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Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse
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Abstract
Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a proinflammatory senescence-associated secretory phenotype. Many genotoxic chemotherapies target proliferating cells nonspecifically, often with adverse reactions. In accord with prior work, we show that several chemotherapeutic drugs induce senescence of primary murine and human cells. Using a transgenic mouse that permits tracking and eliminating senescent cells, we show that therapy-induced senescent (TIS) cells persist and contribute to local and systemic inflammation. Eliminating TIS cells reduced several short- and long-term effects of the drugs, including bone marrow suppression, cardiac dysfunction, cancer recurrence, and physical activity and strength. Consistent with our findings in mice, the risk of chemotherapy-induced fatigue was significantly greater in humans with increased expression of a senescence marker in T cells prior to chemotherapy. These findings suggest that senescent cells can cause certain chemotherapy side effects, providing a new target to reduce the toxicity of anticancer treatments. Significance: Many genotoxic chemotherapies have debilitating side effects and also induce cellular senescence in normal tissues. The senescent cells remain chronically present where they can promote local and systemic inflammation that causes or exacerbates many side effects of the chemotherapy. Cancer Discov; 7(2); 165–76. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 115
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“In addition, through SASP, senescent cells contribute to cancer development162,163 and metastasis164, treatment failure and increased risk of recurrence165.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [165]
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“The SASP can also explain chemotherapy side effects, such as bone marrow suppression, cardiac dysfunction, blood clotting, or cancer relapse (Demaria et al. 2017; Wiley et al. 2019).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Demaria et al. 2017
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“Our study, in accordance with others (Baker et al, 2016; Roos et al, 2016; Demaria et al, 2017), shows that the loss of senescent cardiomyocytes does not adversely alter cardiac function in aged mice.”
From Length-independent telomere damage drives post-mitotic cardiomyocyte senescence (2019) · cites this paper as Demaria et al, 2017
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“Cellular senescence, a central hallmark of aging,13,14 encompasses heterogeneous cellular states triggered by prolonged cell stress resulting in the irreversible arrest of proliferation and permanent changes to cell function in vivo.15,16,17,18,19”
From Uncovering the signatures of aging and senescence in the human dorsolateral prefrontal cortex (2026) · cites this paper as [18]
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“Moreover, these detrimental effects were neutralized via genetic or pharmacological clearance of senescent cells 27 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [27]
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“Interestingly, high expression of p16 INK4a in circulating Tcells before treatment, presumably a surrogate biomarker of system-wide senescent cell burden, correlates with severe chemotherapy- induced fatigue in patients with breast cancer, suggesting that senescent cells might contribute to the reduced tolerance of older individuals to anticancer therapies 27 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [27]
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“Studies in mouse models have demonstrated that TIS promotes cardiac dysfunction, inflammation, bone loss, muscle weakness, renal and hepatic failure, haematopoietic insufficiency, and overall frailty 27,111,202 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [27]
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“In patients with cancer, older age (>65 years) is associated with reduced tolerance to anticancer treatment 27 and a greater risk of developing serious AEs 192 , as well as genetic alterations that might lead to reduced sensitivity to treatment; together these features constitute major hurdles for the successful administration of antineoplastic therapies at efficient doses.”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [27]
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“Therapy-induced senescence plays an important role in determining the outcome of anti-cancer treatment 40, whilst also being responsible for some of its side effects 41.”
From Cardiac glycosides are broad-spectrum senolytics (2019) · cites this paper as [41]
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“These include increases in local and systemic inflammation and cancer reoccurrence (Demaria et al. 2017).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Demaria et al. 2017
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“In some cases, these triggers cause fibroblasts to enter a non-proliferative state termed ‘senescence’71, which is distinct from the phenotype of an aged fibroblast.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [71]
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“For example, DOX-induced systemic senescence was found to promote metastasis in an orthotopic mouse model of breast cancer.”
From Drug repurposing for cancer therapy (2024) · cites this paper as [232]
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“p16 INK4a expression is considered a common and robust, albeit not necessarily specific, marker of senescence, and its promoter activity and transcriptional activation are extensively exploited as reporters of senescent cells invivo 20,23,27,28 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [27]
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“Alkylating agents 27,95,96 (for example, cisplatin, cyclophosphamide and temozolomide), topoisomerase inhibitors 27,65,91,95 (such as doxorubicin, etoposide and camptothecin) and γ- irradiation 78 , but also microtubule inhibitors 27,97,98 (for example, paclitaxel) and, to a lesser extent, vinca alkaloids 78 (for example, vincristine), have all been identified as senescence inducers in preclinical”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [27]
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“In tumour- free mice, exposure to the topoisomerase II inhibitor doxorubicin leads to systemically elevated SASP and functional impairment reminiscent of accelerated ageing, which is only explained in part by direct organ toxicity of this chemotherapeutic agent 27 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [27]
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“Doxorubicin- induced systemic senescence contributed to breast cancer metastasis in an orthotopic mouse model.”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [27]
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“Interestingly, high expression of p16 INK4a in circulating Tcells before treatment, presumably a surrogate biomarker of system-wide senescent cell burden, correlates with severe chemotherapy- induced fatigue in patients with breast cancer, suggesting that senescent cells might contribute to the reduced tolerance of older individuals to anticancer therapies 27 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [27]
In the citing paper
“SASP also mediates the harmful effects of senescent cells which accumulate upon chemotherapy treatment as their chronic presence promotes local and systemic inflammation.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Demaria et al., 2017
In the citing paper
“age-related or therapy-induced senescent cells are mainly linked with secretion of inflammatory factors (Baker et al., 2016; Demaria et al., 2017).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Demaria et al., 2017
In the citing paper
“Elimination of therapy-induced senescent cells can prevent cancer recurrence (Demaria et al., 2017).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Demaria et al., 2017
In the citing paper
“Moreover, senescent cells have been implicated in the adverse effects of some chemotherapeutic regimens as well as in the recurrence of specific neoplasms, at least in mice [969].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [969]
In the citing paper
“whilst also contributing to their side effects 41.”
From Cardiac glycosides are broad-spectrum senolytics (2019) · cites this paper as [41]
In the citing paper
“Via the SASP, senescent cells contribute to multiple chronic health conditions associated with inflammaging, e.g., atherosclerosis (16), osteoarthritis (17), cancer (18), myeloid skewing in the bone marrow (19), pulmonary fibrosis (20), Alzheimer’s disease and Parkinson’s disease (21–23), and insulin resistance (24).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [18]
In the citing paper
“These persisting senescent cells have been recently tied to multiple chronic diseases other than atherosclerosis, including diabetes mellitus,85 obesity,85 Alzheimer’s disease,86 heart failure,10,87 idiopathic pulmonary fibrosis,88,89 chronic obstructive pulmonary disease,90 chronic kidney disease,91 cancer,92 and osteoarthritis.93”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [92]
In the citing paper
“However, chronic senescence promotes cancer.92”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [92]
In the citing paper
“and paradoxically tumorigenesis (Demaria et al., 2017).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Demaria et al., 2017
In the citing paper
“However, senescence may contribute to reduced patient resilience to cancer therapies”
From Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies (2020) · cites this paper as [67]
In the citing paper
“The use of senotherapeutic drugs could potentially be effective in treating a variety of conditions primarily or secondarily mediated by accumulation of senescent cells [6, 33, 67–87].”
From Reducing Senescent Cell Burden in Aging and Disease (2020) · cites this paper as [69]
In the citing paper
“The development of a tumor cell population that escapes from senescence and restarts proliferating may contribute to cancer relapse [342].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [342]
In the citing paper
“Senescent cells have also been postulated to mediate resistance to therapy, while contributing to off-target systemic effects and cancer relapse linked to the treatment with standard anticancer regimens.”
From Meta-hallmarks of aging and cancer (2023) · cites this paper as [200]
In the citing paper
“In the same model, whole-body clearance of p16 + cells generated by doxorubicin treatment reduces signs of systemic frailty and limits tumor recurrence.200”
From Meta-hallmarks of aging and cancer (2023) · cites this paper as [200]
In the citing paper
“Indeed, persistent senescent cells may contribute to detrimental short and long-term side effects of treatment, as well as to metastases and relapse (Demaria et al., 2017).”
From CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought (2018) · cites this paper as Demaria et al., 2017
In the citing paper
“the elimination of therapy-induced senescent cells reduced several side-effects of chemotherapy and even cancer recurrence in mice14.”
From A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells (2020) · cites this paper as [14]
In the citing paper
“Furthermore, ablation of senescent cells after chemotherapy can prevent or delay cancer relapse and spread to distal tissues.59”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [59]
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Metadata
- Authors
- Demaria, M., O'Leary, M. N., Chang, J., Shao, L., Liu, S., Alimirah, F., Koenig, K., Le, C., Mitin, N., Deal, A. M., Alston, S., Academia, E. C., Kilmarx, S., Valdovinos, A., Wang, B., de Bruin, A., Kennedy, B. K., Melov, S., Zhou, D., Sharpless, N. E., Muss, H., & Campisi, J.
- Affiliations
- University Medical Center Groningen (NL)
- 1Buck Institute for Research on Aging, Novato, California.
- University of Arkansas for Medical Sciences (US)
- Buck Institute for Research on Aging (US)
- 4HealthSpan Diagnostics, Research Triangle Park, North Carolina.
- University of North Carolina at Chapel Hill (US)
- 6Department of Pathobiology, University of Utrecht, Utrecht, the Netherlands.
- Corresponding author
- Demaria, Marco
- Campisi, Judith
- ORCID
- Venue
- Cancer Discovery
- Published
- 2017-02-01
- Volume
- 7
- Issue
- 2
- Pages
- 165-176
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC5296251
- OpenAlex
- W2561396377
- Cited by
- 1,338
- References
- 34
- Citations by year
- 2026: 113 · 2025: 153 · 2024: 164 · 2023: 176 · 2022: 198 · 2021: 152 · 2020: 159 · 2019: 105 · 2018: 79 · 2017: 38
- FWCI
- 59.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- UNC Libraries
- Funders
- American-Italian Cancer Foundation
- National Institutes of Health (5r01ag024379-15, AG009909, AG017242, AG041122)
- National Institute on Aging (R56AG009909, R01-AG024379, R37AG009909, P01AG041122, P01AG017242)
- National Cancer Institute (R01CA122023, R01CA166347, R01CA203023, R01CA163896, P30CA016086)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- cellular senescence, therapy-induced senescence, chemotherapy toxicity, senescence-associated secretory phenotype, senolytics, senescent cell elimination, inflammation, tumor recurrence, myelosuppression, cardiotoxicity, chemotherapy-induced fatigue, T cells, genotoxic chemotherapy, transgenic mouse model
- MeSH terms
- Animals, Antineoplastic Agents, Breast Neoplasms, Female, Humans, Mice, Transgenic, Neoplasm Recurrence, Local, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, Cell Proliferation, Mice
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