TRPM2 modulates neutrophil attraction to murine tumor cells by regulating CXCL2 expression
TRPM2 modulates neutrophil attraction to murine tumor cells by regulating CXCL2 expression
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DOI：
10.1007/s00262-018-2249-2
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发表时间：
2019-01-01
影响因子：
5.8
通讯作者：
Granot, Zvi
中科院分区：
文献类型：
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作者：
Gershkovitz, Maya;Fainsod-Levi, Tanya;Granot, Zvi
近年来，免疫细胞被证明在肿瘤生长和转移进展中起关键作用。在这种情况下，嗜中性粒细胞被证明具有促肿瘤和抗肿瘤特性。为了发挥其抗肿瘤作用，中性粒细胞需要向肿瘤细胞迁移并与肿瘤细胞形成物理接触。中性粒细胞以接触依赖性机制分泌H2O2，从而通过激活H2O2依赖性TRPM2 Ca2+通道诱导致死性Ca2+内流。在这里，我们探讨了调节中性粒细胞对肿瘤细胞的化学吸引力的机制。有趣的是，我们发现TRPM2在这种情况下也起作用，因为它调节有效的中性粒细胞化学引诱物的表达。因此，表达降低水平的TRPM2的细胞不被中性粒细胞接近。总之，这些观察结果表明，表达TRPM2水平降低的肿瘤细胞如何在两个相互关联的机制中逃避中性粒细胞的细胞毒性：下调中性粒细胞趋化因子和阻断凋亡的Ca2+依赖性级联反应。这些观察结果证明了TRPM2在嗜中性粒细胞介导的免疫监视中的关键作用，并鉴定了表达低水平TRPM2的细胞作为癌症治疗的潜在靶点。
In recent years, immune cells were shown to play critical roles in tumor growth and metastatic progression. In this context, neutrophils were shown to possess both pro- and anti-tumor properties. To exert their anti-tumor effect, neutrophils need to migrate towards, and form physical contact with tumor cells. Neutrophils secrete H2O2 in a contact-dependent mechanism, thereby inducing a lethal Ca2+ influx via the activation of the H2O2-dependent TRPM2 Ca2+ channel. Here, we explored the mechanism regulating neutrophil chemoattraction to tumor cells. Interestingly, we found that TRPM2 plays a role in this context as well, since it regulates the expression of potent neutrophil chemoattractants. Consequently, cells expressing reduced levels of TRPM2 are not approached by neutrophils. Together, these observations demonstrate how tumor cells expressing reduced levels of TRPM2 evade neutrophil cytotoxicity in two interrelated mechanismsdownregulation of neutrophil chemoattractants and blocking of the apoptotic Ca2+-dependent cascade. These observations demonstrate a critical role for TRPM2 in neutrophil-mediated immunosurveillance and identify cells expressing low levels of TRPM2, as a potential target for cancer therapy.