Cellular senescence: a double‐edged sword in the fight against cancer
Abstract
Over the last few decades, it has become apparent that oncogenic proliferative signals are coupled to a variety of growth inhibitory responses, such as the induction of apoptotic cell death or irreversible cell cycle arrest known as 'cellular senescence'. Thus, both apoptosis and cellular senescence are thought to act as important tumor suppression mechanisms. Unlike apoptotic cells, however, senescent cells remain viable for long periods of time and accumulate with increasing age in various organs and tissues. Moreover, recent studies reveal that although cellular senescence initially functions as a tumor suppressive process, it may eventually exhibit tumor-promoting effects. Therefore, it is conceivable that accumulation of senescent cells during the ageing process in vivo may contribute to the age-related increase in cancer incidence. In this review, we provide an update and perspective on recent advances made in understanding the deleterious side effects of cellular senescence.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Senescent cells express the SASP, a cell-type and signal-specific program of gene expression and cytokine secretion that can sculpt the immune response.
“Senescent cells express a cell type and signal specific program of gene expression and cytokine secretion (the SASP), which can sculpt the immune response (Ohtani et al., 2012).”
From CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought (2018) · cites this paper as Ohtani et al., 2012
Cites
WAF1, a potential mediator of p53 tumor suppression
El-Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, K. W., & Vogelstein, B. (1993) · Cell · doi:10.1016/0092-8674(93)90500-p · Cited by 8,321 · see citing works
CDK inhibitors: positive and negative regulators of G1-phase progression
Sherr, C. J., & Roberts, J. M. (1999) · Genes & Development · doi:10.1101/gad.13.12.1501 · Cited by 6,115 · see citing works
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 · see citing works
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 5,178 · see citing works
Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
Xue, W., Zender, L., Miething, C., Dickins, R. A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., & Lowe, S. W. (2007) · Nature · doi:10.1038/nature05529 · Cited by 2,473 · see citing works
Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors
Campisi, J. (2005) · Cell · doi:10.1016/j.cell.2005.02.003 · Cited by 2,359 · see citing works
Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion
Rodier, F., Coppé, J.-P., Patil, C. K., Hoeijmakers, W. A. M., Muñoz, D. P., Raza, S. R., Freund, A., Campeau, E., Davalos, A. R., & Campisi, J. (2009) · Nature Cell Biology · doi:10.1038/ncb1909 · Cited by 2,232 · see citing works
Oncogene-Induced Senescence Relayed by an Interleukin-Dependent Inflammatory Network
Kuilman, T., Michaloglou, C., Vredeveld, L. C. W., Douma, S., van Doorn, R., Desmet, C. J., Aarden, L. A., Mooi, W. J., & Peeper, D. S. (2008) · Cell · doi:10.1016/j.cell.2008.03.039 · Cited by 2,086 · see citing works
The diverse functions of histone lysine methylation
Martin, C., & Zhang, Y. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1761 · Cited by 2,066 · see citing works
The essence of senescence: Figure 1.
Kuilman, T., Michaloglou, C., Mooi, W. J., & Peeper, D. S. (2010) · Genes & Development · doi:10.1101/gad.1971610 · Cited by 2,038 · see citing works
Senescence of activated stellate cells limits liver fibrosis
Krizhanovsky, V., Yon, M., Dickins, R. A., Hearn, S., Simon, J., Miething, C., Yee, H., Zender, L., & Lowe, S. W. (2008) · Cell · doi:10.1016/j.cell.2008.06.049 · Cited by 2,029 · see citing works
Senescence of Activated Stellate Cells Limits Liver Fibrosis
Krizhanovsky, V., Yon, M., Dickins, R. A., Hearn, S., Simon, J., Miething, C., Yee, H., Zender, L., & Lowe, S. W. (2008) · Cell · doi:10.1016/j.cell.2008.09.015 · Cited by 2,027
Four faces of cellular senescence
Rodier, F., & Campisi, J. (2011) · Journal of Cell Biology · doi:10.1083/jcb.201009094 · Cited by 2,016 · see citing works
Restoration of p53 function leads to tumour regression in vivo
Ventura, A., Kirsch, D. G., McLaughlin, M. E., Tuveson, D. A., Grimm, J., Lintault, L., Newman, J., Reczek, E. E., Weissleder, R., & Jacks, T. (2007) · Nature · doi:10.1038/nature05541 · Cited by 1,820 · see citing works
Chemokine signaling via the CXCR2 receptor reinforces senescence
Acosta, J. C., O'Loghlen, A., Banito, A., Guijarro, M. V., Augert, A., Raguz, S., Fumagalli, M., Da Costa, M., Brown, C., Popov, N., et al. (2008) · Cell · doi:10.1016/j.cell.2008.03.038 · Cited by 1,801 · see citing works
Park, E. J., Lee, J. H., Yu, G.-Y., He, G., Ali, S. R., Holzer, R. G., Österreicher, C. H., Takahashi, H., & Karin, M. (2010) · Cell · doi:10.1016/j.cell.2009.12.052 · Cited by 1,764 · see citing works
Senescence surveillance of pre-malignant hepatocytes limits liver cancer development
Kang, T.-W., Yevsa, T., Woller, N., Hoenicke, L., Wuestefeld, T., Dauch, D., Hohmeyer, A., Gereke, M., Rudalska, R., Potapova, A., et al. (2011) · Nature · doi:10.1038/nature10599 · Cited by 1,621 · see citing works
Reversal of human cellular senescence: roles of the p53 and p16 pathways
Beauséjour, C. M., Krtolica, A., Galimi, F., Narita, M., Lowe, S. W., Yaswen, P., & Campisi, J. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg417 · Cited by 1,457 · see citing works
Oxidant signals and oxidative stress
Finkel, T. (2003) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(03)00002-4 · Cited by 1,393 · see citing works
Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen
Noda, A., Ning, Y., Venable, S. F., Pereira-Smith, O. M., & Smith, J. R. (1994) · Experimental Cell Research · doi:10.1006/excr.1994.1063 · Cited by 1,351 · see citing works
Living on a break: cellular senescence as a DNA-damage response
d'Adda di Fagagna, F. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2440 · Cited by 1,170 · see citing works
Senescence in tumours: evidence from mice and humans
Collado, M., & Serrano, M. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2772 · Cited by 1,124 · see citing works
Chien, Y., Scuoppo, C., Wang, X., Fang, X., Balgley, B., Bolden, J. E., Premsrirut, P., Luo, W., Chicas, A., Lee, C. S., et al. (2011) · Genes & Development · doi:10.1101/gad.17276711 · Cited by 1,046 · see citing works
Freund, A., Patil, C. K., & Campisi, J. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.69 · Cited by 1,039 · see citing works
Feedback between p21 and reactive oxygen production is necessary for cell senescence
Passos, J. F., Nelson, G., Wang, C., Richter, T., Simillion, C., Proctor, C. J., Miwa, S., Olijslagers, S., Hallinan, J., Wipat, A., et al. (2010) · Molecular Systems Biology · doi:10.1038/msb.2010.5 · Cited by 1,019 · see citing works
Alcorta, D. A., Xiong, Y., Phelps, D., Hannon, G., Beach, D., & Barrett, J. C. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.24.13742 · Cited by 1,008 · see citing works
The common biology of cancer and ageing
Finkel, T., Serrano, M., & Blasco, M. A. (2007) · Nature · doi:10.1038/nature05985 · Cited by 988 · see citing works
Senescence-messaging secretome: SMS-ing cellular stress
Kuilman, T., & Peeper, D. S. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2560 · Cited by 909 · see citing works
Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis
Sparmann, A., & Bar‐Sagi, D. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.09.028 · Cited by 854 · see citing works
Regulation of the INK4b–ARF–INK4a tumour suppressor locus: all for one or one for all
Gil, J., & Peters, G. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1987 · Cited by 843 · see citing works
A role for both RB and p53 in the regulation of human cellular senescence*1
SHAY, J. (1991) · Experimental Cell Research · doi:10.1016/0014-4827(91)90453-2 · Cited by 757 · see citing works
The retinoblastoma tumour suppressor in development and cancer
Classon, M., & Harlow, E. (2002) · Nature Reviews Cancer · doi:10.1038/nrc950 · Cited by 738 · see citing works
Hara, E., Smith, R., Parry, D., Tahara, H., Stone, S., & Peters, G. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.3.859 · Cited by 733 · see citing works
Self-citationOpposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence
Ohtani, N., Zebedee, Z., Huot, T. J. G., Stinson, J. A., Sugimoto, M., Ohashi, Y., Sharrocks, A. D., Peters, G., & Hara, E. (2001) · Nature · doi:10.1038/35059131 · Cited by 654 · see citing works
Self-citationOrjalo, A. V., Bhaumik, D., Gengler, B. K., Scott, G. K., & Campisi, J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0905299106 · Cited by 654 · see citing works
Kortlever, R. M., Higgins, P. J., & Bernards, R. (2006) · Nature Cell Biology · doi:10.1038/ncb1448 · Cited by 637 · see citing works
Sage, J., Mulligan, G. J., Attardi, L. D., Miller, A., Chen, S., Williams, B., Theodorou, E., & Jacks, T. (2000) · Genes & Development · doi:10.1101/gad.843200 · Cited by 582 · see citing works
H3K9 methyltransferase G9a and the related molecule GLPPreprint
Shinkai, Y., & Tachibana, M. (2011) · Genes & Development · doi:10.1101/gad.2027411 · Cited by 564 · see citing works
Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry
Sage, J., Miller, A. L., Pérez-Mancera, P. A., Wysocki, J. M., & Jacks, T. (2003) · Nature · doi:10.1038/nature01764 · Cited by 538 · see citing works
Takahashi, A., Ohtani, N., Yamakoshi, K., Iida, S.-I., Tahara, H., Nakayama, K., Nakayama, K. I., Ide, T., Saya, H., & Hara, E. (2006) · Nature Cell Biology · doi:10.1038/ncb1491 · Cited by 528 · see citing works
Self-citationOncogenic Ras-induced secretion of IL6 is required for tumorigenesis
Ancrile, B., Lim, K.-H., & Counter, C. M. (2007) · Genes & Development · doi:10.1101/gad.1549407 · Cited by 422 · see citing works
The outlook for population growth
Lee, R. (2011) · Science · doi:10.1126/science.1208859 · Cited by 415 · see citing works
Dannenberg, J.-H., van Rossum, A., Schuijff, L., & te Riele, H. (2000) · Genes & Development · doi:10.1101/gad.847700 · Cited by 413 · see citing works
Putting the stress on senescence
Serrano, M., & Blasco, M. A. (2001) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00278-7 · Cited by 413 · see citing works
Complete inactivation of DNMT1 leads to mitotic catastrophe in human cancer cells
Chen, T., Hevi, S., Gay, F., Tsujimoto, N., He, T., Zhang, B., Ueda, Y., & Li, E. (2007) · Nature Genetics · doi:10.1038/ng1982 · Cited by 353 · see citing works
Healing and Hurting: Molecular Mechanisms, Functions, and Pathologies of Cellular Senescence
Adams, P. D. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.09.021 · Cited by 326 · see citing works
Coppé, J.-P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., Goldstein, J., Nelson, P. S., Desprez, P.-Y., & Campisi, J. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060301 · Cited by 302 · see citing works
Senescent cells develop a parp-1 and nuclear factor-κB-associated secretome (PNAS).
Ohanna, M., Giuliano, S., Bonet, C., Imbert, V., Hofman, V., Zangari, J., Bille, K., Robert, C., Bressac-de Paillerets, B., Hofman, P., et al. (2011) · Genes & Development · doi:10.1101/gad.625811 · Cited by 267 · see citing works
Hara, E., Tsurui, H., Shinozaki, A., Nakada, S., & Oda, K. (1991) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(91)91403-y · Cited by 260 · see citing works
Self-citationLevy, D., Kuo, A. J., Chang, Y., Schaefer, U., Kitson, C., Cheung, P., Espejo, A. B., Zee, B. M., Liu, C. L., Tangsombatvisit, S., et al. (2010) · Nature Immunology · doi:10.1038/ni.1968 · Cited by 256 · see citing works
Reversal of Senescence in Mouse Fibroblasts through Lentiviral Suppression of p53
Dirac, A. M. G., & Bernards, R. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.c300023200 · Cited by 254 · see citing works
McConnell, B. B., Gregory, F. J., Stott, F. J., Hara, E., & Peters, G. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.3.1981 · Cited by 238 · see citing works
Self-citationTakahashi, A., Imai, Y., Yamakoshi, K., Kuninaka, S., Ohtani, N., Yoshimoto, S., Hori, S., Tachibana, M., Anderton, E., Takeuchi, T., et al. (2012) · Molecular Cell · doi:10.1016/j.molcel.2011.10.018 · Cited by 205 · see citing works
Self-citationLATS tumor suppressor: A new governor of cellular homeostasis
Grieve, S., & Yang, X. (2010) · Cell Cycle · doi:10.4161/cc.9.19.13386 · Cited by 203 · see citing works
The retinoblastoma protein and the regulation of cell cycling
Cobrinik, D. E., Dowdy, S. F., Hinds, P. W., Mittnacht, S., & Weinberg, R. A. (1992) · Trends in Biochemical Sciences · doi:10.1016/0968-0004(92)90443-d · Cited by 201 · see citing works
Real-time in vivo imaging of p16Ink4a reveals cross talk with p53
Yamakoshi, K., Takahashi, A., Hirota, F., Nakayama, R., Ishimaru, N., Kubo, Y., Mann, D. J., Ohmura, M., Hirao, A., Saya, H., et al. (2009) · Journal of Cell Biology · doi:10.1083/jcb.200904105 · Cited by 172 · see citing works
Self-citationRegulation of growth arrest in senescence: Telomere damage is not the end of the story
Herbig, U., & Sedivy, J. M. (2005) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2005.09.002 · Cited by 159 · see citing works
p16INK4a can initiate an autonomous senescence program
Dai, C. Y., & Enders, G. H. (2000) · Oncogene · doi:10.1038/sj.onc.1203438 · Cited by 151 · see citing works
Sharpless, N. E., & DePinho, R. A. (2005) · Nature · doi:10.1038/436636a · Cited by 148 · see citing works
Increased gene dosage of Ink4a/Arf results in cancer resistance and normal agingPreprint
Matheu, A., Pantoja, C., Efeyan, A., Criado, L. M., Martín‐Caballero, J., Flores, J. M., Klatt, P., & Serrano, M. (2004) · Genes & Development · doi:10.1101/gad.310304 · Cited by 137 · see citing works
Takeuchi, S., Takahashi, A., Motoi, N., Yoshimoto, S., Tajima, T., Yamakoshi, K., Hirao, A., Yanagi, S., Fukami, K., Ishikawa, Y., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0801 · Cited by 136 · see citing works
Self-citationInduction of p21 WAF1/CIP1 and Inhibition of Cdk2 Mediated by the Tumor Suppressor p16 INK4a
Mitra, J., Dai, C. Y., Somasundaram, K., El‐Deiry, W. S., Satyamoorthy, K., Herlyn, M., & Enders, G. H. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.5.3916 · Cited by 124 · see citing works
Regulation of ploidy and senescence by the AMPK‐related kinase NUAK1
Humbert, N., Navaratnam, N., Augert, A., Da Costa, M., Martien, S., Wang, J., Martinez, D., Abbadie, C., Carling, D., de Launoit, Y., et al. (2010) · The EMBO Journal · doi:10.1038/emboj.2009.342 · Cited by 115 · see citing works
G9a-mediated Lysine Methylation Alters the Function of CCAAT/Enhancer-binding Protein-β
Pleß, O., Kowenz‐Leutz, E., Knoblich, M., Lausen, J., Beyermann, M., Walsh, M. J., & Leutz, A. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m802132200 · Cited by 107 · see citing works
Opposing roles of NF-κB in anti-cancer treatment outcome unveiled by cross-species investigationsPreprint
Hua, J., Kase, J., Dörr, J. R., Milanovic, M., Lenze, D., Grau, M., Beuster, G., Ji, S., Reimann, M., Lenz, P., et al. (2011) · Genes & Development · doi:10.1101/gad.17620611 · Cited by 99 · see citing works
Gorman, S. D., & Cristofalo, V. J. (1985) · Journal of Cellular Physiology · doi:10.1002/jcp.1041250116 · Cited by 88 · see citing works
Haff, R. F., & Swim, H. E. (1956) · Experimental Biology and Medicine · doi:10.3181/00379727-93-22707 · Cited by 47 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype
Kumari, R., & Jat, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.645593 · Cited by 1,622 · see citing works
“Activated p53 regulates expression of a set of anti-proliferative genes (Olivier et al., 2010; Kastenhuber and Lowe, 2017).”
BackgroundCDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought
Klein, M. E., Kovatcheva, M., Davis, L. E., Tap, W. D., & Koff, A. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.03.023 · Cited by 378 · see citing works
“Senescent cells express a cell type and signal specific program of gene expression and cytokine secretion (the SASP), which can sculpt the immune response (Ohtani et al., 2012).”
BackgroundAging of the cells: Insight into cellular senescence and detection Methods.
Mohamad Kamal, N. S., Safuan, S., Shamsuddin, S., & Foroozandeh, P. (2020) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2020.151108 · Cited by 287 · see citing works
Discovery of piperlongumine as a potential novel lead for the development of senolytic agents
Wang, Y., Chang, J., Liu, X., Zhang, X., Zhang, S., Zhang, X., Zhou, D., & Zheng, G. (2016) · Aging · doi:10.18632/aging.101100 · Cited by 274 · see citing works
Jin Bing, P. A. N., Li, D., Xu, Y., Zhang, J., Wang, Y., Chen, M., Lin, S., Huang, L., Chung, E. J., Citrin, D. E., et al. (2017) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2017.02.216 · Cited by 244 · see citing works
Cellular senescence: Molecular mechanisms and pathogenicity
Wei, W., & Ji, S. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.26956 · Cited by 205 · see citing works
Senescence-associated lncRNAs: senescence-associated long noncoding RNAs
Abdelmohsen, K., Panda, A. C., Kang, M. J., Xu, J. Z., Selimyan, R., Yoon, J., Martindale, J. L., De, S., Wood, W. H., Becker, K. G., et al. (2013) · Aging Cell · doi:10.1111/acel.12115 · Cited by 208 · see citing works
“…changes, the influence of senescence on carcinogenesis has been studied most extensively; it has revealed that senescence constitutes a strong tumor suppressive mechanism, although in some instances, it can enhance different carcinogenic traits (e.g., tissue invasion; Ohtani et al., 2012).”
BackgroundIonizing Radiation-Induced Endothelial Cell Senescence and Cardiovascular Diseases
Wang, Y., Boerma, M., & Zhou, D. (2016) · Radiation Research · doi:10.1667/rr14445.1 · Cited by 204 · see citing works
“, cytokines and chemokines) and extracellular proteases, termed the senescence-associated secretory phenotype (SASP), which causes chronic inflammation and disruption of tissue structure and function (38, 39, 49, 50).”
BackgroundNeri, S. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20102406 · Cited by 188 · see citing works
“Moreover, cellular senescence can prevent/promote tumorigenesis [63].”
NADPH Oxidases and Mitochondria in Vascular Senescence
Salazar, G. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19051327 · Cited by 133 · see citing works
“While senescence may protect against the initiation of tumorigenesis, due to lack of proliferation, the development of the SASP may promote proliferation of an established tumor [4,5].”
BackgroundNoncoding RNA control of cellular senescence
Abdelmohsen, K., & Gorospe, M. (2015) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1297 · Cited by 90 · see citing works
“4,20–23 For instance, in older persons, senescent cells can contribute to tumorigenesis of neighboring cells through the secretion of oncogenic factors such as interleukin (IL)-6, IL-8, IL-1α, granulocyte-macrophage colony stimulating factor (GM-CSF), the growth-regulated oncogene α (GROa), monocyte chemotactic protei…”
BackgroundSenescence-Associated MicroRNAs
Munk, R. B., Panda, A. C., Grammatikakis, I., Gorospe, M., & Abdelmohsen, K. (2017) · International review of cytology · doi:10.1016/bs.ircmb.2017.03.008 · Cited by 84 · see citing works
“Favoring tumorigenesis is the secretion by senescent cells of angiogenic factors (e.g., VEGF) that promote local angiogenesis, and matrix metalloproteinases (MMPs) which make tissues permeable and facilitate both migration and metastasis (Freund et al., 2010; Ohtani et al., 2012).”
BackgroundNicotine in Senescence and Atherosclerosis
Centner, A. M., Bhide, P. G., & Salazar, G. (2020) · Cells · doi:10.3390/cells9041035 · Cited by 82 · see citing works
“While senescence protects against the initiation of tumorigenesis due to a lack of proliferation, the SASP promotes the proliferation of an established tumor [6].”
BackgroundSenolytic activity of piperlongumine analogues: Synthesis and biological evaluation
Liu, X., Wang, Y., Zhang, X., Gao, Z., Zhang, S., Shi, P., Zhang, X., Song, L., Hendrickson, H., Zhou, D., et al. (2018) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2018.06.013 · Cited by 77 · see citing works
Therapeutic targeting of replicative immortality
Yaswen, P., MacKenzie, K. L., Keith, W. N., Hentosh, P., Rodier, F., Zhu, J., Firestone, G. L., Matheu, A., Carnero, A., Bilsland, A. E., et al. (2015) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2015.03.007 · Cited by 74 · see citing works
“[153] Ohtani N, Takahashi A, Mann DJ, Hara E.”
BackgroundSenescent mesenchymal stem cells promote colorectal cancer cells growth via galectin-3 expression
Li, Y., Xu, X., Wang, L., 刘广金, Li, Y., 吴小兵, 荆永光, Li, H., & Wang, G. (2015) · Cell & Bioscience · doi:10.1186/s13578-015-0012-3 · Cited by 69 · see citing works
“cells during the aging process in vivo may contribute to the age-related increase in cancer incidence [4].”
BackgroundLiu, Y., Lomeli, I., & Kron, S. J. (2024) · Cells · doi:10.3390/cells13151281 · Cited by 72 · see citing works
“The persistence of inflammatory SnCs within the TME may promote tumorigenesis, tumor growth, and immunosuppression, antagonizing cancer therapies [18,269].”
BackgroundGarbers, C., Kuck, F., Aparicio-Siegmund, S., Konzak, K., Kessenbrock, M., Sommerfeld, A., Häussinger, D., Lang, P. A., Brenner, D., Mak, T. W., et al. (2013) · Cell Cycle · doi:10.4161/cc.26431 · Cited by 64 · see citing works
“Cellular senescence is linked to age-associated diseases and inflammation and has recently been recognized as an important antitumor barrier.(16) The role of the SASP, however, in tumor progression remains unclear.”
LncRNA-OIS1 regulates DPP4 activation to modulate senescence induced by RAS
Li, L., Breugel, P. C. V., Loayza‐Puch, F., Ugalde, A. P., Korkmaz, G., Messika-Gold, N., Han, R., Lopes, R., Barberà, E. P., Teunissen, H., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky087 · Cited by 58 · see citing works
Senescent fibroblast-derived Chemerin promotes squamous cell carcinoma migration
Farsam, V., Basu, A., Gatzka, M., Treiber, N., Schneider, L. A., Mulaw, M. A., Lucas, T., Kochanek, S., Dummer, R., Levesque, M. P., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.13446 · Cited by 59 · see citing works
“Senescent fibroblasts adopt a senescence-associated secretory phenotype (SASP), consisting of inflammatory cytokines, chemokines and matrix remodeling factors that - depending on the biological context - may contribute to tumor suppression or progression [7, 9].”
BackgroundOrtiz‐Lazareno, P. C., Bravo‐Cuéllar, A., Lerma-Díaz, J. M., Jave‐Suárez, L. F., Aguilar‐Lemarroy, A., Domínguez-Rodríguez, J. R., Gonzalez-Ramella, O. R., Célis, R. D., Gómez-Lomelí, P., & Hernández‐Flores, G. (2014) · Cancer Cell International · doi:10.1186/1475-2867-14-13 · Cited by 58 · see citing works
“Whether cellular senescence induced by antitumor therapy can act as friend or foe is difficult to determine precisely because recent data indicate that factors secreted by senescent cells can also alter the microenvironment and enhance the tumor growth of neighboring tumor cells, indicating that this protective mechan…”
BackgroundLi, Z.-Y., Chen, Z., Zhang, T., Wei, C., & Shi, W. (2016) · Aging · doi:10.18632/aging.101050 · Cited by 53 · see citing works
“It has been reported that cellular senescence is crucial for tumor suppression and that the SASP reinforces senescence, activates immune surveillance to eliminate premalignant cells, and paradoxically also has pro-tumorigenic properties [47].”
Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells
Rysanek, D., Vašicová, P., Kolla, J. N., Sedlák, D., Anděra, L., Bártek, J., & Hodný, Z. (2022) · Aging · doi:10.18632/aging.204207 · Cited by 47 · see citing works
Hunter, S., Arendt, T., & Brayne, C. (2013) · Molecular Neurobiology · doi:10.1007/s12035-013-8445-3 · Cited by 41 · see citing works
“In terms of disease mechanisms, senescence can be seen as a double-edged sword [27].”
BackgroundInfluentialModulation of therapy-induced senescence by reactive lipid aldehydes
Flor, A. C., Doshi, A. P., & Kron, S. J. (2016) · Cell Death Discovery · doi:10.1038/cddiscovery.2016.45 · Cited by 40 · see citing works
“7,8 Although considerable uncertainty remains whether TIS is a desirable outcome of cancer treatment, 9–11 recent studies suggest that senescent cells in tumors may have beneficial effects, including stimulation of antitumor immunity.”
Xu, Q., Ma, P., Hu, C., Chen, L., Xue, L., Wang, Z., Liu, M., Zhu, H., Xu, N., & Lü, N. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041862 · Cited by 40 · see citing works
Han, X., Yuan, T., Zhang, J., Shi, Y., Li, D., Dong, Y., & Fan, S. (2022) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.17333 · Cited by 39 · see citing works
Olaparib induced senescence under P16 or P53 dependent manner in ovarian cancer
Wang, Z., Gao, J., Zhou, J., Liu, H., & Xu, C. (2018) · Journal of Gynecologic Oncology · doi:10.3802/jgo.2019.30.e26 · Cited by 38 · see citing works
“When RB is phosphorylated by these CDKs, it mainly resulting in gene transactivation and then causing cell cycle progression [30].”
BackgroundCellular senescence signaling in cancer: A novel therapeutic target to combat human malignancies
Fakhri, S., Moradi, S. Z., DeLiberto, L. K., & Bishayee, A. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.114989 · Cited by 38 · see citing works
Overexpression of KLF4 promotes cell senescence through microRNA-203-survivin-p21 pathway
Xu, Q., Liu, M., Zhang, J., Xue, L., Zhang, G., Hu, C., Wang, Z., He, S., Chen, L., Ma, K., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.11200 · Cited by 37 · see citing works
Rosiglitazone ameliorates senescence and promotes apoptosis in ovarian cancer induced by olaparib
Wang, Z., Gao, J., Ohno, Y., Liu, H., & Xu, C. (2020) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-019-04025-8 · Cited by 24 · see citing works
Kjoe, P. R. L. M., van der Wall, E., & Schagen, S. B. (2021) · Clinical Breast Cancer · doi:10.1016/j.clbc.2021.08.002 · Cited by 22 · see citing works
Gastrin-Releasing Peptide Receptor Knockdown Induces Senescence in Glioblastoma Cells
Menegotto, P. R., Lopez, P. L. D. C., Souza, B. K., de Farias, C. B., Filippi‐Chiela, E. C., Vieira, I. A., Schwartsmann, G., Lenz, G., & Roesler, R. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-9696-6 · Cited by 22 · see citing works
“Moreover, higher senescence scores have been linked to poor prognosis [27, 28, 34].”
BackgroundMZF1 mediates oncogene-induced senescence by promoting the transcription of p16INK4A
Wu, D., Tan, H., Su, W., Cheng, D., Wang, G., Wang, J., Ma, D. A., Dong, G. M., & Sun, P. (2021) · Oncogene · doi:10.1038/s41388-021-02110-y · Cited by 21 · see citing works
Estepa‐Fernández, A., García‐Fernández, A., Lérida‐Viso, A., Morellá‐Aucejo, Á., Esteve‐Moreno, J. J., Blandez, J. F., Alfonso, M., Candela‐Noguera, V., Vivo‐Llorca, G., Sancenón, F., et al. (2022) · Nano Today · doi:10.1016/j.nantod.2022.101692 · Cited by 19 · see citing works
Bilsland, A. E., Pugliese, A., Liu, Y., Revie, J., Burns, S., McCormick, C., Cairney, C. J., Bower, J. F., Drysdale, M., Narita, M., et al. (2015) · Neoplasia · doi:10.1016/j.neo.2015.08.009 · Cited by 19 · see citing works
“It seems likely that a spectrum of senescence-like responses is possible in cancer cells depending on induction agent and signaling environment [8,9].”
BackgroundYoung at Gut—Turning Back the Clock with the Gut Microbiome
Narasimhan, H., Ren, C. C., Deshpande, S., & Sylvia, K. E. (2021) · Microorganisms · doi:10.3390/microorganisms9030555 · Cited by 17 · see citing works
Dehghan, N., Mousavikia, S. N., Qasempour, Y., & Azimian, H. (2024) · Life Sciences · doi:10.1016/j.lfs.2024.123218 · Cited by 14 · see citing works
The Yin-Yang of DNA Damage Response: Roles in Tumorigenesis and Cellular Senescence
Li, X., Xu, H., Chong-an, X., Lin, M., Song, X., Yi, F., Feng, Y., Coughlan, K. A., Cho, W., Kim, S. W., et al. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms14022431 · Cited by 14 · see citing works
“tumorigenesis and cellular senescence (2) senescence-associated DDR acts as a natural barrier for tumorigenesis, and abrogation of the barrier may rescue defective cell growth and limit cell senescence in the incipient malignant form but at the expense of tumor progression [66–68].”
BackgroundFang, X., Huang, E., Xie, X., Yang, K., Wang, S., Huang, X., & Song, M. L. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.951311 · Cited by 13 · see citing works
“Previous research has shown that senescence is both beneficial and detrimental in the process of tumorigenesis and development, and viewed as an example of the dichotomy of multiple effects in the evolutionary process (Ohtani et al., 2012; Schosserer et al., 2017).”
BackgroundXie, B., Zhao, L., Chen, H., Jin, B., Mao, Z., & Yao, Z. (2013) · Biology of the Cell · doi:10.1111/boc.201200052 · Cited by 13 · see citing works
“Several reviews have highlighted the need for a better understanding of cellular senescence (Campisi, 2005b; Narita and Lowe, 2005; Ohtani et al., 2012; Brondello et al., 2012).”
BackgroundShi, H., Xiao, M., Li, Y., Liu, X., Na, J., Liang, C., Hua, J., Meng, Q., Wei, M., Wang, W., et al. (2025) · Theranostics · doi:10.7150/thno.112633 · Cited by 12 · see citing works
“First, cells accrue senescence-inducing insults—telomere attrition, oxidative damage, and oncogenic mutations—at a higher frequency [53, 64, 82].”
Role of mismatch repair in aging
Wen, J., Wang, Y., Yuan, M., Huang, Z., Zou, Q., Pu, Y., Zhao, B., & Cai, Z. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.64953 · Cited by 12 · see citing works
Investigations into cytotoxic effects of the herbal preparation Abnormal Savda Munziq
Kühnel, H., Adilijiang, A., Dadak, A. M., Wieser, M., Upur, H., Stolze, K., Grillari, J., & Strasser, A. (2015) · Chinese Journal of Integrative Medicine · doi:10.1007/s11655-015-2132-3 · Cited by 12 · see citing works
The emerging role of cellular senescence in complications of COVID-19
Mohiuddin, M., & Kasahara, K. (2021) · Cancer Treatment and Research Communications · doi:10.1016/j.ctarc.2021.100399 · Cited by 11 · see citing works
“Cellular senescence is considered a double-edged sword [30].”
Cellular senescence: Silent operator and therapeutic target in cancer
Ramu, D., Teoh, W. S., Hirpara, J. L., & Pervaiz, S. (2021) · IUBMB Life · doi:10.1002/iub.2460 · Cited by 11 · see citing works
“The first postulates that cellular senescence is genetically induced by telomere shortening during cellular division.(8) Telomeres consist of DNA sequence repeats to protect the ends of DNA from damage and prevent recombination.”
BackgroundYu, S.-L., Kang, M.-S., Kim, H.-Y., Gorospe, C. M., Kim, T.-S., & Lee, S. (2014) · DNA repair · doi:10.1016/j.dnarep.2014.01.005 · Cited by 10 · see citing works
A Study on Proliferation and Gene Expression in Normal Human Urothelial Cells in Culture
Chamorro, C. I., Zeiai, S., Engberg, G. R., Brodin, D., Nordenskjöld, A., & Fossum, M. (2014) · Tissue Engineering Part A · doi:10.1089/ten.tea.2014.0175 · Cited by 8 · see citing works
“27 Whether urothelial cells become resistant to apoptosis after long propagation in culture needs to be determined; however, microarray data showed downregulation of at least two genes in the family of IAP: proteins BIRC3 a threefold change ( - 3) and BIRC5 ( - 7) (Supplementary Table S4) and…”
Hairless mice as an experimental model of infection with Leishmania (Leishmania) amazonensis
Araujo, V. C. P., Fukutani, K. F., Oshiro, E. T., Rodrigues, P. O., Rizk, Y. S., Carollo, C. A., & de Arruda, C. C. P. (2015) · Experimental Parasitology · doi:10.1016/j.exppara.2015.07.010 · Cited by 6 · see citing works
The Epigenetic Landscape of Cellular Senescence
Jha, D., Kumar, R., & Idris, M. G. (2025) · Springer eBooks · doi:10.1007/978-981-96-1041-9_2 · Cited by 1 · see citing works
Gao, Q., Qi, Z., Jin, X., Yang, Z., Yuan, X., Hu, Y., & Yang, X. (2022) · Aesthetic Plastic Surgery · doi:10.1007/s00266-022-02902-x · Cited by 1 · see citing works
CARF Regulates Cellular Senescence and Apoptosis through p53-Dependent and -Independent Pathways
Wadhwa, R., Singh, R., Kaul, Z., & Kaul, S. C. (2013) · Humana Press eBooks · doi:10.1007/978-1-62703-456-2_8
Hoey, C. (2018) · TSpace (University of Toronto)
Oliveira, D. K., & Zamin, L. L. (2021) · Brazilian Journal of Health Review · doi:10.34119/bjhrv4n4-222
Preclinical evaluation of senescence-based strategies to improve cancer therapy
Estepa‐Fernández, A. (2022) · doi:10.4995/thesis/10251/188845
Schalk, M., Seiler, M., Maurer, M., Ebrahimian, A., Feldhofer, B., Rumbold, K., & Kühnel, H. (2025) · Preprints.org · doi:10.20944/preprints202507.1693.v1
- Authors
- Ohtani, N., Takahashi, A., Mann, D. J., & Hara, E.
- Affiliations
- Japan Science and Technology Agency (JP)
- Japanese Foundation For Cancer Research (JP)
- Imperial College London (GB)
- Corresponding author
- Hara, Eiji
- Venue
- Experimental Dermatology
- Publisher
- Wiley
- Published
- 2012-05-24
- Volume
- 21
- Issue
- s1
- Pages
- 1-4
- ISSN
- 0906-6705 (ISSN-L)
- 1600-0625
- OpenAlex
- W2163432085
- Cited by
- 57
- References
- 66
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2022: 7 · 2021: 8 · 2020: 3 · 2019: 1 · 2018: 7 · 2017: 2 · 2016: 7 · 2015: 6 · 2014: 3 · 2013: 6 · 2012: 1
- FWCI
- 0.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Dermatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Science and Technology Agency
- 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, apoptosis, tumor promotion, senescence-associated secretory phenotype, aging, age-related cancer incidence, cell cycle arrest
- MeSH terms
- Animals, Cell Transformation, Neoplastic, DNA Damage, Humans, Inflammation, Models, Biological, Neoplasms, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Cellular Senescence, Apoptosis, Oxidative Stress, Epigenesis, Genetic, Cell Proliferation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review