Wculek Stefanie K, Bridgeman Victoria L, Peakman Freddie, Malanchi Ilaria
Tumour Host Interaction Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK.
Tumour Host Interaction Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK.
iScience. 2020 Jul 24;23(7):101277. doi: 10.1016/j.isci.2020.101277. Epub 2020 Jun 17.
Neoplastic 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.
导致癌症的肿瘤转化是肿瘤生物学中的一个关键问题，可由接触环境物质引发。我们研究了组织的细胞组成是否会导致其在接触特定致癌物后易患癌症。中性粒细胞是参与癌症进展的重要免疫成分，但其对转化细胞生成的贡献尚不清楚。然而，中性粒细胞释放的活性氧（ROS）可导致组织损伤，这可能有利于肿瘤发生。在此，我们表明中性粒细胞通过ROS增强肺细胞中尿烷的基因毒性，直接促成肿瘤转化。中性粒细胞驱动的ROS依赖性DNA损伤及时局限于尿烷暴露，且明显与广泛的组织损伤或炎症无关。中性粒细胞减少的粒细胞集落刺激因子（Gcsf）基因敲除小鼠的肺肿瘤发生率降低，仅在尿烷暴露期间促使中性粒细胞募集可在数月后挽救癌症发病率。这项研究表明，中性粒细胞对致癌物的限时反应会影响组织对癌症的长期易感性。
