Cited by 468Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsTGF-β signaling in diseases

The DOI matches its Crossref record; 166 of the 166 references it cites were found in a registry or an index; 5 of the 151 sources its claims cite were checked for support.

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.

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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

166 of 166 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

104 Not checked yet · 12 No basis given · 10 Own interpretation · 2 Supported · 1 Supported so far · 1 Partly supported · accuracy not yet measured

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The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Senescent cells can be eliminated through a SASP-induced immune response, which can involve both innate and adaptive immunity.”
§ Inside and out; the activities of senescence in cancer > Abstract
What the sources say
- Supported
  The “Senescence surveillance and early tumor prevention” section (p. 2) says cytokines and chemokines secreted by senescent hepatocytes attracted both innate and adaptive immune cells, and that the hepatocytes underwent immune clearance. The review also describes innate and adaptive clearance responses in different disease settings (p. 3). (LLM, conf=0.92)
  cites [111] Hoenicke, L. & Zender, L. Immune surveillance of senescent cells—biological significance in cancer- and non-cancer pathologies. Carcinogenesis 33, 1123–1126 (2012). source
- Not checked yetcites [112] Kang, T.-W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011). This is a seminal study that identifies senescence surveillance involving the adaptive immune response. source
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In the paper
“pharmacological inhibition of PTEN in prostate cancer that is wild type for TP53, results in the inhibition of tumorigenesis with senescence induction in a human xenograft model 152”
§ Inside and out; the activities of senescence in cancer > Box 2: PTEN loss-induced cellular senescence (PICS)
What the sources say
- Supported
  The Figure 2 passage (p. 5) identifies MDA PCa-2b as a prostate cancer cell line with wild-type p53. The Figure 3 passage (p. 6) reports that PTEN inhibitor treatment reduced growth of MDA PCa-2b xenografts and increased senescence-associated staining. (LLM, conf=0.94)
  cites [152] Alimonti, A. et al. A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J. Clin. Invest. 120, 681–693 (2010). source
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In the paper
“senescent cells can exhibit hyperactive mitochondrial respiration (oxidative phosphorylation ) in some contexts.”
§ Inside and out; the activities of senescence in cancer > Abstract
What the sources say
- Not checked yetcites [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 yetcites [42] Kondoh, H. et al. Glycolytic enzymes can modulate cellular life span. Cancer Res. 65, 177–185 (2005). source
- Not checked yetcites [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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In the paper
“In contrast to tumour cells, which typically preferentially use glycolysis in the presence of oxygen to generate energy”
§ Inside and out; the activities of senescence in cancer > Abstract
What the sources say
- Not checked yetcites [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
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Senescent cells are metabolically active.”
§ Inside and out; the activities of senescence in cancer > Abstract
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In the paper
“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 .”
§ Inside and out; the activities of senescence in cancer > Mitochondrial metabolism
What the sources say
- Not checked yetcites [47] Haq, R. et al. Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF. Cancer Cell 23, 302–315 (2013). source
- Not checked yetcites [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
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In the paper
“a series of studies [22][23][24][25][26] identified senescence in several premalignant tumours, both in humans and mice.”
§ Inside and out; the activities of senescence in cancer > Senescence in pre-neoplasia
What the sources say
- Not checked yetcites [22] Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005). source
- Not checked yetcites [23] Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005). source
- Not checked yetcites [24] Collado, M. et al. Tumour biology: Senescence in premalignant tumours. Nature 436, 642–642 (2005). source
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In the paper
“Loss of telomerase activity in mice has been shown to suppress tumorigenesis in various tumour models [13][14][15][16]”
§ Inside and out; the activities of senescence in cancer > Senescence in pre-neoplasia
What the sources say
- Not checked yetcites [13] González-Suárez, E., Samper, E., Flores, J. M. & Blasco, M. A. Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis. Nature Genet. 26, 114–117 (2000). source
- Not checked yetcites [14] Greenberg, R. A. et al. Short dysfunctional telomeres impair tumorigenesis in the INK4a(delta2/3) cancer-prone mouse. Cell 97, 515–525 (1999). source
- Not checked yetcites [15] Qi, L. et al. Short telomeres and ataxia-telangiectasia mutated deficiency cooperatively increase telomere dysfunction and suppress tumorigenesis. Cancer Res. 63, 8188–8196 (2003).
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In the paper
“Senescence can also be induced in response to therapy-induced genotoxic stress.”
§ Inside and out; the activities of senescence in cancer > Therapy-induced senescence
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In the paper
“Various triggers such as tissue damage or tumorigenesis-associated stresses can cause stromal cell senescence”
§ Inside and out; the activities of senescence in cancer > Abstract
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In the paper
“telomere attrition-induced senescence is implicated in these tumour suppressive effects 17 .”
§ Inside and out; the activities of senescence in cancer > Senescence in pre-neoplasia
What the sources say
- Not checked yetcites [17] Feldser, D. M. & Greider, C. W. Short telomeres limit tumor progression in vivo by inducing senescence. Cancer Cell 11, 461–469 (2007). source
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In the paper
“and even promoting tumorigenesis, depending on the context.”
§ Inside and out; the activities of senescence in cancer > Abstract
What the sources say
- Not checked yetcites [91] Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008). source
- Not checked yetcites [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 yetcites [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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In the paper
“The senescence-associated secretory phenotype (SASP) mediates the diverse functionality of senescent cells in an autocrine and paracrine manner”
§ Inside and out; the activities of senescence in cancer > Abstract
What the sources say
- Not checked yetcites [5] Campisi, J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685–705 (2013). source
- Not checked yetcites [6] Hoare, M. & Narita, M. Transmitting senescence to the cell neighbourhood. Nature Cell Biol. 15, 887–889 (2013). source
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In the paper
“which may either facilitate or inhibit tumour progression, depending on the context.”
§ Inside and out; the activities of senescence in cancer > Abstract
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In the paper
“Paradoxically, the diverse effects of the SASP include not only tumour suppressive but also tumorigenic aspects.”
§ Inside and out; the activities of senescence in cancer > Introduction
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In the paper
“activating an immune response”
§ Inside and out; the activities of senescence in cancer > Abstract
What the sources say
- Not checked yetcites [111] Hoenicke, L. & Zender, L. Immune surveillance of senescent cells—biological significance in cancer- and non-cancer pathologies. Carcinogenesis 33, 1123–1126 (2012). source
- Not checked yetcites [112] Kang, T.-W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011). This is a seminal study that identifies senescence surveillance involving the adaptive immune response. source
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In the paper
“Autophagy is activated during senescence”
- Also stated in: § References · boosted
  “This study shows that autophagy is activated during senescence”
§ Inside and out; the activities of senescence in cancer > Abstract
What the sources say
- Not checked yetcites [4] Salama, R., Sadaie, M., Hoare, M. & Narita, M. Cellular senescence and its effector programs. Genes Dev. 28, 99–114 (2014). source
- Not checked yetcites [73] Gewirtz, D. A. Autophagy and senescence: a partnership in search of definition. Autophagy 9, 808–812 (2013). source
- Not checked yetcites [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
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In the paper
“These pathways collectively contribute to the establishment and maintenance of senescent cells and their fitness.”
§ Inside and out; the activities of senescence in cancer > Introduction
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In the paper
“OIS was initially described in culture, where the ectopic expression of oncogenic HRAS-G12V, or its downstream effectors paradoxically led to premature senescence [19][20][21] .”
§ Inside and out; the activities of senescence in cancer > Senescence in pre-neoplasia
What the sources say
- Not checked yetcites [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
- Not checked yetcites [20] Lin, A. W. et al. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 12, 3008–3019 (1998). source
- Not checked yetcites [21] Zhu, J., Woods, D., McMahon, M. & Bishop, J. M. Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev. 12, 2997–3007 (1998). source
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In the paper
“the senescence response can have profound cell autonomous and non-cell autonomous activities in vivo 5,6 .”
§ Inside and out; the activities of senescence in cancer > Introduction
What the sources say
- Not checked yetcites [5] Campisi, J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685–705 (2013). source
- Not checked yetcites [6] Hoare, M. & Narita, M. Transmitting senescence to the cell neighbourhood. Nature Cell Biol. 15, 887–889 (2013). source
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In the paper
“Quijano et al. 53 showed that the inhibition of FA oxidation in OIS cells results in a reduced production of many SASP components.”
§ Inside and out; the activities of senescence in cancer > Mitochondrial metabolism
What the sources say
- Not checked yetcites [53] Quijano, C. et al. Oncogene-induced senescence results in marked metabolic and bioenergetic alterations. Cell Cycle 11, 1383–1392 (2012). source
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In the paper
“when Kras G12D -driven PDA development is accompanied by loss of Trp53 (and is thus senescence defective), autophagy deficiency instead accelerated tumour progression.”
§ Inside and out; the activities of senescence in cancer > Autophagy
What the sources say
- Not checked yetcites [87] Rosenfeldt, M. T. et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature 504, 296–300 (2014). source
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In the paper
“In the lung model, regardless of p53 status, autophagy deficiency diverts adenoma or adenocarcinoma into oncocytoma, a rare and predominantly benign tumour characterised by the accumulation of respiration-defective mitochondria 88 .”
§ Inside and out; the activities of senescence in cancer > Autophagy
What the sources say
- Not checked yetcites [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
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In the paper
“Kaplon et al. 41 recently showed that increased mitochondrial oxidative phosphorylation is critical for OIS induction.”
§ Inside and out; the activities of senescence in cancer > Mitochondrial metabolism
What the sources say
- Not checked yetcites [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
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In the paper
“Te Poele et al. 31 showed that TIS was also evident in human breast cancer samples taken from patients who had undergone pre-operative neoadjuvant chemotherapy.”
§ Inside and out; the activities of senescence in cancer > Therapy-induced senescence
What the sources say
- Not checked yetcites [31] Poele te, R. H., Okorokov, A. L., Jardine, L., Cummings, J. & Joel, S. P. DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res. 62, 1876–1883 (2002).
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In the paper
“these studies suggest that the p53-mediated senescence pathway can affect therapeutic outcome, particularly in an apoptosisdefective context.”
§ Inside and out; the activities of senescence in cancer > Therapy-induced senescence
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In the paper
“The loss of tumour suppressors, such as PTEN 23 (BOX 2), RB 27 , neurofribromin 1 (NF1) 28 and inositol polyphosphate-4-phosphatase, type II (INPP4B) 29 , has also been associated with senescence in premalignant tumours.”
§ Inside and out; the activities of senescence in cancer > Senescence in pre-neoplasia
What the sources say
- Not checked yetcites [23] Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005). source
- Not checked yetcites [27] Shamma, A. et al. Rb regulates DNA damage response and cellular senescence through E2F-dependent suppression of N-ras isoprenylation. Cancer Cell 15, 255–269 (2009). source
- Not checked yetcites [28] Courtois-Cox, S. et al. A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell 10, 459–472 (2006). source
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In the paper
“but its importance varies depending on the context.”
§ Inside and out; the activities of senescence in cancer > Abstract
What the sources say
- Not checked yetcites [65] Hoare, M., Young, A. R. J. & Narita, M. Autophagy in cancer: Having your cake and eating it. Semin. Cancer Biol. 21, 397–404 (2011).
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“Braumüller et al. 126 confirmed that IFNγ and TNF induce senescence in a number of different cancers both in vitro and in vivo.”
§ Inside and out; the activities of senescence in cancer > Cytokine-mediated senescence
What the sources say
- Not checked yetcites [126] Braumüller, H. et al. T-helper-1-cell cytokines drive cancer into senescence. Nature 494, 361–365 (2013). This study shows that tumours can be induced into senescence by cytokines that are derived from TAA-activated CD4+ T H 1 cells. source
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In the paper
“Therefore, timely activation of HSCs and elimination of senescent activated HSCs are critical for tissue integrity in this model.”
§ Inside and out; the activities of senescence in cancer > Senescence in the stroma
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In the paper
“With a number of different cancer models in the p16-reporter mouse, including transgenic autochthonous, transplanted and spontaneous tumours, the authors showed that early neoplastic events induce stromal senescence often much earlier than the tumours became palpable.”
§ Inside and out; the activities of senescence in cancer > Senescence in the stroma
What the sources say
- Not checked yetcites [124] Burd, C. E. et al. Monitoring tumorigenesis and senescence in vivo with a p16(INK4a)-luciferase model. Cell 152, 340–351 (2013). This study shows a close and general correlation between stromal senescence and early neoplastic events in a new p16-'monitor' mouse model. source
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In the paper
“the matricellular protein CCN1 (also known as CYR61), which is secreted from damaged hepatocytes, can trigger senescence in activated HSCs 122”
§ Inside and out; the activities of senescence in cancer > Senescence in the stroma
What the sources say
- Not checked yetcites [122] Kim, K.-H., Chen, C.-C., Monzon, R. I. & Lau, L. F. Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts. Mol. Cell. Biol. 33, 2078–2090 (2013). source
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“Another example involves adaptive immunity and T H 1 T cell cytokines that can directly drive cancer cells into senescence 126”
§ Inside and out; the activities of senescence in cancer > Cytokine-mediated senescence
What the sources say
- Not checked yetcites [126] Braumüller, H. et al. T-helper-1-cell cytokines drive cancer into senescence. Nature 494, 361–365 (2013). This study shows that tumours can be induced into senescence by cytokines that are derived from TAA-activated CD4+ T H 1 cells. source
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In the paper
“paracrine pro-senescence factors, such as insulin-like growth factor binding protein 7 (IGFBP7), IL-1 and transforming growth factor-β (TGFß), were also identified 6,93,106,107”
§ Inside and out; the activities of senescence in cancer > Senescence-associated secretory phenotype (SASP)
What the sources say
- Not checked yetcites [6] Hoare, M. & Narita, M. Transmitting senescence to the cell neighbourhood. Nature Cell Biol. 15, 887–889 (2013). source
- Not checked yetcites [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 yetcites [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
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In the paper
“The development of psoriatic plaques is accompanied by activation of CD4 + T cells and other immune cells, which provide a plethora of cytokines and chemokines, including TNF and IFNγ 136”
§ Inside and out; the activities of senescence in cancer > Cytokine-mediated senescence
What the sources say
- Not checked yetcites [136] Nickoloff, B. J. & Nestle, F. O. Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities. J. Clin. Invest. 113, 1664–1675 (2004). source
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“fibroblasts induced to senesce in culture promoted the proliferation and invasiveness of their neighbouring (pre)malignant epithelial cells 91,[103][104][105]119”
§ Inside and out; the activities of senescence in cancer > Senescence in the stroma
What the sources say
- Not checked yetcites 91,[103][104][105]119
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“Tag-activated CD4 + T H 1 cells expressing a T cell receptor specific for the Tag peptide (Tag-T H 1 cells) have a tumour suppressive role, which requires that the target tumour cells respond to both the IFNγ and tumour necrosis factor (TNF) signals produced by the Tag-T H 1 cells 128”
§ Inside and out; the activities of senescence in cancer > Cytokine-mediated senescence
What the sources say
- Not checked yetcites [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
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“the same group later showed that these cells were arrested due to senescence 126”
§ Inside and out; the activities of senescence in cancer > Cytokine-mediated senescence
What the sources say
- Not checked yetcites [126] Braumüller, H. et al. T-helper-1-cell cytokines drive cancer into senescence. Nature 494, 361–365 (2013). This study shows that tumours can be induced into senescence by cytokines that are derived from TAA-activated CD4+ T H 1 cells. source
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In the paper
“senescent cells actively communicate with neighbouring cells and the extracellular matrix through a plethora of secretory factors, including extracellular proteases, cytokines and chemokines, and growth factors.”
§ Inside and out; the activities of senescence in cancer > Senescence-associated secretory phenotype (SASP)
What the sources say
- Not checked yetcites [89] Kuilman, T. & Peeper, D. S. Senescence-messaging secretome: SMS-ing cellular stress. Nature Rev. Cancer 9, 81–94 (2009). source
- Not checked yetcites [90] Coppé, 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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“psoriasis, an immune-mediated cutaneous chronic inflammatory disease is associated with a reduced risk for cancer 134”
§ Inside and out; the activities of senescence in cancer > Cytokine-mediated senescence
What the sources say
- Not checked yetcites [134] Nickoloff, B. J., Ben-Neriah, Y. & Pikarsky, E. Inflammation and cancer: is the link as simple as we think? J. Invest. Dermatol. 124, x–xiv (2005). source
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“these remarkably similar findings across different tumour models suggest that stromal senescence activated by neoplastic events is generally tumorigenic.”
§ Inside and out; the activities of senescence in cancer > Senescence in the stroma
What the sources say
- Not checked yetcites [124] Burd, C. E. et al. Monitoring tumorigenesis and senescence in vivo with a p16(INK4a)-luciferase model. Cell 152, 340–351 (2013). This study shows a close and general correlation between stromal senescence and early neoplastic events in a new p16-'monitor' mouse model. source
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In the paper
“if the tumour cells fail to respond to either IFN or TNF, Tag-T H 1 cells do not just fail to suppress tumour growth, instead they promote tumour growth in RIP-Tag2 mice 128”
§ Inside and out; the activities of senescence in cancer > Cytokine-mediated senescence
What the sources say
- Not checked yetcites [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
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“senescent activated HSCs limit hepatocellular carcinoma (HCC) development in the presence of the chemical carcinogen diethyl nitrosamine (DEN), at least in part through activating a 'classical' tumour-suppressive M1 phenotype of macrophages, which provides an anti-tumour microenvironment and eventually eliminates senescent HSCs”
§ Inside and out; the activities of senescence in cancer > Senescence in the stroma
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In the paper
“IL-6 and IL-8 secreted from senescent cells promote tumorigenesis in premalignant, but not normal cells.”
§ Inside and out; the activities of senescence in cancer > Senescence-associated secretory phenotype (SASP)
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In the paper
“the chemokine GRO1 (also known as CXCL1), which is secreted from transformed cells, can induce senescence in stromal fibroblasts 125”
§ Inside and out; the activities of senescence in cancer > Cytokine-mediated senescence
What the sources say
- Not checked yetcites [125] Yang, G. et al. The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc. Natl Acad. Sci. USA 103, 16472–16477 (2006). source
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In the paper
“Thus tumour apoptosis can locally provoke cytokine-mediated senescence in this model.”
§ Inside and out; the activities of senescence in cancer > Cytokine-mediated senescence
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In the paper
“studies in a spontaneous mouse melanoma model suggest that dormancy in micrometastatic lesions is mediated by immunosurveillance 131,132”
§ Inside and out; the activities of senescence in cancer > Cytokine-mediated senescence
What the sources say
- Not checked yetcites [131] Lengagne, R. et al. Distinct role for CD8 T cells toward cutaneous tumors and visceral metastases. J. Immunol. 180, 130–137 (2008). source
- Not checked yetcites [132] Eyles, J. et al. Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J. Clin. Invest. 120, 2030–2039 (2010). source
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In the paper
“cytostatic CD8 + T cells suppress the expansion of the disseminated tumour cells 132”
§ Inside and out; the activities of senescence in cancer > Cytokine-mediated senescence
What the sources say
- Not checked yetcites [132] Eyles, J. et al. Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J. Clin. Invest. 120, 2030–2039 (2010). source
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The nature of the SASP and its targets, and the overall downstream outcomes, vary considerably depending on the cellular context, type of stress, and type of model used (FIG.2).”
§ Inside and out; the activities of senescence in cancer > Senescence-associated secretory phenotype (SASP)
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“CD8 + T cells also secrete cytostatic cytokines, including IFNγ and TNF.”
§ Inside and out; the activities of senescence in cancer > Cytokine-mediated senescence
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, senescence, which was long thought to be purely a stress response, also appears to be physiologically programmed.”
§ Inside and out; the activities of senescence in cancer > Embryogenesis:
hedged
None of the sources cited for this claim have been checked yet.
In the paper
“| DNA damage | Eμ-Myc; ectopic Bcl2 | cyclophosphamide | Lymphoma regression | 32, 43 | | | |”
§ Inside and out; the activities of senescence in cancer > Additional information
What the sources say
- Not checked yetcites [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
- Not checked yetcites [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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In the paper
“This was the first study showing that chemotherapy-induced tumour senescence contributed to the improved survival in mice, in an apoptosis defective context.”
§ Inside and out; the activities of senescence in cancer > References
What the sources say
- Not checked yetcites [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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In the paper
“| | Eμ-Myc | | | | Cdk2 ablation | Lymphomagenesis delay | 157 |”
§ Inside and out; the activities of senescence in cancer > Additional information
What the sources say
- Not checked yetcites [157] Campaner, S. et al. Cdk2 suppresses cellular senescence induced by the c-myc oncogene. Nature 12, 54–59 (2010).
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In the paper
“| MDM2 inhibitor | Pten loxP/loxP ; Pb-Cre | Nutlin-3 | Prostate tumour size decreased | 152 | | | |”
§ Inside and out; the activities of senescence in cancer > Additional information
What the sources say
- Not checked yetcites [152] Alimonti, A. et al. A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J. Clin. Invest. 120, 681–693 (2010). source
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In the paper
“Here also a TNF and IFNγ cocktail might provide a dominant tumour suppressor activity through cytokine-induced senescence.”
§ Inside and out; the activities of senescence in cancer > Cytokine-mediated senescence
What the sources say
- Not checked yetcites [135] Nickoloff, B. J. Creation of psoriatic plaques: the ultimate tumor suppressor pathway. A new model for an ancient T-cell-mediated skin disease. J. Cutan. Pathol. 28, 57–64 (2001). source
hedged
conditional
In the paper
“They showed that ERVWE1-mediated cell fusion induces senescence.”
§ Inside and out; the activities of senescence in cancer > Embryogenesis:
What the sources say
- Not checked yetcites [151] Chuprin, A. et al. Cell fusion induced by ERVWE1 or measles virus causes cellular senescence. Genes Dev. 27, 2356–2366 (2013). source
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In the paper
“| T H 1 cell cytokines | RIP-Tag2 | | | IFNγ and TNF | Pancreatic β-cell tumour regression | 126 |”
§ Inside and out; the activities of senescence in cancer > Additional information
What the sources say
- Not checked yetcites [126] Braumüller, H. et al. T-helper-1-cell cytokines drive cancer into senescence. Nature 494, 361–365 (2013). This study shows that tumours can be induced into senescence by cytokines that are derived from TAA-activated CD4+ T H 1 cells. source
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In the paper
“Even in the same tissue, the same triggers can either suppress (by inducing senescence) or promote tumorigenesis, as in the case for cytokine-induced senescence 128,143”
§ Inside and out; the activities of senescence in cancer > Concluding remarks
What the sources say
- Not checked yetcites [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 yetcites [143] Pribluda, A. et al. A senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism. Cancer Cell 24, 242–256 (2013). source
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In the paper
“This was the first study to show that the innate immune response eliminates the senescent cells induced in tumours in mice.”
§ Inside and out; the activities of senescence in cancer > References
What the sources say
- Not checked yetcites [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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In the paper
“| mTOR inhibitor | Eμ-Myc | | | | Everolimus | Lymphoma regression | 160 |”
§ Inside and out; the activities of senescence in cancer > Additional information
What the sources say
- Not checked yetcites [160] Wall, M. et al. The mTORC1 inhibitor everolimus prevents and treats Eμ-Myc lymphoma by restoring oncogene-induced senescence. Cancer Discov. 3, 82–95 (2013). source
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In the paper
“metabolic intermediates of the TCA cycle affect epigenetic-mediated control of gene expression through regulating the modification of histones and DNA 137,138”
§ Inside and out; the activities of senescence in cancer > Concluding remarks
What the sources say
- Not checked yetcites [137] Kaelin, W. G. & McKnight, S. L. Influence of metabolism on epigenetics and disease. Cell 153, 56–69 (2013). source
- Not checked yetcites [138] Lu, C. & Thompson, C. B. Metabolic regulation of epigenetics. Cell. Metab. 16, 9–17 (2012). source
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, similar to apoptosis, senescence also contributes to embryonic patterning.”
§ Inside and out; the activities of senescence in cancer > Embryogenesis:
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In the paper
“| | Pten loxP/loxP ; Pb-Cre | Skp2 ablation | Prostate cancer restriction | 156 | | | |”
§ Inside and out; the activities of senescence in cancer > Additional information
What the sources say
- Not checked yetcites [156] Lin, H.-K. et al. Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence. Nature 464, 374–379 (2010). source
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In the paper
“selective killing of those p16-expressing cells in a premature ageing mouse model also delays ageing phenotypes 148”
§ Inside and out; the activities of senescence in cancer > Box 1: Consequences of cellular senescence: aging and development
What the sources say
- Not checked yetcites [148] Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2012). source
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In the paper
“the outcome of endogenous p53 reactivation can be senescence and/or cell death depending on the tumour type 35,141,142”
§ Inside and out; the activities of senescence in cancer > Concluding remarks
What the sources say
- Not checked yetcites [35] Ventura, A. et al. Restoration of p53 function leads to tumour regression in vivo. Nature 445, 661–665 (2007). source
- Not checked yetcites [141] Martins, C. P., Brown-Swigart, L. & Evan, G. I. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 127, 1323–1334 (2006). source
- Not checked yetcites [142] Dickins, R. A. et al. Tissue-specific and reversible RNA interference in transgenic mice. Nature Genet. 39, 914–921 (2007). source
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In the paper
“| PTEN inhibitor | Human prostate cancer xenograft VO-OHpic [ | Tumour growth inhibition | 152 | | | |”
§ Inside and out; the activities of senescence in cancer > Additional information
What the sources say
- Not checked yetcites [152] Alimonti, A. et al. A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J. Clin. Invest. 120, 681–693 (2010). source
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In the paper
“The SASP, however, has been shown to be mainly regulated through persistent DDR 96”
§ Inside and out; the activities of senescence in cancer > Box 2: PTEN loss-induced cellular senescence (PICS)
What the sources say
- Not checked yetcites [96] Rodier, F. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nature 11, 973–979 (2009).
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“in the senescence immunosurveillance model, senescence per se may not be a very efficient tumour suppressor, at least in some tumour models.”
§ Inside and out; the activities of senescence in cancer > Concluding remarks
hedged
In the paper
“| DNA damage | Eμ-Nras G12V ; ectopic Bcl2 | Doxorubicin | Lymphoma regression | 22 | | | |”
§ Inside and out; the activities of senescence in cancer > Additional information
What the sources say
- Not checked yetcites [22] Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005). source
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In the paper
“TP53 up-regulation upon PTEN inhibition appears to be dependent on mTOR activity, which increases TP53 translation 152”
§ Inside and out; the activities of senescence in cancer > Box 2: PTEN loss-induced cellular senescence (PICS)
What the sources say
- Not checked yetcites [152] Alimonti, A. et al. A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J. Clin. Invest. 120, 681–693 (2010). source
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In the paper
“unlike OIS, PICS occurs in the absence of transient hyper-proliferation and a DNA damage response (DDR) 152”
§ Inside and out; the activities of senescence in cancer > Box 2: PTEN loss-induced cellular senescence (PICS)
What the sources say
- Not checked yetcites [152] Alimonti, A. et al. A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J. Clin. Invest. 120, 681–693 (2010). source
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In the paper
“| | hematopoietic system | BCR-ABL suppression | Regression of pro-B cell leukemia | 116 | | | |”
§ Inside and out; the activities of senescence in cancer > Additional information
What the sources say
- Not checked yetcites [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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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus PICS might provide a unique opportunity, where pro-senescence therapy may be separable from the potential side effects derived from the SASP.”
§ Inside and out; the activities of senescence in cancer > Box 2: PTEN loss-induced cellular senescence (PICS)
hedged
conditional
None of the sources cited for this claim have been checked yet.
In the paper
“The analogy between senescence and dormancy in some tumours also implies that the in vivo senescence-like arrest may be unstable, because dormant tumour cells can regrow after long periods of time 130,140”
§ Inside and out; the activities of senescence in cancer > Concluding remarks
What the sources say
- Not checked yetcites [130] Quesnel, B. Tumor dormancy and immunoescape. APMIS 116, 685–694 (2008). source
- Not checked yetcites [140] Giancotti, F. G. Mechanisms governing metastatic dormancy and reactivation. Cell 155, 750–764 (2013). source
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In the paper
“This was the first study to show that hepatic stellate cell senescence controls fibrosis through the SASP.”
§ Inside and out; the activities of senescence in cancer > References
What the sources say
- Not checked yetcites [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
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In the paper
“This study shows that tumours can be induced into senescence by cytokines derived from tumour associated antigen (TAA)-activated CD4+ Th1 cells.”
§ Inside and out; the activities of senescence in cancer > References
What the sources say
- Not checked yetcites [126] Braumüller, H. et al. T-helper-1-cell cytokines drive cancer into senescence. Nature 494, 361–365 (2013). This study shows that tumours can be induced into senescence by cytokines that are derived from TAA-activated CD4+ T H 1 cells. source
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None of the sources cited for this claim have been checked yet.
In the paper
“These studies 91,92 describe the critical role of proinflammatory cytokines and their receptors in senescence.”
§ Inside and out; the activities of senescence in cancer > References
What the sources say
- Not checked yetcites [91] Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008). source
- Not checked yetcites [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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In the paper
“This study shows a close and general correlation between stromal senescence and early neoplastic events in a new p16-monitor mouse model.”
§ Inside and out; the activities of senescence in cancer > References
What the sources say
- Not checked yetcites [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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correlational
In the paper
“This is a seminal study identifying 'senescence-surveillance' involving the adaptive immune response.”
§ Inside and out; the activities of senescence in cancer > References
What the sources say
- Not checked yetcites [112] Kang, T.-W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011). This is a seminal study that identifies senescence surveillance involving the adaptive immune response. source
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In the paper
“and that TIS cells are sensitive to blocking glucose use or autophagy, which causes ER-related apoptosis.”
§ Inside and out; the activities of senescence in cancer > References
What the sources say
- Not checked yetcites [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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In the paper
“and that the inhibition of autophagy delays of onset of senescence and SASP.”
§ Inside and out; the activities of senescence in cancer > References
What the sources say
- Not checked yetcites [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
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In the paper
“and that depletion of ME1 or ME2 induces senescence in both normal and tumour cells.”
§ Inside and out; the activities of senescence in cancer > References
What the sources say
- Not checked yetcites [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
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In the paper
“This study identified the inflammasome as a critical regulator of the SASP.”
§ Inside and out; the activities of senescence in cancer > References
What the sources say
- Not checked yetcites [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
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It may state two separate claims as one. 37
Probably not a substantial claim. 8
The quote only partly states this claim. 3

The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“activated HSCs become senescent, exhibiting a typical SASP, including the expression of extracellular matrix degrading enzymes and proinflammatory cytokines.”
§ Inside and out; the activities of senescence in cancer > Senescence in the stroma
What the sources say
- Partly supported
  The Results section on p53 action in HSCs describes CCl4-induced fibrosis and HSC activation; the Introduction says HSCs eventually senesce after an initial proliferative phase. The Results section on HSC SASP reports secretion of cytokines including IL-6 and IFNγ by senescent HSCs. Our copy does not establish the claimed expression of extracellular-matrix-degrading enzymes as part of that SASP. (LLM, conf=0.85)
  cites [94] Lujambio, A. et al. Non-cell-autonomous tumor suppression by p53. Cell 153, 449–460 (2013). sourceExperimental — accuracy not yet measured
- Partly supported
  The Results section reports that activated HSCs become senescent in CCl4-treated mouse livers. It also reports matrix metalloproteinase and cytokine-gene upregulation in senescent activated HSCs, but that expression analysis used cultured primary human HSCs induced to senesce with etoposide, not HSCs from the mouse fibrosis model. The claim overextends the SASP finding to that model. (LLM, conf=0.86)
  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. sourceExperimental — accuracy not yet measured
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It may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“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”
§ Inside and out; the activities of senescence in cancer > Concluding remarks
What the sources say
- Supported
  The Results state that senescent cells in treated p53 wild-type mammary tumors did not undergo apoptosis; the Discussion says p53-mediated arrest prevented mitosis despite chemotherapy-induced DNA damage. The Results and Discussion also link persistent senescent cells and their cytokines to proliferation of neighboring tumor cells and possible relapse. These findings come from a breast-tumor model. (LLM, conf=0.88)
  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
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Inside and out; the activities of senescence in cancer > Abstract
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Probably not a substantial claim. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“the long-term fate of senescent cells, which, similar to apoptotic cells, can be cleared from lesions in some contexts.”
§ Inside and out; the activities of senescence in cancer > Introduction
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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.”
§ Inside and out; the activities of senescence in cancer > Therapy-induced senescence
What the sources say
- Not checked yetcites [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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It may state two separate claims as one.
In the paper
“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.”
§ Inside and out; the activities of senescence in cancer > Mitochondrial metabolism
What the sources say
- Not checked yetcites [53] Quijano, C. et al. Oncogene-induced senescence results in marked metabolic and bioenergetic alterations. Cell Cycle 11, 1383–1392 (2012). source
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Senescence has a heterogeneous phenotype in terms of cellular markers: multiple markers are required to define senescence with confidence.”
§ Inside and out; the activities of senescence in cancer > Introduction
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correlational
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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] .”
§ Inside and out; the activities of senescence in cancer > Introduction
What the sources say
- Not checked yetcites [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 yetcites [3] Kuilman, T., Michaloglou, C., Mooi, W. J. & Peeper, D. S. The essence of senescence. Genes Dev. 24, 2463–2479 (2010). source
- Not checked yetcites [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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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“including reinforcing or inducing senescence”
§ Inside and out; the activities of senescence in cancer > Abstract
What the sources say
- Not checked yetcites [91] Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008). source
- Not checked yetcites [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 yetcites [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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In the paper
“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).”
§ Inside and out; the activities of senescence in cancer > Mitochondrial metabolism
What the sources say
- Not checked yetcites [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
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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 .”
§ Inside and out; the activities of senescence in cancer > Autophagy
What the sources say
- Not checked yetcites [58] Narita, M. et al. Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science 332, 966–970 (2011). source
- Not checked yetcites [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
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It may state two separate claims as one.
In the paper
“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 .”
§ Inside and out; the activities of senescence in cancer > Mitochondrial metabolism
What the sources say
- Not checked yetcites [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
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Senescence typically depends on the p53 and RB pathways, but other effector programs confer additional layers of regulation.”
§ Inside and out; the activities of senescence in cancer > Introduction
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It may state two separate claims as one.
In the paper
“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 .”
§ Inside and out; the activities of senescence in cancer > Autophagy
What the sources say
- Not checked yetcites [87] Rosenfeldt, M. T. et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature 504, 296–300 (2014). source
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Inside and out; the activities of senescence in cancer > Cytokine-mediated senescence
What the sources say
- Not checked yetcites [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 yetcites [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
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It may state two separate claims as one.
In the paper
“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”
§ Inside and out; the activities of senescence in cancer > Cytokine-mediated senescence
What the sources say
- Not checked yetcites [36] Reimann, M. et al. Tumor stroma-derived TGF-b limits Myc-Driven lymphomagenesisvia Suv39h1-dependent senescence. Cancer Cell 17, 262–272 (2010). source
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Inside and out; the activities of senescence in cancer > Senescence in the stroma
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It may state two separate claims as one.
In the paper
“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”
§ Inside and out; the activities of senescence in cancer > Cytokine-mediated senescence
What the sources say
- Not checked yetcites [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
plain
direct
It may state two separate claims as one.
In the paper
“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”
§ Inside and out; the activities of senescence in cancer > Clearance of senescent cells through an immune response
What the sources say
- Not checked yetcites [118] Guerra, C. et al. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell 19, 728–739 (2011). source
hedged
direct
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Inside and out; the activities of senescence in cancer > Cytokine-mediated senescence
What the sources say
- Not checked yetcites [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
- Not checked yetcites [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
plain
direct
It may state two separate claims as one.
In the paper
“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.”
§ Inside and out; the activities of senescence in cancer > Autophagy
What the sources say
- Not checked yetcites [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
hedged
conditional
It may state two separate claims as one.
In the paper
“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”
§ Inside and out; the activities of senescence in cancer > Senescence in the stroma
What the sources say
- Not checked yetcites [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
hedged
conditional
It may state two separate claims as one.
In the paper
“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”
§ Inside and out; the activities of senescence in cancer > Cytokine-mediated senescence
What the sources say
- Not checked yetcites [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
hedged
direct
It may state two separate claims as one.
In the paper
“human melanocytic naevi (an OIS model), remain non-proliferative for decades without transformation into malignant melanoma 25”
§ Inside and out; the activities of senescence in cancer > Clearance of senescent cells through an immune response
What the sources say
- Not checked yetcites [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
plain
direct
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“these same factors can facilitate senescence in a cell-autonomous fashion, thus amplifying the phenotype 91,92,105”
§ Inside and out; the activities of senescence in cancer > Senescence-associated secretory phenotype (SASP)
What the sources say
- Not checked yetcites [91] Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008). source
- Not checked yetcites [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 yetcites [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
plain
direct
It may state two separate claims as one.
In the paper
“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.”
§ Inside and out; the activities of senescence in cancer > Clearance of senescent cells through an immune response
What the sources say
- Not checked yetcites [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
plain
direct
It may state two separate claims as one.
In the paper
“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”
§ Inside and out; the activities of senescence in cancer > Clearance of senescent cells through an immune response
What the sources say
- Not checked yetcites [118] Guerra, C. et al. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell 19, 728–739 (2011). source
plain
direct
It may state two separate claims as one.
In the paper
“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”
§ Inside and out; the activities of senescence in cancer > Clearance of senescent cells through an immune response
What the sources say
- Not checked yetcites [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
plain
direct
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The SASP also attracts innate immune cells that in turn eliminate the senescent HSCs and facilitate the resolution of fibrosis 94,120”
§ Inside and out; the activities of senescence in cancer > Senescence in the stroma
What the sources say
- Not checked yetcites [94] Lujambio, A. et al. Non-cell-autonomous tumor suppression by p53. Cell 153, 449–460 (2013). source
- Not checked yetcites [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
plain
direct
It may state two separate claims as one.
In the paper
“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”
§ Inside and out; the activities of senescence in cancer > Cytokine-mediated senescence
What the sources say
- Not checked yetcites [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
hedged
correlational
It may state two separate claims as one.
In the paper
“| | LSL-Kras G12V ; RERTn +/ERT | Cdk4 ablation | development | 158 | | | |”
- Also stated in: § Additional information · plain
  “| | | | | | Suppression of non-small cell lung carcinoma | | |”
§ Inside and out; the activities of senescence in cancer > Additional information
What the sources say
- Not checked yetcites [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
plain
direct
The quote only partly states this claim.
In the paper
“This is a seminal study that identified OIS of human melanocytic naevi.”
§ Inside and out; the activities of senescence in cancer > References
What the sources say
- Not checked yetcites [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
plain
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“This seminal paper established the concept of OIS.”
§ Inside and out; the activities of senescence in cancer > References
What the sources say
- Not checked yetcites [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
boosted
direct
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Embryonic cell senescence is p21, but not p53, dependent, is accompanied by the SASP, and these cells are eliminated by macrophages 149,150”
§ Inside and out; the activities of senescence in cancer > Embryogenesis:
What the sources say
- Not checked yetcites [149] Muñoz-Espín, D. et al. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118 (2013). source
- Not checked yetcites [150] Storer, M. et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155, 1119–1130 (2013). source
plain
direct
It may state two separate claims as one.
In the paper
“| CDK4 inhibitor | LSL-Kras G12V ; RERTn +/ERT | PD0332991 | development | 158 | | | |”
- Also stated in: § Additional information · plain
  “| | | | | | Suppression of non-small cell lung carcinoma | | |”
§ Inside and out; the activities of senescence in cancer > Additional information
What the sources say
- Not checked yetcites [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
plain
direct
The quote only partly states this claim.
None of the sources cited for this claim have been checked yet.
In the paper
“The partial induction of senescence in tumours could eradicate or exacerbate the tumours 110,113”
§ Inside and out; the activities of senescence in cancer > Concluding remarks
What the sources say
- Not checked yetcites [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 yetcites [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
hedged
conditional
It may state two separate claims as one.
In the paper
“This study established the metabolomics profile of OIS cells, identifying active PDH with increased mitochondrial respiration during OIS.”
§ Inside and out; the activities of senescence in cancer > References
What the sources say
- Not checked yetcites [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
plain
correlational
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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]”
§ Inside and out; the activities of senescence in cancer > Box 1: Consequences of cellular senescence: aging and development
What the sources say
- Not checked yetcites [145][146][147]
plain
direct
It may state two separate claims as one.
In the paper
“| SKP2 inhibitor | xenografts | | | SKP2 Inhibitor#25 | Tumour growth inhibition | 159 |”
- Also stated in: § Additional information · plain
  “| | Human lung and prostate cancer | | | | | | |”
§ Inside and out; the activities of senescence in cancer > Additional information
What the sources say
- Not checked yetcites [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
plain
direct
The quote only partly states this claim.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Inside and out; the activities of senescence in cancer > Box 2: PTEN loss-induced cellular senescence (PICS)
What the sources say
- Not checked yetcites [153] Schlomm, T. et al. Clinical significance of p53 alterations in surgically treated prostate cancers. Mod. Pathol. 21, 1371–1378 (2008). source
- Not checked yetcites [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
plain
correlational
It may state two separate claims as one.
In the paper
“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”
§ Inside and out; the activities of senescence in cancer > Box 2: PTEN loss-induced cellular senescence (PICS)
What the sources say
- Not checked yetcites [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
plain
direct
It may state two separate claims as one.
In the paper
“| | haematopoietic system | MYC suppression | lymphoma | 116 | | | |”
§ Inside and out; the activities of senescence in cancer > Additional information
What the sources say
- Not checked yetcites [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
plain
direct
Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“unlike p16-ablation, elimination of p16-expressing cells does not facilitate tumorigenesis in this model.”
§ Inside and out; the activities of senescence in cancer > Box 1: Consequences of cellular senescence: aging and development
plain
It may state two separate claims as one.
In the paper
“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.”
§ Inside and out; the activities of senescence in cancer > References
What the sources say
- Not checked yetcites [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
hedged
conditional
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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”
§ Inside and out; the activities of senescence in cancer > References
What the sources say
- Not checked yetcites [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
boosted
direct
It may state two separate claims as one.
In the paper
“This study shows that Malic enzymes (MEs) and p53 reciprocally repress each other”
§ Inside and out; the activities of senescence in cancer > References
What the sources say
- Not checked yetcites [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
boosted
direct
Probably not a substantial claim. The paper’s conclusions may not depend on it.

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?

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.

Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
- § Inside and out; the activities of senescence in cancer > Autophagy
  “Interestingly, the effect of autophagy inhibition in Kras G12V -driven lung tumorigenesis (another OIS model 24 ) is distinct from the pancreas model.”
- § Inside and out; the activities of senescence in cancer > Autophagy
  “Thus, 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.”

1 of 1

1 retracted

Tissue-specific Autophagy Alterations and Increased Tumorigenesis in Mice Deficient in Atg4C/Autophagin-3
Mariño, G., Salvador-Montoliu, N., Fueyo, A., Knecht, E., Mizushima, N., & López-Otı́n, C. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m701194200 · Cited by 427
Retracted
The Hallmarks of Aging
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013) · Cell · doi:10.1016/j.cell.2013.05.039 · Cited by 14,982
The serial cultivation of human diploid cell strains
Hayflick, L., & Moorhead, P. S. (1961) · Experimental Cell Research · doi:10.1016/0014-4827(61)90192-6 · Cited by 8,508
Autophagy: Renovation of Cells and Tissues
Mizushima, N., & Komatsu, M. (2011) · Cell · doi:10.1016/j.cell.2011.10.026 · Cited by 6,615
The limited in vitro lifetime of human diploid cell strains
Hayflick, L. (1965) · Experimental Cell Research · doi:10.1016/0014-4827(65)90211-9 · Cited by 5,876
Telomeres shorten during ageing of human fibroblasts
Harley, C. B., Futcher, A. B., & Greider, C. W. (1990) · Nature · doi:10.1038/345458a0 · Cited by 5,750
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,218
The senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206
Cellular senescence: when bad things happen to good cells
Campisi, J., & d'Adda di Fagagna, F. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2233 · Cited by 4,441
Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Sluis, B., Kirkland, J. L., & van Deursen, J. M. (2011) · Nature · doi:10.1038/nature10600 · Cited by 3,670

Show all 161 references

Sorted by citations

Senescence in Health and Disease
He, S., & Sharpless, N. E. (2017) · Cell · doi:10.1016/j.cell.2017.05.015 · Cited by 1,766
Autophagy maintains stemness by preventing senescence
García-Prat, L., Martínez-Vicente, M., Perdiguero, E., Ortet, L., Rodríguez-Ubreva, J., Rebollo, E., Ruiz-Bonilla, V., Gutarra, S., Ballestar, E., Serrano, A. L., et al. (2016) · Nature · doi:10.1038/nature16187 · Cited by 1,355
Cellular Senescence: Aging, Cancer, and Injury
Calcinotto, A., Kohli, J., Zagato, E., Pellegrini, L., Demaria, M., & Alimonti, A. (2019) · Physiological Reviews · doi:10.1152/physrev.00020.2018 · Cited by 1,270
“Cellular senescence plays important roles in different phases of tumorigenesis such as tumor initiation (OIS), establishment [PTEN loss–induced cellular senescence (PICS), TIS], and escape (258) (FIGURE 4).”
Background
Senescence-associated reprogramming promotes cancer stemness
Milanovic, M., Fan, D. N. Y., Belenki, D., Däbritz, J. H. M., Zhao, Z., Yu, Y., Dörr, J. R., Dimitrova, L., Lenze, D., Monteiro Barbosa, I. A., et al. (2018) · Nature · doi:10.1038/nature25167 · Cited by 1,131
Revisiting the hallmarks of cancer.
Fouad, Y. A., & Aanei, C. M. (2017) · Europe PMC (PubMed Central) · Cited by 875

See all 468

Authors: Pérez-Mancera, P. A., Young, A. R. J., & Narita, M.
Affiliations: University of Cambridge (GB)
Corresponding author: Narita, Masashi
ORCID: Pérez-Mancera, Pedro A.
Young, Andrew R. J.
Narita, Masashi
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: green
www.repository.cam.ac.uk
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature reviews. Cancer (publishedVersion)
PubMed (publishedVersion)
Apollo (University of Cambridge) (submittedVersion)
Funders: Cancer Research UK (15890)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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

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Inside and out: the activities of senescence in cancer

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