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Role of NOX2-Derived Reactive Oxygen Species in NK Cell-Mediated Control of Murine Melanoma Metastasis

Journal article
Authors Ebru Aydin
Junko Johansson
Faisal Hayat Nazir
Kristoffer Hellstrand
Anna Martner
Published in Cancer Immunology Research
Volume 5
Issue 9
Pages 804-811
ISSN 2326-6066
Publication year 2017
Published at Sahlgrenska Cancer Center
Pages 804-811
Language en
Links dx.doi.org/10.1158/2326-6066.cir-16...
Keywords neutrophil nadph oxidase, acute myeloid-leukemia, tumor-cells, respiratory burst, hydrogen-peroxide, interferon-gamma, dendritic cells, b16 melanoma, cancer, histamine, Oncology, Immunology
Subject categories Cancer and Oncology

Abstract

The NADPH oxidase of myeloid cells, NOX2, generates reactive oxygen species (ROS) to eliminate pathogens and malignant cells. NOX2-derived ROS have also been proposed to dampen functions of natural killer (NK) cells and other antineoplastic lymphocytes in the microenvironment of established tumors. The mechanisms by which NOX2 and ROS influence the process of distant metastasis have only been partially explored. Here, we utilized genetically NOX2-deficient mice and pharmacologic inhibition of NOX2 to elucidate the role of NOX2 for the hematogenous metastasis of melanoma cells. After intravenous inoculation of B16F1 or B16F10 cells, lung metastasis formation was reduced in B6.129S6 Cybb(m1DinK) (Nox2-KO) versus Nox2-sufficient wild-type (WT) mice. Systemic treatment with the NOX2-inhibitor histamine dihydrochloride (HDC) reduced melanoma metastasis and enhanced the infiltration of IFN gamma-producing NK cells into lungs of WT but not of Nox2-KO mice. IFN gamma-deficient B6.129S7-Ifngt(m1Ts)/ J mice were prone to develop melanoma metastases and did not respond to in vivo treatment with HDC. We propose that NOX2-derived ROS facilitate metastasis of melanoma cells by downmodulating NK-cell function and that inhibition of NOX2 may restore IFN gamma-dependent, NK cell-mediated clearance of melanoma cells.

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