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Immune surveillance of senescent cells--biological significance in cancer- and non-cancer pathologies
Open accessAbstract
Cellular senescence, a state of stable growth arrest, can occur in response to various stress stimuli such as telomere shortening, treatment with chemotherapeutic drugs or the aberrant activation of oncogenes. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it has become clear that this 'secretory phenotype' can have pro- as well as anti-tumorigenic effects. Recent work from our laboratory showed that premalignant, senescent hepatocytes are recognized and cleared through an antigen-specific immune response and that this immune response, designated as 'senescence surveillance' is crucial for tumor suppression in the liver [(Kang,T.W. et al. (2011) Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature, 479, 547-551]. It is an emerging concept that immune responses against senescent cells have a broader biological significance in cancer- as well as non-cancer pathologies and current data suggest that distinct immune responses are engaged to clear senescent cells in different disease settings. In this review article, we will discuss different examples how immune responses against senescent cells are involved to restrict disease progression in cancer- and non-cancer pathologies.
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In the citing paper
“In the case of senescent tumor cells, there is good evidence that they are subjected to strict immune surveillance and are efficiently removed by phagocytosis”
From The Hallmarks of Aging (2013) · cites this paper as Hoenicke and Zender, 2012
Experimental — accuracy not yet measuredIn the citing paper
“Although senescent cells can be recognized by T helper cells and cleared by macrophages and natural killer lymphocytes [27,34,35], their number has been shown to increase with normal ageing in tissues of humans, primates and rodents [36,37].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [35]
In the citing paper
“Senescent cells can be eliminated through a SASP-induced immune response, which can involve both innate and adaptive immunity.”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [111]
In the citing paper
“activating an immune response”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [111]
In the citing paper
“Indeed, senescent cells formed following tissue damage can promote their own clearance by secreting chemo-attractants that recruit and activate immune cells [265].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [265]
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“At present, senescence immunotherapy is an emerging research field (Burton and Stolzing, 2018; Hoenicke and Zender, 2012; Krizhanovsky et al., 2008; Sagiv et al., 2013).”
BackgroundTherapeutic 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 82
Cellular senescence is a promising target for chronic wounds: a comprehensive review
Wang, Z., & Shi, C. (2020) · Burns & Trauma · doi:10.1093/burnst/tkaa021 · Cited by 73
Premature aging/senescence in cancer cells facing therapy: good or bad?
Calvo, L., Ghadaouia, S., Martinez, A., & Rodier, F. (2015) · Biogerontology · doi:10.1007/s10522-015-9593-9 · Cited by 74
Telomere Dysfunction and Cell Senescence in Chronic Lung Diseases: Therapeutic Potential
Adnot, S., Amsellem, V., Boyer, L., Marcos, É., Saker, M., Houssaini, A., Kebe, K., Dagouassat, M., Lipskaia, L., & Boczkowski, J. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.06.007 · Cited by 69
Zhang, Y., Yang, B., Wang, J., Cheng, F., Shi, K., Ying, L., Wang, C., Xia, K., Huang, X., Gong, Z., et al. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/9503562 · Cited by 70
Telomeric aging: mitotic clock or stress indicator?
Koliada, A. K., Krasnienkov, D. S., & Vaiserman, A. M. (2015) · Frontiers in Genetics · doi:10.3389/fgene.2015.00082 · Cited by 67
“In this process, senescent cells interact with their environment by secreting various growth factors and cytokines, being thereby recognized and eliminated by an antigen-specific immune response (Hoenicke and Zender, 2012; Sagiv and Krizhanovsky, 2013).”
BackgroundKhalil, R., Diab‐Assaf, M., & Lemaître, J.-M. (2023) · Cells · doi:10.3390/cells12060915 · Cited by 68
“The intricacy of senescence and SASP regulation is illustrated by the lncRNA MIR31HG, which, depending on its cellular localization, can both induce and delay senescence [104].”
BackgroundNatural killer cell recognition of in vivo drug-induced senescent multiple myeloma cells
Antonangeli, F., Soriani, A., Ricci, B., Ponzetta, A., Benigni, G., Morrone, S., Bernardini, G., & Santoni, A. (2016) · OncoImmunology · doi:10.1080/2162402x.2016.1218105 · Cited by 67
“and senescent cells can be recognized by the immune system, senescence is thought to be a major barrier to tumor formation.(12) This finding has attracted the attention of the scientific”
BackgroundZheng, J., Jiang, L., Zhang, L., Yang, L., Deng, J., You, Y., Li, N., Wu, H., Li, W., Lü, J., et al. (2012) · Carcinogenesis · doi:10.1093/carcin/bgs307 · Cited by 65
The Spectrum of Reactive Cholangiocytes in Primary Sclerosing Cholangitis
Guicciardi, M. E., Trussoni, C. E., LaRusso, N. F., & Gores, G. J. (2019) · Hepatology · doi:10.1002/hep.31067 · Cited by 65
“(33) Indeed, SASP modulates the immune surveillance of senescent cells and can attract immune cells, especially macrophages, to senescent cells for their elimination.(38,39) Although the involvement of other cell types cannot be ruled out, in vitro coculture”
BackgroundSenescent T cells: Beneficial and detrimental roles
Laphanuwat, P., Gomes, D. C. O., & Akbar, A. N. (2023) · Immunological Reviews · doi:10.1111/imr.13206 · Cited by 63
da Silva, B. D. O., Ramos, L. F., & Moraes, K. C. M. (2017) · Cell Biology International · doi:10.1002/cbin.10790 · Cited by 62
“In addition, a remarkable characteristic of senescent cells is the senescence-associated secretory phenotype (SASP) generated as a consequence of the increased expression and secretion of interleukins, chemokines, growth factors, and proteases (Hoenicke and Zender, 2012), mediated by the activity of transcription fact…”
BackgroundOxidative Stress and Cellular Senescence Are Involved in the Aging Kidney
Márquez‐Expósito, L., Tejedor-Santamaria, L., Valentijn, F. A., Tejera‐Muñoz, A., Rayego‐Mateos, S., Marchant, V. A., Rodrigues-Díez, R. R., Rubio-Soto, I., Knoppert, S. N., Ortíz, A., et al. (2022) · Antioxidants · doi:10.3390/antiox11020301 · Cited by 60
A principle of organization which facilitates broad Lamarckian-like adaptations by improvisation
Soen, Y., Knafo, M., & Elgart, M. (2015) · Biology Direct · doi:10.1186/s13062-015-0097-y · Cited by 56
PIM ‐1 modulates cellular senescence and links IL ‐6 signaling to heterochromatin formation
Jin, B., Wang, Y., Wu, C., Liu, K. Y., Chen, H., & Mao, Z. B. (2014) · Aging Cell · doi:10.1111/acel.12249 · Cited by 56
“Increasing evidences have shown that cellular senescence acts as a protective mechanism against carcinogenesis (Lanigan et al., 2011; Hoenicke & Zender, 2012; Vargas et al., 2012).”
BackgroundSuccess after failure: the role of endometrial stem cells in recurrent miscarriage
Lucas, E. S., Dyer, N. P., Fishwick, K. J., Ott, S., & Brosens, J. J. (2016) · Reproduction · doi:10.1530/rep-16-0306 · Cited by 56
“An alternative scenario is that influx of immune cells, and specifically uterine natural killer cells, during the luteal phase plays a key role in homeostatic balancing of the stromal subpopulations through selective clearance of senescent cells (Hoenicke & Zender 2012).”
Periodontal Disease and Senescent Cells: New Players for an Old Oral Health Problem?
Aquino-Martínez, R., Khosla, S., Farr, J. N., & Monroe, D. G. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207441 · Cited by 59
“This process is called senescent cell immune surveillance, in which the release of senescence-associated proinflammatory signals play essential roles in attracting neutrophils, macrophages, lymphocytes and natural killer cells [67,83,85].”
BackgroundInfluentialMerkt, W., Zhou, Y., Han, H., & Lagares, D. (2021) · Wound Repair and Regeneration · doi:10.1111/wrr.12952 · Cited by 62
“59,62,63 In the context of wound healing, NK cells expressing TRAIL have been involved in the resolution of the tissue repair programme by promoting apoptosis of senescent myofibroblasts and other cell types.”
The Janus Face of Death Receptor Signaling during Tumor Immunoediting
Reilly, E. O., Tirincsi, A., Logue, S. E., & Szegezdi, É. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00446 · Cited by 51
Stabilization of telomere by the antioxidant property of polyphenols: Anti-aging potential
Maleki, M., Khelghati, N., Alemi, F., Bazdar, M., Asemi, Z., Majidinia, M., Sadeghpoor, A., Mahmoodpoor, A., Jadidi‐Niaragh, F., Targhazeh, N., et al. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.118341 · Cited by 53
Cellular Senescence and Periodontitis: Mechanisms and Therapeutics
Chen, S., Zhou, D., Liu, O., Chen, H., Wang, Y., & Zhou, Y. (2022) · Biology · doi:10.3390/biology11101419 · Cited by 51
“The SASP promotes the migration of immune cells that help remove senescent cells [88].”
BackgroundBrauer, E., Lange, T., Keller, D., Görlitz, S., Cho, S., Keye, J., Gossen, M., Petersen, A., & Kornak, U. (2022) · Aging Cell · doi:10.1111/acel.13744 · Cited by 50
“Senescent cells secrete a variety of pro- inflammatory cytokines as part of the senescence- associated secretory phenotype (SASP) (Coppé et al., 2010) that lead to the recruitment of the immune system and subsequent cell clearance (Hoenicke & Zender, 2012; Kang et al., 2011).”
BackgroundNovoa, B., Pereiro, P., López‐Muñoz, A., Varela, M., Forn‐Cuní, G., Anchelin, M., Dios, S., Romero, A., Martinez‐López, A., Medina‐Gali, R. M., et al. (2019) · Aging Cell · doi:10.1111/acel.13020 · Cited by 41
“Indeed, it has been reported that these cell types, together with macrophages, play a pivotal role in the clearance of senescent cells (Hoenicke & Zender, 2012).”
BackgroundAlexander, E., Hildebrand, D. G., Kriebs, A., Obermayer, K., Manz, M., Rothfuss, O. C., Eßmann, F., & Schulze‐Osthoff, K. (2013) · Journal of Cell Science · doi:10.1242/jcs.128835 · Cited by 47
“Finally, these cytokines or other secreted factors have been shown to attract immune cells in an inflammatory response, leading to the elimination of senescent tumor cells (Kang et al., 2011; Xue et al., 2007; Hoenicke and Zender, 2012).”
BackgroundA tale of the good and bad: Cell senescence in bone homeostasis and disease
Liu, X., & Wan, M. (2019) · International review of cytology · doi:10.1016/bs.ircmb.2019.03.005 · Cited by 45
Feng, M., Kim, J., Field, K. P., Reid, C., Chatzistamou, I., & Shim, M. (2019) · FASEB BioAdvances · doi:10.1096/fba.2019-00041 · Cited by 44
Neutrophil extracellular traps and long COVID
Shafqat, A., Omer, M. H., Albalkhi, I., Razzak, G. A., Abdulkader, H. S., Rab, S. A., Sabbah, B. N., AlKattan, K. M., & Yaqinuddin, A. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1254310 · Cited by 49
Cellular senescence in tissue repair: every cloud has a silver lining
Yun, M. H. (2018) · The International Journal of Developmental Biology · doi:10.1387/ijdb.180081my · Cited by 44
“Furthermore, due to its capacity to alter the microenvironment and promote inflammation (Hoenicke and Zender, 2012), the SASP has been proposed to contribute to tissue malfunction and degeneration.”
BackgroundModulation 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
Lee, Y., Chen, Y.-Y., Yeh, Y.-L., Wang, Y., & Chen, R.-J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20112716 · Cited by 39
“If the senescent cancer cells in treated tumor tissue cannot be completely eliminated by a proper senescence immune surveillance response, the treatment is failing [9,10].”
BackgroundNovel PET Imaging Probe for Quantitative Detection of Senescence In Vivo
Xiang, X., Dong, C., Zhou, L., Liu, J., Rabinowitz, Z. M., Zhang, Y., Guo, H., He, F., Chen, X., Wang, Y., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00179 · Cited by 41
Rajesh, K., Papadakis, A. I., Kazimierczak, U., Peidis, P., Wang, S., Ferbeyre, G., Kaufman, R. J., & Koromilas, A. E. (2013) · Aging · doi:10.18632/aging.100620 · Cited by 41
Al-Rajhi, N., Soudy, H., Ahmed, S. A., Elhassan, T. A. M., Mohammed, S. F., Khoja, H. A., & Ghebeh, H. (2020) · BMC Cancer · doi:10.1186/s12885-020-06757-w · Cited by 38
“A recent trial has shown that multiple immunotherapeutic agents can synergize to enhance endogenous antitumor immunity [6].”
Role of Senescent Renal Cells in Pathophysiology of Diabetic Kidney Disease
Wiley, C. D. (2020) · Current Diabetes Reports · doi:10.1007/s11892-020-01314-y · Cited by 38
Wang, A., Yang, F., Tian, Y., Su, J.-H., Gu, Q., Chen, W., Gong, S.-X., Ma, X., Qin, X.-P., & Jiang, Z. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.656139 · Cited by 41
Metadata
- Authors
- Hoenicke, L., & Zender, L.
- Affiliations
- Helmholtz Centre for Infection Research (DE)
- Medizinische Hochschule Hannover (DE)
- Corresponding author
- Zender, L.
- Venue
- Carcinogenesis
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-04-02
- Volume
- 33
- Issue
- 6
- Pages
- 1123-1126
- ISSN
- 0143-3334 (ISSN-L)
- 1460-2180
- OpenAlex
- W2121022075
- Cited by
- 248
- References
- 40
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 11 · 2023: 15 · 2022: 26 · 2021: 21 · 2020: 31 · 2019: 24 · 2018: 24 · 2017: 14 · 2016: 22 · 2015: 14 · 2014: 12 · 2013: 17 · 2012: 1
- FWCI
- 1.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Carcinogenesis (publishedVersion)
- PubMed (publishedVersion)
- HZI (Helmholtz Centre for Infection Research) (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
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- cellular senescence, senescence-associated secretory phenotype, tumor suppression, liver cancer, antigen-specific immune response, tumor immunology, telomere shortening, chemotherapy-induced senescence, oncogene activation
- MeSH terms
- Humans, Immunologic Surveillance, Liver, Neoplasms, Precancerous Conditions, Cytokines, Cellular Senescence, Disease Progression, Chemokines, Hepatocytes
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