TRPM2 Mediates Neutrophil Killing of Disseminated Tumor Cells
TRPM2 Mediates Neutrophil Killing of Disseminated Tumor Cells
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DOI：
10.1158/0008-5472.can-17-3614
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发表时间：
2018-05-15
期刊：
影响因子：
11.2
通讯作者：
Granot, Zvi
中科院分区：
文献类型：
--
作者：
Gershkovitz, Maya;Caspi, Yaki;Granot, Zvi
中性粒细胞在癌症中起关键作用，有促肿瘤和抗肿瘤中性粒细胞亚群的报道。抗肿瘤中性粒细胞亚群具有杀死肿瘤细胞并限制转移扩散的能力，但并非所有肿瘤细胞都同样易受中性粒细胞细胞毒性的影响。由于逃避中性粒细胞的细胞有更大的机会形成转移，我们探索了中性粒细胞杀死肿瘤细胞的机制。以前的研究表明，中性粒细胞的细胞毒性是由H2O2的分泌介导的。我们在这里报告，中性粒细胞的细胞毒性是Ca2+依赖性的，并介导的TRPM2，一种普遍表达的H2O2依赖性Ca2+通道。干扰TRPM2表达限制肿瘤细胞增殖，导致肿瘤生长减弱。同时，TRPM2表达水平降低的细胞受到保护，从中性粒细胞的细胞毒性和种子更有效地在premetastatic lung.Significance：这些研究结果确定的机制，利用中性粒细胞杀死播散的肿瘤细胞，并限制转移扩散。(C)2018年AACR。
Neutrophils play a critical role in cancer, with both protumor and antitumor neutrophil subpopulations reported. The antitumor neutrophil subpopulation has the capacity to kill tumor cells and limit metastatic spread, yet not all tumor cells are equally susceptible to neutrophil cytotoxicity. Because cells that evade neutrophils have greater chances of forming metastases, we explored the mechanism neutrophils use to kill tumor cells. Neutrophil cytotoxicity was previously shown to be mediated by secretion of H2O2. We report here that neutrophil cytotoxicity is Ca2+ dependent and is mediated by TRPM2, a ubiquitously expressed H2O2-dependent Ca2+ channel. Perturbing TRPM2 expression limited tumor cell proliferation, leading to attenuated tumor growth. Concomitantly, cells expressing reduced levels of TRPM2 were protected from neutrophil cytotoxicity and seeded more efficiently in the premetastatic lung.Significance: These findings identify the mechanism utilized by neutrophils to kill disseminated tumor cells and to limit metastatic spread. (C) 2018 AACR.