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Cancer Cell. 2017 Dec 11;32(6):869-883.e5. doi: 10.1016/j.ccell.2017.11.004.

Myeloid Cell-Derived Reactive Oxygen Species Induce Epithelial Mutagenesis.

Author information

1
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt/Main, Germany.
2
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt/Main, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Frankfurt Medical School, 60590 Frankfurt/Main, Germany.
3
Institute of Pathology, University of Munich, 80337 Munich, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
4
TRON - Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH, 55131 Mainz, Germany.
5
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; TRON - Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH, 55131 Mainz, Germany; University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany.
6
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt/Main, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: greten@gsh.uni-frankfurt.de.

Abstract

Increased oxidative stress has been suggested to initiate and promote tumorigenesis by inducing DNA damage and to suppress tumor development by triggering apoptosis and senescence. The contribution of individual cell types in the tumor microenvironment to these contrasting effects remains poorly understood. We provide evidence that during intestinal tumorigenesis, myeloid cell-derived H2O2 triggers genome-wide DNA mutations in intestinal epithelial cells to stimulate invasive growth. Moreover, increased reactive oxygen species (ROS) production in myeloid cells initiates tumor growth in various organs also in the absence of a carcinogen challenge in a paracrine manner. Our data identify an intricate crosstalk between myeloid cell-derived ROS molecules, oxidative DNA damage, and tumor necrosis factor α-mediated signaling to orchestrate a tumor-promoting microenvironment causing invasive cancer.

KEYWORDS:

GPx4; cancer initiation; chronic inflammation; myeloid cells; oxidative stress

PMID:
29232557
DOI:
10.1016/j.ccell.2017.11.004
[Indexed for MEDLINE]
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