Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel.
Department of Medical Neurobiology, Institute for Medical Research Israel-Canada and The Edmond and Lily Safra Center for Brain Sciences, Hebrew University Medical School, Jerusalem, Israel.
Cancer Res. 2018 May 15;78(10):2680-2690. doi: 10.1158/0008-5472.CAN-17-3614. Epub 2018 Feb 28.
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 HO We report here that neutrophil cytotoxicity is Ca dependent and is mediated by TRPM2, a ubiquitously expressed HO-dependent Ca 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. These findings identify the mechanism utilized by neutrophils to kill disseminated tumor cells and to limit metastatic spread. .
中性粒细胞在癌症中发挥着关键作用，已有报道称存在促进肿瘤和抗肿瘤的中性粒细胞亚群。抗肿瘤中性粒细胞亚群能够杀伤肿瘤细胞并限制转移扩散，但并非所有肿瘤细胞都同样容易受到中性粒细胞细胞毒性的影响。因为逃避中性粒细胞的细胞形成转移的机会更大，所以我们探索了中性粒细胞杀死肿瘤细胞的机制。先前的研究表明，中性粒细胞的细胞毒性是通过 HO 的分泌来介导的，我们在这里报告称，中性粒细胞的细胞毒性依赖于 Ca，并由 TRPM2 介导，TRPM2 是一种广泛表达的依赖于 HO 的 Ca 通道。干扰 TRPM2 的表达会限制肿瘤细胞的增殖，从而导致肿瘤生长减弱。同时，表达水平降低的 TRPM2 的细胞免受中性粒细胞细胞毒性的影响，并更有效地在转移前的肺部播种。这些发现确定了中性粒细胞用来杀死播散的肿瘤细胞并限制转移扩散的机制。
