Alcohol Metabolism Enriches Squamous Cell Carcinoma Cancer Stem Cells That Survive Oxidative Stress via Autophagy.
Alcohol Metabolism Enriches Squamous Cell Carcinoma Cancer Stem Cells That Survive Oxidative Stress via Autophagy.
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DOI：
10.3390/biom11101479
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发表时间：
2021-10-07
期刊：
影响因子：
5.5
通讯作者：
Nakagawa H
中科院分区：
文献类型：
--
作者：
Shimonosono M;Tanaka K;Flashner S;Takada S;Matsuura N;Tomita Y;Sachdeva UM;Noguchi E;Sangwan V;Ferri L;Momen-Heravi F;Yoon AJ;Klein-Szanto AJ;Diehl JA;Nakagawa H
背景：饮酒（乙醇）是头颈癌和食管鳞状细胞癌（SCC）的主要危险因素。然而，乙醇 (EtOH) 如何影响 SCC 稳态尚不完全清楚。方法：我们利用三维 (3D) 类器官和异种移植肿瘤移植模型来研究 EtOH 暴露如何影响瘤内 SCC 细胞群，包括由高 CD44 表达（CD44H 细胞）定义的推定癌症干细胞。结果：使用由 SCC 细胞系、患者来源的异种移植肿瘤和患者活检产生的 3D 类器官，我们发现乙醇通过乙醇脱氢酶代谢，诱导与线粒体超氧化物生成和线粒体去极化相关的氧化应激，导致类器官内大多数 SCC 细胞凋亡。然而，CD44H 细胞经历自噬以消除 EtOH 诱导的线粒体功能障碍和细胞凋亡，并随后在暴露于 EtOH 时在类器官和异种移植肿瘤中富集。重要的是，抑制自噬会增加 EtOH 介导的细胞凋亡，并降低 CD44H 细胞富集、异种移植肿瘤生长和类器官形成率。结论：本研究提供了 EtOH 如何影响 SCC 细胞的机制见解，并将自噬确立为治疗 EtOH 相关 SCC 的潜在治疗靶点。
Background: Alcohol (ethanol) consumption is a major risk factor for head and neck and esophageal squamous cell carcinomas (SCCs). However, how ethanol (EtOH) affects SCC homeostasis is incompletely understood. Methods: We utilized three-dimensional (3D) organoids and xenograft tumor transplantation models to investigate how EtOH exposure influences intratumoral SCC cell populations including putative cancer stem cells defined by high CD44 expression (CD44H cells). Results: Using 3D organoids generated from SCC cell lines, patient-derived xenograft tumors, and patient biopsies, we found that EtOH is metabolized via alcohol dehydrogenases to induce oxidative stress associated with mitochondrial superoxide generation and mitochondrial depolarization, resulting in apoptosis of the majority of SCC cells within organoids. However, CD44H cells underwent autophagy to negate EtOH-induced mitochondrial dysfunction and apoptosis and were subsequently enriched in organoids and xenograft tumors when exposed to EtOH. Importantly, inhibition of autophagy increased EtOH-mediated apoptosis and reduced CD44H cell enrichment, xenograft tumor growth, and organoid formation rate. Conclusions: This study provides mechanistic insights into how EtOH may influence SCC cells and establishes autophagy as a potential therapeutic target for the treatment of EtOH-associated SCC.
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食管鳞状细胞癌的空间瘤内异质性和时间克隆进化
影响因子：
30.8
作者：
Hao, Jia-Jie;Lin, De-Chen;Dinh, Huy Q.;Mayakonda, Anand;Jiang, Yan-Yi;Chang, Chen;Jiang, Ye;Lu, Chen-Chen;Shi, Zhi-Zhou;Xu, Xin;Zhang, Yu;Cai, Yan;Wang, Jin-Wu;Zhan, Qi-Min;Wei, Wen-Qiang;Berrnan, Benjamin P.;Wang, Ming-Rong;Koeffler, H. Phillip
通讯作者：
Koeffler, H. Phillip
影响因子：
4.7
作者：
Lee, James J.;Natsuizaka, Mitsuteru;Nakagawa, Hiroshi
通讯作者：
Nakagawa, Hiroshi
DOI：
10.1016/j.chc.2016.02.005
发表时间：
2016-07-01
影响因子：
2.4
作者：
Hadland, Scott E.;Levy, Sharon
通讯作者：
Levy, Sharon
影响因子：
50.3
作者：
Ishimoto, Takatsugu;Nagano, Osamu;Saya, Hideyuki
通讯作者：
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影响因子：
9.7
作者：
Choi, Jae-Il;Jang, Sung Ill;Lim, Jong-Baeck
通讯作者：
Lim, Jong-Baeck