Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice.
Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice.
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DOI：
10.1126/science.aao4227
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发表时间：
2018-09-28
期刊：
影响因子：
--
通讯作者：
Egeblad M
中科院分区：
文献类型：
--
作者：
Albrengues J;Shields MA;Ng D;Park CG;Ambrico A;Poindexter ME;Upadhyay P;Uyeminami DL;Pommier A;Küttner V;Bružas E;Maiorino L;Bautista C;Carmona EM;Gimotty PA;Fearon DT;Chang K;Lyons SK;Pinkerton KE;Trotman LC;Goldberg MS;Yeh JT;Egeblad M
来自原发肿瘤的癌细胞可以扩散到其他组织，保持休眠状态，临床检测不到多年。对于导致这些休眠细胞“苏醒”、恢复增殖并发展为转移的线索，人们知之甚少。研究小鼠模型，我们发现烟草烟雾暴露或鼻腔注入脂多糖引起的持续肺部炎症可将弥散的、休眠的癌细胞转化为积极生长的转移细胞。持续的炎症诱导中性粒细胞胞外陷阱（NETs）的形成，而这些是唤醒休眠癌症所必需的。机制分析显示，两种net相关蛋白酶，中性粒细胞弹性蛋白酶和基质金属蛋白酶9，依次裂解层粘连蛋白。蛋白水解重组的层粘连蛋白通过激活整合素- 3β -1信号传导诱导休眠癌细胞增殖。抗net重构层粘连蛋白的抗体阻止休眠细胞的觉醒。旨在防止休眠细胞觉醒的疗法可能会延长癌症患者的生存期。
Cancer cells from a primary tumor can disseminate to other tissues, remaining dormant and clinically undetectable for many years. Little is known about the cues that cause these dormant cells to “awaken,” resume proliferating and develop into metastases. Studying mouse models, we found that sustained lung inflammation caused by tobacco smoke exposure or nasal instillation of lipopolysaccharide converted disseminated, dormant cancer cells to aggressively growing metastases. Sustained inflammation induced the formation of neutrophil extracellular traps (NETs), and these were required for awakening dormant cancer. Mechanistic analysis revealed that two NET-associated proteases, neutrophil elastase and matrix metalloproteinase 9, sequentially cleaved laminin. The proteolytically remodeled laminin induced proliferation of dormant cancer cells by activating integrin alpha-3beta-1 signaling. Antibodies against NET-remodeled laminin prevented awakening of dormant cells. Therapies aimed at preventing dormant cell awakening could potentially prolong the survival of cancer patients.
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影响因子：
64.8
作者：
Headley MB;Bins A;Nip A;Roberts EW;Looney MR;Gerard A;Krummel MF
通讯作者：
Krummel MF
影响因子：
11.2
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Barkan D;Kleinman H;Simmons JL;Asmussen H;Kamaraju AK;Hoenorhoff MJ;Liu ZY;Costes SV;Cho EH;Lockett S;Khanna C;Chambers AF;Green JE
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Green JE
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5.5
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Urban, Constantin F.
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21.3
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--
影响因子：
28.2
作者：
Catena R;Bhattacharya N;El Rayes T;Wang S;Choi H;Gao D;Ryu S;Joshi N;Bielenberg D;Lee SB;Haukaas SA;Gravdal K;Halvorsen OJ;Akslen LA;Watnick RS;Mittal V
通讯作者：
Mittal V