TRPM2 Mediates Neutrophil Killing of Disseminated Tumor Cells.

Maya Gershkovitz,Tanya Fainsod-Levi,Merav E Shaul,Yoav D Shaul,Rotem Karni,Yaki Caspi,Zvi Granot,Ben Katz,Yasuo Mori,Lola Polyansky,Leonor Cohen-Daniel,Janna Michaeli,Shaya Lev,Alexander M Binshtok,Zvi G Fridlender,Saleh Khawaled,Ronit V Sionov,Rami I Aqeilan

doi:10.1158/0008-5472.can-17-3614

Maya Gershkovitz, Tanya Fainsod-Levi + Show 16 more

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https://doi.org/10.1158/0008-5472.can-17-3614

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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.

Highlights

Cancer-related mortality is often associated with metastatic spread to distant organs
Neutrophil-induced tumor cell death is Ca2þ dependent In previous work [15], we have shown that neutrophil cytotoxicity is catalase sensitive, implicating H2O2 in the killing process (Fig. 1A; Supplementary Fig. S1A)
To gain further insight into the molecular mechanisms involved in neutrophil-mediated tumor cell death, we used 4T1 breast cancer cells and looked for effects induced by H2O2, which simulates the cytotoxic effects of neutrophils

Summary

Introduction

Cancer-related mortality is often associated with metastatic spread to distant organs. It has become apparent that nonmalignant cells in the various tumor microenvironments (e.g., primary tumor, circulation, premetastatic, and metastatic sites) acquire unique traits and play a critical role in cancer progression [1]. In this context, the study of neutrophils, the most abundant type of white blood cells in the human circulation, was somewhat neglected. Neutrophils were perceived as a homogeneous population of terminally differentiated myeloid cells playing a critical role in inflammation and in fighting infections.

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