Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse.
Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse.
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DOI：
10.1158/2159-8290.cd-16-0241
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发表时间：
2017-02
期刊：
影响因子：
28.2
通讯作者：
Campisi J
中科院分区：
文献类型：
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作者：
Demaria M;O'Leary MN;Chang J;Shao L;Liu S;Alimirah F;Koenig K;Le C;Mitin N;Deal AM;Alston S;Academia EC;Kilmarx S;Valdovinos A;Wang B;de Bruin A;Kennedy BK;Melov S;Zhou D;Sharpless NE;Muss H;Campisi J
细胞衰老通过不可逆转地阻止细胞增殖来抑制癌症。衰老细胞获得与衰老相关的促炎分泌表型。许多基因毒性化疗针对的是非特异性的增殖细胞，通常会出现不良反应。与之前的工作一致，我们发现几种化疗药物可以诱导原代小鼠和人类细胞衰老。使用可以跟踪和消除衰老细胞的转基因小鼠，我们证明了治疗诱导的衰老(TIS)细胞持续存在，并有助于局部和全身炎症。消除TIS细胞减少了药物的几个短期和长期影响，包括骨髓抑制、心脏功能障碍、癌症复发以及体力和体力。与我们在小鼠身上的发现一致，在化疗前T细胞中衰老标记物表达增加的人类，化疗导致疲劳的风险明显更大。这些发现表明，衰老细胞可以引起一定的化疗副作用，为降低抗癌治疗的毒性提供了新的靶点。
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.