Myeloid Cell-Derived Reactive Oxygen Species Induce Epithelial Mutagenesis

Publication date: 11 December 2017
Source:Cancer Cell, Volume 32, Issue 6
Author(s): Özge Canli, Adele M. Nicolas, Jalaj Gupta, Fabian Finkelmeier, Olga Goncharova, Marina Pesic, Tobias Neumann, David Horst, Martin Löwer, Ugur Sahin, Florian R. Greten
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.

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Teaser

Canli et al. show that excessive H2O2 produced by myeloid cells, independent of cytokines, transforms intestinal epithelial cells (IEC) by triggering genome-wide DNA mutations. H2O2 also induces IEC to secrete cytokines and chemokines, via a TNFα autocrine loop, to recruit myeloid cells for promotion of tumor invasion.


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