Abstract
SummaryNeoplastic transformation causing cancer is a key problem in tumor biology and can be triggered by exposure to environmental substances. We investigated whether the cellular composition of a tissue contributes to its predisposition to cancer upon a specific carcinogen. Neutrophils are important immune components involved in cancer progression, but their contribution to generation of transformed cells is elusive. Yet, neutrophil-released reactive oxygen species (ROS) can cause tissue damage, which potentially favors tumorigenesis. Here, we show that neutrophils contribute directly to neoplastic transformation by amplifying the genotoxicity of urethane in lung cells via ROS. Neutrophil-driven ROS-dependent DNA damage is timely restricted to urethane exposure and notably uncoupled from broad tissue damage or inflammation. Neutropenic granulocyte colony-stimulating factor (Gcsf)-knockout mice show reduced lung tumorigenesis, and forcing neutrophil recruitment only during urethane exposure rescues cancer incidence months later. This study shows that the time-restricted neutrophil response to carcinogens can impact the long-term tissue susceptibility to cancer.
Highlights
The strong impact of environmental factors as key determinants of cancer development was highlighted by epidemiologic studies showing that people who migrated to distant countries developed cancer types typical of the local population rather than of their homelands (Higginson et al, 1992)
SUMMARY Neoplastic transformation causing cancer is a key problem in tumor biology and can be triggered by exposure to environmental substances
We show that neutrophils contribute directly to neoplastic transformation by amplifying the genotoxicity of urethane in lung cells via reactive oxygen species (ROS)
Summary
The strong impact of environmental factors as key determinants of cancer development was highlighted by epidemiologic studies showing that people who migrated to distant countries developed cancer types typical of the local population rather than of their homelands (Higginson et al, 1992). Numerous chemical carcinogens, including cigarette smoke, can trigger genetic mutations that are at the origin of cancer. Genotoxic events inducing tumorigenesis are accompanied by a promoting inflammation (Coussens and Werb, 2002). The important role of neutrophils, the first inflammatory cells to be recruited to the affected tissue upon injury, in patients with cancer, is progressively becoming evident (Shaul and Fridlender, 2019). Neutrophils are emerging as an important player in tissue injury and in post-injury tissue regeneration (Phillipson and Kubes, 2019). Several recent studies have shown conflicting functions of neutrophils in both promoting and limiting tumorigeneses (Coffelt et al, 2016), suggesting a context-dependent regulation
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