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Cited by 138Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsCancer-related Molecular Pathways

Implications of Cellular Senescence in Tissue Damage Response, Tumor Suppression, and Stem Cell Biology

Open access
Krizhanovsky, V., Xue, W., Zender, L., Yon, M., Hernando, E., Lowe, S.W.·2008·Cold Spring Harbor Symposia on Quantitative Biology
DOI 10.1101/sqb.2008.73.048PMC PMC3285266
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Abstract

Cellular senescence is characterized by an irreversible cell cycle arrest that, when bypassed by mutation, contributes to cellular immortalization. Activated oncogenes induce a hyperproliferative response, which might be one of the senescence cues. We have found that expression of such an oncogene, Akt, causes senescence in primary mouse hepatoblasts in vitro. Additionally, AKT-driven tumors undergo senescence in vivo following p53 reactivation and show signs of differentiation. In another in vivo system, i.e., liver fibrosis, hyperproliferative signaling through AKT might be a driving force of the senescence in activated hepatic stellate cells. Senescent cells up-regulate and secrete molecules that, on the one hand, can reinforce the arrest and, on the other hand, can signal to an innate immune system to clear the senescent cells. The mechanisms governing senescence and immortalization are overlapping with those regulating self-renewal and differentiation. These respective control mechanisms, or their disregulation, are involved in multiple pathological conditions including fibrosis, wound healing, and cancer. Understanding extracellular cues that regulate these processes may enable new therapies for these conditions.

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Registry

Crossref · 10.1101/sqb.2008.73.048

Cites

52 of 52 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 63 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    These immune cells were often in close proximity to cells expressing the senescent markers p53, p21, and Hmga1.

    “These immune cells were often in close proximity to cells expressing the senescent markers p53, p21, and Hmga1 (Krizhanovsky et al. 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Krizhanovsky et al. 2008

      Not checked in the free run.

  • Findingown data

    Dox-induced p53 reactivation in these tumors resulted in tumor regression.

    “Addition of Dox and p53 reactivation resulted in tumor regression.”
    Quote in the paperSubstantial claim
  • Findingcitation

    p53−/−;INK4a/ARF−/− activated stellate cells display increased BrdU incorporation compared to wild-type cells.

    “Moreover, p53−/−;INK4a/ARF−/− cells display increased bromodeoxyuridine (BrdU) incorporation compared to wild-type cells (Krizhanovsky et al. 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Krizhanovsky et al. 2008

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  • Findingown data

    Senescence protects against liver fibrosis partly by stimulating immune clearance of senescent cells.

    “Although our results suggest that senescence protects against liver fibrosis, in part, by stimulating clearance of these cells by the immune systems”
    Quote in the paperSubstantial claim
  • Findingcitation

    In fibrotic livers from CCl4-treated mice, lymphocytes (including NK cells), macrophages, and neutrophils were detected adjacent to hepatic stellate cells.

    “Using a combination of electron microscopy and immunophenotying by immunofluorescence, we noted that lymphocytes (including NK cells), macrophages, and neutrophils were detected adjacent to HSCs in fibrotic livers from CCl4-treated mice (Fig. 5A) (Krizhanovsky et al. 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Krizhanovsky et al. 2008

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  • May combine two claims. 28
  • Classified as probably not a substantial claim. 3

  • May combine two claims.

    Findingcitation

    Following Dox treatment, p53 was induced, a substantial percentage of tumor cells became SA-β-gal positive, and tumors shrank and virtually disappeared after 20 days.

    “Following Dox treatment, p53 was induced, and a substantial percentage of tumor cells became SA-β-gal positive (Fig. 1B); moreover, the tumors shrank and virtually disappeared after 20 days (Xue et al. 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Xue et al. 2007

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  • May combine two claims.

    Findingown data

    Numerous activated stellate cells were retained in anti-NK antibody-treated mice, while activated stellate cells were almost completely eliminated in polyI:C-treated mice.

    “Numerous activated stellate cells were retained in the livers of anti-NK antibody-treated mice (Fig. 5B). In contrast, activated stellate cells were almost completely eliminated in the livers of polyI:C-treated mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Wild-type hepatoblasts infected with activated Akt exhibit flattened morphology and SA-β-gal positivity, whereas p53−/− hepatoblasts continue to proliferate and reach confluence.

    “Hepatoblasts derived from wild-type embryos infected with Akt exhibit flattened morphology and stain positive for SA-β-gal, whereas p53−/− hepatoblasts continue to proliferate and easily reach confluence when seeded at low density (Fig. 1A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Wild-type activated stellate cells eventually undergo senescence in vitro and do not form colonies, whereas p53−/−;INK4a/ARF−/− cells do not undergo senescence and continue to proliferate.

    “Whereas wild-type cells eventually undergo senescence in vitro and do not form colonies, p53−/−;INK4a/ARF−/− cells do not undergo senescence and continue to proliferate (Fig. 3A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    Senescent cells increase molecules that mediate immune interactions, which may lead to their later removal.

    “Moreover, senescent cells up-regulate a wide array of molecules that mediate interactions with the immune system that, in turn, may signal their subsequent elimination.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Untreated tumors remained SA-β-gal negative and continued to grow.

    “In contrast, tumors present in untreated mice remained SA-β-gal negative and continued to grow.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Senescent cells triggered an immune response in vivo, causing infiltration of immune cells into the tumor and clearance of senescent cells.

    “Senescent cells triggered an immune response in vivo, resulting in infiltration of immune cells into the tumor and clearance of senescent cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    p53 reactivation in tumor cells led to cellular senescence rather than apoptosis, and this was associated with markers of cellular differentiation.

    “p53 reactivation in the tumor cells led to cellular senescence and not apoptosis, which was also associated with markers of cellular differentiation (see Figure S3 in Xue et al. 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Xue et al. 2007

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    Findingnone given

    Within 20 days of stopping CCl4 treatment, liver fibrosis was almost resolved and senescent cells were not detected.

    “Interestingly, within 20 days of stopping CCl4 treatment, liver fibrosis was almost resolved and senescent cells were not detected.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Livers from anti-NK antibody-treated mice retained more senescent cells and fibrosis than controls, whereas senescent cells and fibrosis were more rapidly cleared in livers from polyI:C-treated mice.

    “Livers from mice treated with the anti-NK antibody retained more senescent cells and fibrosis than controls, whereas senescent cells and fibrosis were more rapidly cleared in livers from mice treated with polyI:C (Krizhanovsky et al. 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Krizhanovsky et al. 2008

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Reactivation of the p53 pathway in tumors leads to activation of the senescence program and tumor clearance by the innate immune system in vivo.

    “We have demonstrated that reactivation of the p53 pathway in tumors leads to activation of the senescence program and tumor clearance by the innate immune system in vivo (Xue et al. 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Xue et al. 2007

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Liver fibrosis was significantly more pronounced in p53−/−;INK4a/ARF−/− mice than in wild-type mice and was accompanied by a significant increase in αSMA expression.

    “Liver fibrosis was significantly more pronounced in mutant p53−/−;INK4a/ARF−/− mice than in wild-type mice (Krizhanovsky et al. 2008) and was accompanied by a significant increase in the expression of the activated stellate cell marker αSMA (Fig. 3B) (see also Krizhanovsky et al. 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Krizhanovsky et al. 2008

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Immune targeting of senescent cells has a key role in tumor suppression and tissue fibrosis.

    “our studies show that this targeting has a key role in tumor suppression and tissue fibrosis (Xue et al. 2007; Krizhanovsky et al. 2008).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Xue et al. 2007

      Not checked in the free run.

    • cites Krizhanovsky et al. 2008

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

    Premisecitation

    Senescence is a stable or irreversible cell-cycle arrest that limits proliferative capacity and prevents immortalization.

    “Cellular senescence is a stable formof a cell cycle arrest program that limits the proliferative potential of cells and thereby prevents immortalization.”
    • Also stated in: § Abstract · plain
      “Cellular senescence is characterized by an irreversible cell cycle arrest that, when bypassed by mutation, contributes to cellular immortalization.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hayflick and Moorhead 1961

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DNA damage is a potent trigger of senescence and is induced by telomere attrition during replicative exhaustion.

    “One of the most potent triggers of senescence is DNA damage, which is induced by telomere attrition during replicative exhaustion (Vaziri et al. 1997).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Vaziri et al. 1997

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Loss of a tumor suppressor may be required for maintenance of some tumors, and during senescence cell-autonomous and non-cell-autonomous processes cooperate to eliminate formerly malignant cells.

    “These results suggest that loss of a tumor suppressor may be required for the maintenance of some tumors; moreover, during cellular senescence in this system, cell-autonomous processes and non-cell-autonomous processes cooperate to eliminate the formerly malignant cell.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Senescence of activated stellate cells triggers a coordinated program that limits damage response by reducing cell number and matrix production while promoting repair by signaling elimination of senescent cells.

    “Therefore, the senescence of activated stellate cells triggers a coordinated program that acts to inhibit the damage response by limiting the number of the cells and ECM production, on the one hand, and promoting tissue repair by signaling the elimination of senescence cells, on the other hand (Fig. 6).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Liver fibrosis is characterized by extracellular matrix deposition by activated hepatic stellate cells, the main fibrogenic cell type in the liver.

    “In biopsies, liver fibrosis is characterized by depositions of the extracellular matrix (ECM) known as fibrotic scars, which is deposited by activated hepatic stellate cells (HSCs), the main fibrogenic cell type in the liver.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bataller and Brenner 2005

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescent activated stellate cells up-regulate molecules involved in natural killer cell recognition and can be preferentially targeted by these cells in vitro.

    “we have shown that senescent activated stellate cells up-regulate the expression of molecules involved in natural killer (NK) cell recognition and, furthermore, can be preferentially targeted by these cells in vitro (Krizhanovsky et al. 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Krizhanovsky et al. 2008

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  • May combine two claims.

    Premisecitation

    Senescent cells display a large flattened shape and accumulate SA-β-gal activity, which distinguishes them from most quiescent cells.

    “Senescent cells display a large flattened morphology and accumulate a senescence-associated β-galactosidase (SA-β-gal) activity distinguishing them from most quiescent cells (Campisi and d’Adda di Fagagna 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Campisi and d’Adda di Fagagna 2007

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Senescence acts as a tumor suppressive mechanism in liver carcinoma and as a program that limits liver fibrosis.

    “Recently, we demonstrated that senescence functions as both a tumor suppressive mechanism in liver carcinoma and a program that limits liver fibrosis.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Xue et al. 2007

      Not checked in the free run.

    • cites Krizhanovsky et al. 2008

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  • May combine two claims.

    Premisecitation

    Oncogene-induced senescence provides an initial barrier to malignancies in skin, prostate, hematopoietic and other systems, whereas telomere-based senescence may attenuate tumor progression.

    “First, oncogene-induced senescence provides an initial barrier to the development of malignancies in skin, prostate, and hematopoietic and other systems, whereas telomere-based senescence may attenuate tumor progression (Narita and Lowe 2005).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Narita and Lowe 2005

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    If senescence processes occur in premalignant settings, senescence would limit tumorigenesis by preventing proliferation while exposing damaged cells to immune surveillance leading to their elimination.

    “If these processes occur in premalignant settings, senescence would limit tumorigenesis by preventing proliferation while at the same time exposing the damaged cells to a form of immune surveillance leading to their elimination.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The signal triggering senescence likely involves INK4a/ARF activation and a DNA-damage response caused by replication stress.

    “The nature of this signal is the topic of much debate and likely involves activation of the INK4a/ARF locus as well as a DNA-damage response through signals produced by replication stress (Bartkova et al. 2006; Di Micco et al. 2006).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bartkova et al. 2006

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    • cites Di Micco et al. 2006

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

    Interpretationreasoning

    The overlaps may reflect mechanisms that first controlled cell numbers in normal tissues and were later co-opted into tumor suppressive mechanisms against uncontrolled division.

    “these overlaps might have a deeper meaning, reflecting mechanisms that initially evolved to control cell numbers in normal tissues but were later incorporated into intrinsic tumor suppressive mechanisms to limit uncontrolled cell division.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PTEN inactivation can trigger senescence and restrict hematopoietic stem cell self-renewal.

    “inactivation of the PTEN tumor suppressor can trigger senescence and limits the self-renewal of hematopoietic stem cells (Yilmaz et al. 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yilmaz et al. 2006

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  • May combine two claims.

    Interpretationreasoning

    Senescence and immortalization, and differentiation and self-renewal, share signaling mechanisms and are two sides of one coin.

    “the processes of senescence and immortalization, and differentiation and self-renewal, share overlapping signaling mechanisms and can be viewed as two sides of the same coin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    p16 accumulates in some stem cells with age and limits their self-renewal.

    “p16 accumulates in certain stem cells with age and acts to limit self-renewal (Janzen et al. 2006; Krishnamurthy et al. 2006; Molofsky et al. 2006).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Janzen et al. 2006

      Not checked in the free run.

    • cites Krishnamurthy et al. 2006

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    • cites Molofsky et al. 2006

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  • May combine two claims.

    Interpretationcitation

    Quiescent hepatic stellate cells may act as regional multipotent progenitors that cannot self-renew but can differentiate into multiple lineages.

    “These cells might serve as regional multipotent progenitors that are unable to self-renew but are able to differentiate into multiple lineages.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The decision to proliferate is controlled by multiple pathways that can support self-renewal or allow senescence bypass and immortalization.

    “Thus, the critical cellular decision to proliferate is regulated by multiple pathways, which can positively affect self-renewal or enable bypass of senescence and facilitate cellular immortalization.”
    Quote in the paperSubstantial claim
30 of 30

  • The paper relies on this without support.

    The mouse models of hepatocellular carcinoma and liver fibrosis used in the study are representative of the corresponding human diseases.

    “We previously used a mouse model of liver carcinoma to determine the consequence of reactivating the p53 pathway in liver tumors (Xue et al. 2007).”
    “To investigate the role of cellular senescence in fibrosis progression, we induced fibrosis in mice by twice-weekly treatment with 1 ml/kg of CCl4 for 6 weeks (Fig. 2A).”

  • The paper relies on this without support.

    The immune system's clearance of senescent cells observed in mice is a mechanism that can be generalized to humans.

    “Therefore, the innate immune system can contribute to the elimination of senescent stellate cells from the fibrotic liver.”

  • The paper relies on this without support.

    Chronic inflammation from viruses, alcohol abuse, or nonalcoholic steatohepatitis is required for hepatocellular carcinoma in humans.

    “chronic inflammation produced by viruses, alcohol abuse, or nonalcoholic steatohepatitis is a prerequisite for the development of hepatocellular carcinoma in humans.”

  • The paper relies on this without support.

    Oncogene activation or other hyperproliferative signals are key triggers of senescence in tumor suppression.

    “one of the key triggers of senescence is oncogene activation or other signals that produce a hyperproliferative response.”

  • The paper relies on this without support.

    Mutations that disable the senescence program promote cellular immortalization and eventually cancer.

    “Mutations that disable the senescence program—for example, loss of p53, Rb, and IGFBP7 or overexpression of Bmi-1 and CBX7—facilitate cellular immortalization and ultimately cancer development.”

  • The paper relies on this without support.

    INK4a/ARF locus gene products are key elements preventing cell immortalization.

    “gene products of INK4a/ARF locus are established key elements in prevention of cell immortalization.”

  • The paper relies on this without support.

    p16/INK4a inhibits cyclin-dependent kinases 2 and 4, preventing Rb phosphorylation and cell cycle progression.

    “p16/INK4a inhibits cyclin-dependent kinases 2 and 4, thereby preventing Rb phosphorylation and cell cycle progression.”
7 of 7

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?

  • The proliferation and survival defects in late-generation telomerase-knockout mice are caused by a subset of critically short telomeres rather than by a reduction in mean telomere length.

    “The defects in proliferation and survival seen in late-generation telomerase-knockout mice appear to be caused by a subset of critically short telomeres, rather than a reduction in mean telomere length.”

    From Telomeres and telomerase in cancer (2010) · cites this paper as [68]

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Collado M Gil J Efeyan A Guerra C Schuhmacher AJ Barradas M Benguria A Zaballos A Flores JM Barbacid M Beach D Serrano M Tumour biology: Senescence in premalignant tumours Nature 2005 436 642 16079833

Cited by

Sorted by citations

Authors
Krizhanovsky, V., Xue, W., Zender, L., Yon, M., Hernando, E., & Lowe, S. W.
Affiliations
  • Cold Spring Harbor Laboratory (US)
  • Universidade de São Paulo (BR)
  • New York University (US)
  • Howard Hughes Medical Institute (US)
ORCID
Venue
Cold Spring Harbor Symposia on Quantitative Biology
Publisher
Cold Spring Harbor Laboratory
Published
2008-01-01
Volume
73
Issue
0
Pages
513-522
ISSN
  • 0091-7451 (ISSN-L)
  • 1943-4456
DOI
10.1101/sqb.2008.73.048
PMC
PMC3285266
OpenAlex
W2138631175
Semantic Scholar
4cc2055fb20e58a4bb05876dcbdf93d230afc3bd
Cited by
138
References
52
Citations by year
2026: 5 · 2025: 8 · 2024: 8 · 2023: 12 · 2022: 10 · 2021: 6 · 2020: 10 · 2019: 6 · 2018: 7 · 2017: 5 · 2016: 8 · 2015: 6 · 2014: 7 · 2013: 7 · 2012: 13
Type
posted content
Language
en
Open access
Locations
  • Cold Spring Harbor Symposia on Quantitative Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
Funders
  • Howard Hughes Medical Institute
  • Leukemia and Lymphoma Society
  • Cold Spring Harbor Laboratory
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico
  • National Institutes of Health
  • National Institute on Aging (AG-16379, R01AG016379)
  • National Cancer Institute (P30CA008748)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
cellular senescence, tumor suppression, stem cell biology, hepatoblasts, p53 reactivation, hepatic stellate cells, liver fibrosis, cell immortalization, senescence-associated secretory phenotype, wound healing
MeSH terms
Animals, Cell Transformation, Neoplastic, Humans, Immunity, Innate, Liver Cirrhosis, Liver Neoplasms, Experimental, Neoplasms, Oncogenes, Stem Cells, Wound Healing, Signal Transduction, Gene Expression, Genes, p53, Cellular Senescence, Phosphatidylinositol 3-Kinases, Cell Proliferation, Oncogene Protein v-akt, Mice, Hepatic Stellate Cells

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