Dataset Information

Early Neutrophil Responses to Chemical Carcinogenesis Shape Long-Term Lung Cancer Susceptibility.

ABSTRACT: 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.

SUBMITTER: Wculek SK

PROVIDER: S-EPMC7334367 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Early Neutrophil Responses to Chemical Carcinogenesis Shape Long-Term Lung Cancer Susceptibility.

Wculek Stefanie K SK Bridgeman Victoria L VL Peakman Freddie F Malanchi Ilaria I

iScience 20200617 7

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, whic ...[more]

PMID: 32619702

Similar Datasets

Project description:BACKGROUND:Hypercoagulation and neutrophilia are described in several cancers, however, whether they are involved in lung carcinogenesis is currently unknown. Emodin is the main bioactive component from Rheum palmatum and has many medicinal values, such as anti-inflammation and anticancer. This study is to investigate the contributions of neutrophils to the effects of emodin on hypercoagulation and carcinogenesis. METHODS:The effects of emodin on neutrophil phenotypes were assessed by cell proliferation, morphological changes, phagocytosis and autophagy in vitro. The anti-coagulation and cancer-preventing actions of emodin were evaluated in the urethane-induced lung carcinogenic model. The expressions of Cit-H3 and PAD4 in lung sections were assessed by immunohistochemistry, CD66b+ neutrophils were distinguished by immunofluorescence, and cytokines and ROS were examined with ELISA. The neutrophils-regulating and hypercoagulation-improving efficacies of emodin were confirmed in a Lewis lung cancer allograft model. The related targets and pathways of emodin were predicted by network pharmacology. RESULTS:In vitro, emodin at the dose of 20 µM had no effect on cell viability in HL-60N1 but increased ROS and decreased autophagy and thus induced apoptosis in HL-60N2 with the morphological changes. In the urethane-induced lung carcinogenic model, before lung carcinogenesis, urethane induced obvious hypercoagulation which was positively correlated with lung N2 neutrophils. There were the aggravated hypercoagulation and lung N2 neutrophils after lung carcinoma lesions. Emodin treatment resulted in the ameliorated hypercoagulation and lung carcinogenesis accompanied by the decreased N2 neutrophils (CD66b+) in the alveolar cavity. ELISA showed that there were more IFN-γ, IL-12 and ROS and less IL-6, TNF-α and TGF-β1 in the alveolar cavity in the emodin group than those in the control group. Immunohistochemical analysis showed that emodin treatment decreased Cit-H3 and PAD4 in lung sections. In the Lewis lung cancer allograft model, emodin inhibits tumor growth accompanied by the attenuated coagulation and intratumor N2 neutrophils. Network pharmacology indicated the multi-target roles of emodin in N2 neutrophil activation. CONCLUSIONS:This study suggests a novel function of emodin, whereby it selectively suppresses N2 neutrophils to prevent hypercoagulation and lung carcinogenesis.

Project description:BackgroundRadiographic end points commonly are included in therapeutic trials for systemic sclerosis (SSc)-interstitial lung disease (ILD); however, the relationship between these outcomes and long-term mortality is unclear.Research questionDo short-term changes in radiographic measures of ILD predict long-term survival in patients with SSc?Study design and methodsThe Scleroderma Lung Study (SLS) I and II evaluated the safety and efficacy of cyclophosphamide (in SLS I and II) and mycophenolate mofetil (in SLS II) for the treatment of SSc-ILD. Changes in the extent of ILD over time were assessed on high-resolution CT scans of the chest by quantitative image analysis, an approach that applies a computer-based algorithm to assess changes in the radiographic extent of ILD objectively. Participants subsequently were followed for up to 12 years (SLS I) and 8 years (SLS II). Cox proportional hazards models determined whether the change in the quantitative radiographic extent of ILD predicted survival, adjusting for other known predictors of survival.ResultsAmong SLS I and II participants, 82 and 90 had follow-up imaging scans, respectively, and were included in the analysis. Participants in both trials who showed an increase in the total quantitative radiographic extent of ILD scores of ≥ 2% at 12 months (SLS I) or 24 months (SLS II) experienced significantly worse long-term survival than those with change scores of < 2% (P ≤ .01, log-rank test). In the multivariate Cox models, radiographic progression remained associated with worse long-term survival in SLS I (P = .089) and SLS II (P = .014).InterpretationData from two independent clinical trial cohorts with extensive long-term follow-up demonstrated that radiographic progression of ILD over 12 to 24 months, in both treatment and placebo arms, can predict increased risk for long-term mortality in patients with SSc. These findings suggest that radiographic end points may serve as surrogates for mortality in SSc-ILD.

Dataset Information

Early Neutrophil Responses to Chemical Carcinogenesis Shape Long-Term Lung Cancer Susceptibility.

Publications

Early Neutrophil Responses to Chemical Carcinogenesis Shape Long-Term Lung Cancer Susceptibility.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets