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TRPM2 modulates neutrophil attraction to murine tumor cells by regulating CXCL2 expression

  • Maya Gershkovitz
  • Tanya Fainsod-Levi
  • Tamir Zelter
  • Ronit V. Sionov
  • Zvi Granot
Original Article
  • 156 Downloads

Abstract

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 mechanisms—downregulation 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.

Keywords

Neutrophils TRPM2 CXCL2 Immune evasion 

Abbreviations

ADCC

Antibody-dependent cellular cytotoxicity

ATCC

American Type Culture Collection

CXCL1

Chemokine (C-X-C motif) ligand 1

CXCL2

Chemokine (C-X-C motif) ligand 2

CXCL5

Chemokine (C-X-C motif) ligand 5

CXCL12

Chemokine (C-X-C motif) ligand 12

CXCR2

Chemokine receptor type 2

IL1β

Interleukin 1 beta

IL6

Interleukin 6

MET

Mesenchymal–epithelial transition tyrosine kinase receptor

NDN

Normal density neutrophils

qPCR

Quantitative real-time PCR

TRPM2

Transient receptor potential melastatin 2

Notes

Author contributions

MG and ZG conceived and designed the experiments; MG, TFL, TZ, and RVS performed the experiments; ZG supervised the experiments; MG and ZG wrote the manuscript.

Funding

Zvi Granot was supported by Grants from the I-CORE Gene Regulation in Complex Human Disease, Center no. 41/11, the Israel Science Foundation (756/15), the Israel Cancer Research Foundation (RCDA), The Rosetrees Trust, and the Israel Cancer Association.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interests.

Supplementary material

262_2018_2249_MOESM1_ESM.pdf (46 kb)
Supplementary material 1 (PDF 46 KB)
262_2018_2249_MOESM2_ESM.mov (7.3 mb)
Supplementary material 2 (MOV 7512 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Maya Gershkovitz
    • 1
  • Tanya Fainsod-Levi
    • 1
  • Tamir Zelter
    • 1
  • Ronit V. Sionov
    • 1
  • Zvi Granot
    • 1
  1. 1.Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel CanadaHebrew University Medical SchoolJerusalemIsrael

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