Cellular Senescence Promotes Skin Carcinogenesis through p38MAPK and p44/42MAPK Signaling
Cellular Senescence Promotes Skin Carcinogenesis through p38MAPK and p44/42MAPK Signaling
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DOI：
10.1158/0008-5472.can-20-0108
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发表时间：
2020-09-01
期刊：
影响因子：
11.2
通讯作者：
Campisi, Judith
中科院分区：
文献类型：
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作者：
Alimirah, Fatouma;Pulido, Tanya;Campisi, Judith
细胞衰老需要不可逆转的生长停滞，这在一定程度上是为了预防癌症。特别地，衰老细胞分泌促炎和生长刺激分子，称为衰老相关分泌表型（SASP），其与培养物和异种移植模型中的癌细胞增殖相关。然而，在什么肿瘤阶段以及衰老和SASP如何在体内对内源性肿瘤生长起作用尚不清楚。为了了解衰老在癌症病因学中的作用，我们将p16- 3 MR转基因小鼠（允许在体内识别和选择性消除衰老细胞）置于已建立的鳞状细胞皮肤癌两步方案中，其中肿瘤发生由致癌物7，12-二甲基苯并[a]蒽启动，然后由12-O-十四烷酰基-佛波醇-13-乙酸酯（TPA）促进。我们发现TPA通过诱导衰老和SASP促进皮肤癌变。在非肿瘤p16- 3 MR小鼠中使用化疗后两步致癌方案全身诱导衰老，通过升高p38 MAPK和MAPK/ERK信号增强良性乳头状瘤向癌的转化。消融衰老细胞减少p38 MAPK和MAPK/ERK信号传导，从而防止良性乳头状瘤发展为癌。因此，我们首次表明衰老细胞是肿瘤促进剂，而不是肿瘤引发剂，并且它们通过升高p38 MAPK和MAPK/ERK信号刺激皮肤癌变。这些发现为开发新的治疗方法对抗衰老引发的癌症铺平了道路。意义：这些发现将化疗诱导的衰老确定为肿瘤促进的罪魁祸首，表明化疗后消除衰老细胞可能会减少数十年后第二种癌症的发生。
Cellular senescence entails an irreversible growth arrest that evolved in part to prevent cancer. Paradoxically, senescent cells secrete proinflammatory and growth-stimulatory molecules, termed the senescence-associated secretory phenotype (SASP), which is correlated with cancer cell proliferation in culture and xenograft models. However, at what tumor stage and how senescence and the SASP act on endogenous tumor growth in vivo is unknown. To understand the role of senescence in cancer etiology, we subjected p16-3MR transgenic mice, which permit the identification and selective elimination of senescent cells in vivo, to the well-established two-step protocol of squamous cell skin carcinoma, in which tumorigenesis is initiated by a carcinogen 7,12-dimethylbenz[a]anthracene, and then promoted by 12-O-tetradecanoyl-phorbol-13-acetate (TPA). We show that TPA promotes skin carcinogenesis by inducing senescence and a SASP. Systemic induction of senescence in nontumor-bearing p16-3MR mice using a chemotherapy followed by the two-step carcinogenesis protocol potentiated the conversion of benign papillomas to carcinomas by elevating p38MAPK and MAPK/ERK signaling. Ablation of senescent cells reduced p38MAPK and MAPK/ERK signaling, thereby preventing the progression of benign papillomas to carcinomas. Thus, we show for the first time that senescent cells are tumor promoters, not tumor initiators, and that they stimulate skin carcinogenesis by elevating p38MAPK and MAPK/ERK signaling. These findings pave the way for developing novel therapeutics against senescence-fueled cancers.Significance: These findings identify chemotherapy-induced senescence as a culprit behind tumor promotion, suggesting that elimination of senescent cells after chemotherapy may reduce occurrence of second cancers decades later.