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Senescence in tumours: evidence from mice and humans
Open accessAbstract
The importance of cellular senescence, which is a stress response that stably blocks proliferation, is increasingly being recognized. Senescence is prevalent in pre-malignant tumours, and progression to malignancy requires evading senescence. Malignant tumours, however, may still undergo senescence owing to interventions that restore tumour suppressor function or inactivate oncogenes. Senescent tumour cells can be cleared by immune cells, which may result in efficient tumour regression. Standard chemotherapy also has the potential to induce senescence, which may partly underlie its therapeutic activity. Although these concepts are well supported in mouse models, translating them to clinical oncology remains a challenge.
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“There is little doubt that the senescence growth arrest suppresses the development of cancer (8, 48, 136).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [136]
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In the citing paper
“Other senescence markers have been shown to be overexpressed or activated in cancer152.”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [152]
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“Whatever the case, the examples above, and a growing list of similar studies (Collado and Serrano, 2010), argue that cellular senescence restrains cancer by imposing a cell-autonomous block to the proliferation of oncogenically damaged/stressed cells (Fig. 2).”
From Four faces of cellular senescence (2011) · cites this paper as Collado and Serrano, 2010
In the citing paper
“A SASP profile can be further determined by the activation of molecular cascades linked to p53/p21 (due to persistent double strands breaks/telomere shortening)”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [24]
In the citing paper
“but also to p16/Rb (due to epigenetic modifications) [3,22,24,25,26]”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [24]
In the citing paper
“It is believed that senescence is a key mechanism by which p53 suppresses tumorigenesis (Braig and Schmitt, 2006; Collado and Serrano, 2010).”
From p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells (2013) · cites this paper as Collado and Serrano, 2010
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“Therefore, it has been proposed that senescence escape is required for tumor progression to overt malignancy [18,21].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [21]
In the citing paper
“However, senescence has also been implicated both in promoting carcinogenesis 15 and in age-related pathologies 16,17 through its autocrine and paracrine effects, known as the senescence-associated secretory phenotype (SASP) originally described by the Campisi group.18,19”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [15]
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BackgroundDYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly
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“Oncogene-induced senescence in premalignant lesions in mouse models as well as in some human tumors could serve as a protective tumor suppressor mechanism (for review, see Collado and Serrano 2010).”
BackgroundMetformin: Multi-faceted protection against cancer
Barco, S. D., Vázquez‐Martín, A., Cufí, S., Oliveras‐Ferraros, C., Bosch‐Barrera, J., Joven, J., Martı́n-Castillo, B., & Menéndez, J. A. (2011) · Oncotarget · doi:10.18632/oncotarget.387 · Cited by 307
“Studies of human cancer tissues and cancerprone mice argue strongly that cellular senescence is an important physiological mechanism in protecting cells against malignant transformation [154-156].”
BackgroundTargeting senescent cells in translational medicine
Paez‐Ribes, M., González‐Gualda, E., Doherty, G. J., & Muñoz‐Espín, D. (2019) · EMBO Molecular Medicine · doi:10.15252/emmm.201810234 · Cited by 293
“A major consequence of senescence appears to prevent propagation of pre-malignant cells, providing a crucial barrier to tumorigenesis (Collado & Serrano, 2010).”
BackgroundCellular senescence and the aging brain
Chinta, S. J., Woods, G., Rane, A., Demaria, M., Campisi, J., & Andersen, J. K. (2015) · Experimental Gerontology · doi:10.1016/j.exger.2014.09.018 · Cited by 282
“The senescence response arrests cell proliferation , stably and essentially irreversibly, in response to stresses that puts cells at risk for malignant transformation (Campisi, 2001; Collado and Serrano, 2010; Prieri et al., 2008).”
Rho GTPase signaling in cancer progression and dissemination
Crosas‐Molist, E., Samain, R., Kohlhammer, L., Orgaz, J. L., George, S. L., Maiques, Ó., Barcelo, J., & Sanz‐Moreno, V. (2021) · Physiological Reviews · doi:10.1152/physrev.00045.2020 · Cited by 289
Cell fusion induced by ERVWE1 or measles virus causes cellular senescence
Chuprin, A., Gal, H., Biron-Shental, T., Biran, A., Amiel, A., Rozenblatt, S., & Krizhanovsky, V. (2013) · Genes & Development · doi:10.1101/gad.227512.113 · Cited by 262
“These triggers as well as others yet unidentified lead to senescent cell accumulation in aged tissues, premalignant lesions, tumors after therapy, and tissue damage (Dimri et al. 1995; Schmitt et al. 2002; Krizhanovsky et al. 2008; Collado and Serrano 2010; Jun and Lau 2010; Kuilman et al. 2010).”
BackgroundBird, T. G., Müller, M., Boulter, L., Vincent, D. F., Ridgway, R. A., Lopez-Guadamillas, E., Lu, W.-Y., Jamieson, T., Govaere, O., Campbell, A. D., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aan1230 · Cited by 261
“They also express a suite of senescence markers (38), including markers of the DNA damage response, growth arrest and the SASP.”
Self-citationFarr, J. N., & Khosla, S. (2019) · Bone · doi:10.1016/j.bone.2019.01.015 · Cited by 263
“What is becoming clear, however, is that in addition to the wellestablished mechanism of tumor suppression to protect against unrestricted growth of damaged cells and prevent cancer [15, 16], senescent cells and their SASP have important roles in, for example, fine-tuning embryonic development [17, 18] and promoting t…”
BackgroundCharacterization of novel markers of senescence and their prognostic potential in cancer
Althubiti, M., Lezina, L., Carrera, S., Jukes-Jones, R., Giblett, S. M., Antonov, A., Barlev, N., Saldanha, G. S., Pritchard, C. A., Cain, K., et al. (2014) · Cell Death & Disease · doi:10.1038/cddis.2014.489 · Cited by 256
“Senescence is usually defined as a permanent cell cycle arrest in which cells remain metabolically active and adopt characteristic phenotypic changes.(2) Senescent cells often appear multinucleated, large and extended, and exhibit spindle and vacuolization features.”
BackgroundAbrogation of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanomagenesisPreprint
Vredeveld, L. C. W., Possik, P. A., Smit, M. A., Meissl, K., Michaloglou, C., Horlings, H. M., Ajouaou, A., Kortman, P. C., Dankort, D. L., McMahon, M., et al. (2012) · Genes & Development · doi:10.1101/gad.187252.112 · Cited by 283
“The factors and pathways identified in this way will likely be relevant for other tumor settings as well, as OIS is seen in many tissue types (Collado and Serrano 2010).”
BackgroundGut bacteria identified in colorectal cancer patients promote tumourigenesis via butyrate secretion
Okumura, S., Konishi, Y., Narukawa, M., Sugiura, Y., Yoshimoto, S., Arai, Y., Sato, S., Yoshida, Y., Tsuji, S., Uemura, K., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-25965-x · Cited by 273
Benhamed, M., Herbig, U., Ye, T., Dejean, A., & Bischof, O. (2012) · Nature Cell Biology · doi:10.1038/ncb2443 · Cited by 252
“dtd" [ ]> Cellular senescence represents a robust and essentially irreversible tumour-suppressive barrier that cells must overcome to develop into a full-blown malignanc”
Cell Senescence: Role in Aging and Age-Related Diseases
Campisi, J., & Robert, L. (2014) · Interdisciplinary Topics in Gerontology and Geriatrics · doi:10.1159/000358899 · Cited by 240
Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure
Pagliarini, R. A., Shao, W., & Sellers, W. R. (2015) · EMBO Reports · doi:10.15252/embr.201439949 · Cited by 264
Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer
Haston, S., Gonzalez-Gualda, E., Morsli, S., Ge, J., Reen, V., Calderwood, A., Moutsopoulos, I., Panousopoulos, L., Deletic, P., Carreno, G., et al. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.05.004 · Cited by 251
“of damaged cells to proliferate.(13) Paradoxically, cellular senescence can also exert a variety of tumor-promoting effects, depending on the cellular context and composition of the SASP.”
BackgroundA Senescence-Inflammatory Switch from Cancer-Inhibitory to Cancer-Promoting Mechanism
Pribluda, A., Elyada, E., Wiener, Z., Hamza, H., Goldstein, R. E., Biton, M., Burstain, I., Morgenstern, Y., Brachya, G., Billauer, H., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.06.005 · Cited by 239
“It is likely that CKIa ablation as a single genetic alteration may in fact mimic the cumulative effect of multiple genetic alterations in human colorectal cancer, many of which, like the Ras pathway mutations, culminate in DDR and senescence (Collado and Serrano, 2010; Figure 8).”
BackgroundVendetti, F. P., Lau, A., Schamus, S., Conrads, T. P., O’Connor, M. J., & Bakkenist, C. J. (2015) · Oncotarget · doi:10.18632/oncotarget.6247 · Cited by 252
Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies
Wyld, L., Bellantuono, I., Tchkonia, T., Morgan, J., Turner, O., Foss, F., George, J., Danson, S., & Kirkland, J. L. (2020) · Cancers · doi:10.3390/cancers12082134 · Cited by 235
“Other mechanisms of tumour suppression have been proposed [35].”
BackgroundFibronectin in Cancer: Friend or Foe
Lin, T.-C., Yang, C.-H., Cheng, L.-H., Chang, W., Lin, Y.-R., & Cheng, H.-C. (2019) · Cells · doi:10.3390/cells9010027 · Cited by 241
Nuclear morphology is a deep learning biomarker of cellular senescence
Heckenbach, I., Mkrtchyan, G. V., Ezra, M. B., Bakula, D., Madsen, J. S., Nielsen, M. H., Oró, D., Osborne, B., Covarrubias, A. J., Idda, M. L., et al. (2022) · Nature Aging · doi:10.1038/s43587-022-00263-3 · Cited by 232
“Although oncogenic events are associated with the formation of senescent cells 17 , we speculate that individuals with higher propensity toward developing senescent cells have reduced formation of malignant neoplasm and are at lower risk of cancer.”
BackgroundKhongkow, P., Gomes, A., Gong, C., Man, E. P. S., Tsang, J. W.-H., Zhao, F., Monteiro, L. J., Coombes, R. C., Medema, R. H., Khoo, U., et al. (2015) · Oncogene · doi:10.1038/onc.2015.152 · Cited by 235
Glucocorticoids suppress selected components of the senescence‐associated secretory phenotype
Laberge, R., Zhou, L., Sarantos, M. R., Rodier, F., Freund, A., de Keizer, P. L. J., Liu, S., Demaria, M., Cong, Y., Kapahi, P., et al. (2012) · Aging Cell · doi:10.1111/j.1474-9726.2012.00818.x · Cited by 229
“Cellular senescence is a potent tumor suppressive mechanism that arrests the proliferation, essentially irreversibly, of cells at risk for malignant transformation (Campisi, 2001; Collado & Serrano, 2010).”
BackgroundSuram, A., Kaplunov, J., Patel, P. L., Ruan, H., Cerutti, A., Boccardi, V., Fumagalli, M., Di Micco, R., Mirani, N., Gurung, R. L., et al. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.132 · Cited by 227
“Studies conducted using mouse model systems suggest that cellular senescence arrests tumour growth before cells become malignant and invade surrounding tissue (Collado and Serrano, 2010).”
Wiel, C., Lallet-Daher, H., Gitenay, D., Gras, B., Le Calvé, B., Augert, A., Ferrand, M., Prevarskaya, N., Simonnet, H., Vindrieux, D., et al. (2014) · Nature Communications · doi:10.1038/ncomms4792 · Cited by 231
Karachaliou, N., Mayo, C., Costa, C., Magrí, I., Giménez-Capitán, A. A., Molina‐Vila, M. Á., & Rosell, R. (2012) · Clinical Lung Cancer · doi:10.1016/j.cllc.2012.09.007 · Cited by 241
miR-29 and miR-30 regulate B-Myb expression during cellular senescence
Martínez, I., Cazalla, D., Almstead, L. L., STEITZ, J. A., & DiMaio, D. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1017346108 · Cited by 221
“S is an important block to cell cycle progression during the aging of cells in culture and is a fundamental barrier that cells must bypass during carcinogenesis (1, 2).”
BackgroundCellular Differences in Protein Synthesis Regulate Tissue Homeostasis
Buszczak, M., Signer, R. A. J., & Morrison, S. J. (2014) · Cell · doi:10.1016/j.cell.2014.09.016 · Cited by 224
Immunosurveillance of senescent cells: the bright side of the senescence program
Sagiv, A., & Krizhanovsky, V. (2013) · Biogerontology · doi:10.1007/s10522-013-9473-0 · Cited by 208
“Since its initial discovery, DCR2 has been widely used, along with other biomarkers, to characterize senescent cells in premalignant lesions albeit its functional role to the senescence program has been unknown (Collado et al. 2005; Collado and Serrano 2010).”
BackgroundHerdy, J. R., Traxler, L., Agarwal, R. K., Karbacher, L., Schlachetzki, J. C. M., Boehnke, L., Zangwill, D., Galasko, D., Glass, C. K., Mertens, J., et al. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.11.010 · Cited by 208
Barascu, A., Le Chalony, C., Pennarun, G., Genet, D., Imam, N., Lopez, B., & Bertrand, P. (2012) · The EMBO Journal · doi:10.1038/emboj.2011.492 · Cited by 206
“Consistently, senescence can be induced by replicative stress or oncogene expression (Collado and Serrano, 2010).”
SASP: Tumor Suppressor or Promoter? Yes!
Rao, S. G., & Jackson, J. G. (2016) · Trends in Cancer · doi:10.1016/j.trecan.2016.10.001 · Cited by 206
Cartilage regeneration and ageing: Targeting cellular plasticity in osteoarthritis
Varela-Eirín, M., Loureiro, J., Fonseca, E., Corrochano, S., Caeiro, J. R., Collado, M., & Mayán, M. D. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.12.006 · Cited by 206
Self-citationIsoform-specific p73 knockout mice reveal a novel role for ΔNp73 in the DNA damage response pathwayPreprint
Wilhelm, M., Rufini, A., Wetzel, M. K., Tsuchihara, K., Inoue, S., Tomasini, R., Itie-YouTen, A., Wakeham, A. C., Arsenian‐Henriksson, M., Melino, G., et al. (2010) · Genes & Development · doi:10.1101/gad.1873910 · Cited by 214
“Indeed, activation of the p16–RB axes is known to play a role in the establishment of senescence in tumors and to act in parallel to or overlapping with the Arf–p53 axes (Campisi and d’Adda di Fagagna 2007; Collado and Serrano 2010).”
BackgroundHan, Y., & Kim, S. Y. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00906-w · Cited by 201
The two sides of chromosomal instability: drivers and brakes in cancer
Hosea, R., Hillary, S., Naqvi, S., Wu, S., & Kasim, V. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01767-7 · Cited by 226
“362,363 In addition, senescent cells could be further cleared through autophagic cell death.”
BackgroundFan, T., Jiang, S., Chung, N., Alikhan, A., Ni, C., Lee, C. R., & Hornyak, T. J. (2011) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-10-0511 · Cited by 199
“Since senescence is a distinct mechanism of tumor suppression (2, 15, 16), determining how melanoma cells escape senescence and devising methods to restore senescence to these cells may be important for developing additional therapeutic options for this malignancy.”
BackgroundCellular senescence in cancer: from mechanisms to detection
Ou, H., Hoffmann, R. J., González‐López, C., Doherty, G. J., Korkola, J. E., & Muñoz‐Espín, D. (2020) · Molecular Oncology · doi:10.1002/1878-0261.12807 · Cited by 208
Histone variant H2A.J accumulates in senescent cells and promotes inflammatory gene expression
Contrepois, K., Coudereau, C., Benayoun, B. A., Schuler, N., Roux, P.-F., Bischof, O., Courbeyrette, R., Carvalho, C., Thuret, J.-Y., Ma, Z., et al. (2017) · Nature Communications · doi:10.1038/ncomms14995 · Cited by 191
“Up-regulated genes were greatly enriched in GO terms related to inflammatory/immune/secreted proteins (35/50 top GO classes) as previously reported for senescent cells (Supplementary Data 2).”
Akkız, H., Gieseler, R. K., & Canbay, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25147873 · Cited by 191
“The authors suggested that HSCs are deactivated in the healing liver [193].”
BackgroundMethodInfluentialHIF1α is required for survival maintenance of chronic myeloid leukemia stem cells
Zhang, H., Li, H., Xi, H. S., & Li, S. (2012) · Blood · doi:10.1182/blood-2011-10-387381 · Cited by 196
Nuclear Morphometric Analysis (NMA): Screening of Senescence, Apoptosis and Nuclear Irregularities
Filippi‐Chiela, E. C., Oliveira, M. M., Jurkovski, B., Callegari-Jacques, S. M., da Silva, V. D., & Lenz, G. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042522 · Cited by 200
“Both replicative senescence and oncogene-induced senescence are important anti-cancer mechanisms and reactivation of senescence by therapy may represent a good anticancer strategy [4,5].”
BackgroundOncogene-induced senescence: a double edged sword in cancer
Liu, X., Ding, J., & Meng, L. (2018) · Acta Pharmacologica Sinica · doi:10.1038/aps.2017.198 · Cited by 204
Assessing cell and organ senescence biomarkers
de Jesus, B. B., & Blasco, M. A. (2012) · Circulation Research · doi:10.1161/circresaha.111.247866 · Cited by 187
Metadata
- Authors
- Collado, M., & Serrano, M.
- Affiliations
- Spanish National Cancer Research Centre (ES)
- Venue
- Nature Reviews Cancer
- Published
- 2010-01
- Volume
- 10
- Issue
- 1
- Pages
- 51-57
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- PMC
- PMC3672965
- OpenAlex
- W2087999409
- Cited by
- 1,124
- References
- 58
- Citations by year
- 2026: 34 · 2025: 40 · 2024: 56 · 2023: 73 · 2022: 60 · 2021: 64 · 2020: 47 · 2019: 67 · 2018: 66 · 2017: 66 · 2016: 73 · 2015: 81 · 2014: 104 · 2013: 102 · 2012: 82
- FWCI
- 6.97
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- 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
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- oncogene-induced senescence, cellular senescence, tumor suppressor function, tumor regression, chemotherapy-induced senescence, senescence therapy, mouse tumor model
- MeSH terms
- Animals, Disease Models, Animal, Humans, Neoplasms, Cellular Senescence, Mice
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