Cellular senescence promotes adverse effects of chemotherapy and cancer relapse

By M. Demaria, Monique N. O’Leary, Jianhui Chang, Lijian Shao, Su Liu, F. Alimirah, Kristin Koenig, Catherine Le, N. Mitin, A. Deal and 12 more. Cancer Discovery, 2016

1,127 citations recorded by the source corpus.

Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a pro-inflammatory senescence-associated secretory phenotype. Many genotoxic chemotherapies target proliferating cells non-specifically, 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 anti-cancer treatments.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/b910e71116a1c4b64c68d4638d112adb01029a7a

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Citations in the corpus

Mechanisms and functions of cellular senescence. (2018, positive): “In fact, elimination of senescent cells in this context prevents tumor relapse (17).”
The senescence-associated secretory phenotype and its physiological and pathological implications (2024, neutral): “Moreover, cell surface proteins, such as CD36 (also known as platelet glycoprotein 4) 85 and CD40L 86 , are also essential for the activation of NF-κB and its downstream SASP, which might be crucial for mediating external signals from senescence inducers.”
A proteomic atlas of senescence-associated secretomes for aging biomarker development (2019, background): “For 64 example, telomere attrition resulting from repeated cell division (replicative 65 senescence), ionizing radiation, chromatin disruption, and activation of certain 66 oncogenes all can cause senescence-inducing genotoxic stresses, as can genotoxic 67 therapeutic drugs, such as certain anti-can”
Senescence and aging: Causes, consequences, and therapeutic avenues (2018, background): “Senolytic therapy also reduces the incidence of metastasis, the leading cause of cancer-related deaths (Demaria et al., 2016).”
Mitochondrial metabolism and cancer (2017, background): “Intriguingly, ROS-driven cellular senescence can paradoxically support proliferation in a cell-extrinsic manner, as it sustains the secretion of mitogenic factors that act on neighboring cancer cells with intact proliferative capacities [99, 100].”
Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “Moreover, in mouse, the accumulation of senescent cells in normal tissue induced by the chemotherapy has been recently linked to a premature aging phenotype and to cancer-related fatigue, a syndrome commonly experienced by patients treated with chemoradiotherapy (88).”
Unmasking Transcriptional Heterogeneity in Senescent Cells (2017, methodology): “We induced senescence by various means, including those used in the previous analyses (ionizing radiation, replication, and oxidative stress), as well as doxorubicin, a DNA-damaging chemotherapeutic agent known to cause senescence [30]) (Figures S3A–S3D).”
Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021, background): “However, NF-κB dependent pro-inflammatory factors are the key components of SASP with IL-6 and IL8 being the most conserved and robustly expressed cytokines (Hardy et al., 2005; Davalos et al., 2010; Freund et al., 2010; Soto-Gamez and Demaria, 2017).”
Drug resistance and combating drug resistance in cancer (2019, background): “For example, Doxorubicin and Cisplatin used in chemotherapy by inducing cell death can also initiate senescence[85,86].”
Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 (2018, background): “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].”