    “These experiments collectively demonstrate that the SASP can promote cancer cell growth, challenging the view that senescence is primordially a beneficial process involved in preventing cancer progression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cellular reprogramming can be induced in vivo by senescent cells through SASP activation, and this can be stimulated in different models of tissue damage.

    “Furthermore, cellular reprogramming, which is the process by which adult differentiated cells can be induced to become functionally equivalent to embryonic stem cells, can be induced in vivo by senescent cells through SASP activation, and this can be stimulated in different models of tissue damage.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cells undergoing damage-induced senescence are often cleared by the immune system, as several SASP factors are cytokines and chemokines that can modulate the local immune environment.

    “Cells undergoing damage-induced senescence are often cleared by the immune system, as several SASP factors are cytokines and chemokines that can modulate the local immune environment.2,3,5,70,71”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [2] Munoz-Espin, D. & Serrano, M. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496 (2014). source

      Not checked in the free run.

    • cites [3] He, S. & Sharpless, N. E. Senescence in health and disease. Cell 169, 1000–1011 (2017). source

      Not checked in the free run.

    • cites [5] Rodier, F. & Campisi, J. Four faces of cellular senescence. J. Cell Biol. 192, 547–556 (2011). source

      Not checked in the free run.

    • cites [70] Vicente, R., Mausset-Bonnefont, A. L., Jorgensen, C., Louis-Plence, P. & Brondello, J. M. Cellular senescence impact on immune cell fate and function. Aging Cell 15, 400–16 (2016). source

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    • cites [71] Velarde, M. C., Demaria, M. & Campisi, J. Senescent cells and their secretory phenotype as targets for cancer therapy. Interdiscip. Top. Gerontol. 38, 17–27 (2013). source

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  • May combine two claims.

    Premisecitation

    This leads to the inhibition of anti-tumour T-cell responses and enhanced tumour growth.

    “Furthermore, it was shown that this leads to the inhibition of anti-tumour T-cell responses and enhanced tumour growth.77”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Ruhland, M. K. et al. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nat. Commun. 7, 11762 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The mechanistic target of rapamycin (mTOR) complex can either counteract or facilitate reprogramming by cell-intrinsic and cell-extrinsic mechanisms, respectively.

    “In this sense, a crucial role for the mechanistic target of rapamycin (mTOR) complex has recently been unveiled, whereby it can either counteract or facilitate reprogramming by cell-intrinsic and cell-extrinsic mechanisms, respectively.69”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Aarts, M. et al. Coupling shRNA screens with single-cell RNA-seq identifies a dual role for mTOR in reprogramming-induced senescence. Genes Dev. 31, 2085–2098 (2017). source

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    Premisecitation

    While senescence is a barrier to reprogramming in vitro, the paracrine activities of senescent cells can promote the expression of stem cell markers and proliferation of neighbouring cells in vivo, and IL6 is a key player in driving this process.

    “While senescence is a barrier to reprogramming in vitro, the paracrine activities of senescent cells can promote the expression of stem cell markers and proliferation of neighbouring cells in vivo, 66–68 and IL6 is a key player in driving this process.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [66] Mosteiro, L. et al. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science 354, (2016). source

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    • cites [67] Chiche, A. et al. Injury-induced senescence enables in vivo reprogramming in skeletal muscle. Cell. Stem Cell. 20, 407–14.e4 (2017). source

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    • cites [68] Mosteiro, L., Pantoja, C., de Martino, A. & Serrano, M. Senescence promotes in vivo reprogramming through p16(INK)(4a) and IL-6. Aging Cell (2017). PubMed PMID: 29280266. Epub 2017/12/28. eng. https://doi.org/10.1111/acel.12711 . source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Senescent cells, through their SASP, can induce undifferentiated cellular states; depending on the context, this can be beneficial (e.g. tissue regeneration) or harmful (e.g. promotion of tumour-initiating cells).

    “Together, these data suggest that senescent cells, through their SASP, can induce undifferentiated cellular states; depending on the context, this can be beneficial (e.g. tissue regeneration) or harmful (e.g. promotion of tumour-initiating cells).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Since senescent cells are generally abundant in benign tumours and also present at low numbers in several malignancies, their paracrine activities could contribute to tumour progression and cancer metastasis.

    “Since senescent cells are generally abundant in benign tumours and also present at low numbers in several malignancies,31–34,57 their paracrine activities could contribute to tumour progression and cancer metastasis.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [31] Collado, M. et al. Tumour biology: senescence in premalignant tumours. Nature 436, 642 (2005). source

      Not checked in the free run.

    • cites [32] Haugstetter, A. M. et al. Cellular senescence predicts treatment outcome in metastasised colorectal cancer. Br. J. Cancer 103, 505–509 (2010). source

      Not checked in the free run.

    • cites [33] Vizioli, M. G. et al. Evidence of oncogene-induced senescence in thyroid carcinogenesis. Endocr. Relat. Cancer 18, 743–757 (2011). source

      Not checked in the free run.

    • cites [34] Reimann, M. et al. Tumor stroma-derived TGF-beta limits myc-driven lymphomagenesis via Suv39h1-dependent senescence. Cancer Cell. 17, 262–272 (2010). source

      Not checked in the free run.

    • cites [57] Kim, Y. H. et al. Senescent tumor cells lead the collective invasion in thyroid cancer. Nat. Commun. 8, 15208 (2017).

      Not checked in the free run.

20 of 20

  • The paper relies on this without support.

    The pro-tumourigenic paracrine effects of senescent cells observed in in vitro and mouse models are representative of human cancer pathogenesis.

    “The evidence described here suggests cellular senescence acts as a double-edged sword in cancer pathogenesis, which demands further attention in order to support the use of senolytic or SASP-modulating compounds for cancer treatment.”
1 of 1

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?

  • Senescence has the potential to spread damage to surrounding tissue via paracrine signaling with SASP factors, while simultaneously using autocrine reinforcement to maintain their senescent phenotype.

    “Senescence has the potential to spread damage to surrounding tissue via paracrine signaling with SASP factors, while simultaneously using autocrine reinforcement to maintain their senescent phenotype [48].”

    From DNA repair deficiency and senescence in concussed professional athletes involved in contact sports (2019) · cites this paper as [48]

  • Cellular senescence can cause significant effects on brain health and function by affecting various cell types and spreading its effects to surrounding tissue.

    “In particular, cellular senescence can cause significant effects on brain health and function by affecting various cell types and spreading its effects to surrounding tissue [48].”

    From DNA repair deficiency and senescence in concussed professional athletes involved in contact sports (2019) · cites this paper as [48]

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Authors
Gonzalez-Meljem, J. M., Apps, J. R., Fraser, H. C., & Martinez-Barbera, J. P.
Affiliations
University College London (GB)
ORCID
Venue
British Journal of Cancer
Publisher
Springer Science and Business Media LLC
Published
2018-04-19
Volume
118
Issue
10
Pages
1283-1288
ISSN
  • 0007-0920 (ISSN-L)
  • 1532-1827
DOI
10.1038/s41416-018-0066-1
PMC
PMC5959857
OpenAlex
W2800736744
Semantic Scholar
3b072afd7ed2cc52c4b72a5870ba6ae122914888
Cited by
183
References
85
Citations by year
2026: 15 · 2025: 24 · 2024: 17 · 2023: 26 · 2022: 38 · 2021: 27 · 2020: 21 · 2019: 9 · 2018: 6
FWCI
2.06
Type
journal article
Language
en
Open access
Licence
Locations
  • British Journal of Cancer (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
  • Cancer Research UK (S_1731)
  • National Institute for Health and Care Research
  • University College London
  • CHILDREN with CANCER UK (15/190, W1055)
  • Brain Tumour Charity (GN-000382)
  • Consejo Nacional de Ciencia y Tecnología
  • Great Ormond Street Hospital for Children
  • Medical Research Council (MR/M000125/1, 1764958)
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, paracrine signaling, tumourigenesis, tumor angiogenesis, tumor invasion and metastasis, cellular reprogramming, cancer stem cells, tumor microenvironment, senolytics, tumor immunology
MeSH terms
Cell Movement, Humans, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasms, Cellular Senescence, Paracrine Communication, Cell Proliferation, Carcinogenesis, Cellular Reprogramming

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 2026-10-10.

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

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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