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Cancer Res. 2018 May 15;78(10):2680-2690. doi: 10.1158/0008-5472.CAN-17-3614. Epub 2018 Feb 28.

TRPM2 Mediates Neutrophil Killing of Disseminated Tumor Cells.

Author information

1
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel.
2
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.
3
Institute of Pulmonary Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
4
The Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel.
5
Department of Biochemistry, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel.
6
Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan.
7
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel. zvikag@ekmd.huji.ac.il.

Abstract

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. Cancer Res; 78(10); 2680-90. ©2018 AACR.

PMID:
29490946
DOI:
10.1158/0008-5472.CAN-17-3614
[Indexed for MEDLINE]
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