Dataset Information

Lung adenocarcinoma promotion by air pollutants.

ABSTRACT: A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development¹. Here we propose that environmental particulate matter measuring ≤2.5 μm (PM_2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM_2.5 levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1β. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for PM_2.5 air pollutants and provide impetus for public health policy initiatives to address air pollution to reduce disease burden.

SUBMITTER: Hill W

PROVIDER: S-EPMC7614604 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Lung adenocarcinoma promotion by air pollutants.

Hill William W Lim Emilia L EL Weeden Clare E CE Lee Claudia C Augustine Marcellus M Chen Kezhong K Kuan Feng-Che FC Marongiu Fabio F Evans Edward J EJ Moore David A DA Rodrigues Felipe S FS Pich Oriol O Bakker Bjorn B Cha Hongui H Myers Renelle R van Maldegem Febe F Boumelha Jesse J Veeriah Selvaraju S Rowan Andrew A Naceur-Lombardelli Cristina C Karasaki Takahiro T Sivakumar Monica M De Swapnanil S Caswell Deborah R DR Nagano Ai A Black James R M JRM Martínez-Ruiz Carlos C Ryu Min Hyung MH Huff Ryan D RD Li Shijia S Favé Marie-Julie MJ Magness Alastair A Suárez-Bonnet Alejandro A Priestnall Simon L SL Lüchtenborg Margreet M Lavelle Katrina K Pethick Joanna J Hardy Steven S McRonald Fiona E FE Lin Meng-Hung MH Troccoli Clara I CI Ghosh Moumita M Miller York E YE Merrick Daniel T DT Keith Robert L RL Al Bakir Maise M Bailey Chris C Hill Mark S MS Saal Lao H LH Chen Yilun Y George Anthony M AM Abbosh Christopher C Kanu Nnennaya N Lee Se-Hoon SH McGranahan Nicholas N Berg Christine D CD Sasieni Peter P Houlston Richard R Turnbull Clare C Lam Stephen S Awadalla Philip P Grönroos Eva E Downward Julian J Jacks Tyler T Carlsten Christopher C Malanchi Ilaria I Hackshaw Allan A Litchfield Kevin K DeGregori James J Jamal-Hanjani Mariam M Swanton Charles C

Nature 20230405 7955

A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development<sup>1</sup>. Here we propose that environmental particulate matter measuring ≤2.5 μm (PM<sub>2.5</sub>), known to be associated with lung cancer risk, promotes lung cancer by acting on cell ...[more]

PMID: 37020004

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Project description:BackgroundEngineered carbon nanotubes are currently used in many consumer and industrial products such as paints, sunscreens, cosmetics, toiletries, electronic processes and industrial lubricants. Carbon nanotubes are among the more widely used nanoparticles and come in two major commercial forms, single-walled carbon nanotubes (SWCNT) and the more rigid, multi-walled carbon nanotubes (MWCNT). The low density and small size of these particles makes respiratory exposures likely. Many of the potential health hazards have not been investigated, including their potential for carcinogenicity. We, therefore, utilized a two stage initiation/promotion protocol to determine whether inhaled MWCNT act as a complete carcinogen and/or promote the growth of cells with existing DNA damage. Six week old, male, B6C3F1 mice received a single intraperitoneal (ip) injection of either the initiator methylcholanthrene(MCA, 10 μg/g BW, i.p.), or vehicle (corn oil). One week after i.p. injections, mice were exposed by inhalation to MWCNT (5 mg/m³, 5 hours/day, 5 days/week) or filtered air (controls) for a total of 15 days. At 17 months post-exposure, mice were euthanized and examined for lung tumor formation.ResultsTwenty-three percent of the filtered air controls, 26.5% of the MWCNT-exposed, and 51.9% of the MCA-exposed mice, had lung bronchiolo-alveolar adenomas and lung adenocarcinomas. The average number of tumors per mouse was 0.25, 0.81 and 0.38 respectively. By contrast, 90.5% of the mice which received MCA followed by MWCNT had bronchiolo-alveolar adenomas and adenocarcinomas with an average of 2.9 tumors per mouse 17 months after exposure. Indeed, 62% of the mice exposed to MCA followed by MWCNT had bronchiolo-alveolar adenocarcinomas compared to 13% of the mice that received filtered air, 22% of the MCA-exposed, or 14% of the MWCNT-exposed. Mice with early morbidity resulting in euthanasia had the highest rate of metastatic disease. Three mice exposed to both MCA and MWCNT that were euthanized early had lung adenocarcinoma with evidence of metastasis (5.5%). Five mice (9%) exposed to MCA and MWCNT and 1 (1.6%) exposed to MCA developed serosal tumors morphologically consistent with sarcomatous mesotheliomas, whereas mice administered MWCNT or air alone did not develop similar neoplasms.ConclusionsThese data demonstrate that some MWCNT exposures promote the growth and neoplastic progression of initiated lung cells in B6C3F1 mice. In this study, the mouse MWCNT lung burden of 31.2 μg/mouse approximates feasible human occupational exposures. Therefore, the results of this study indicate that caution should be used to limit human exposures to MWCNT.

Project description:ObjectivesOur study aims to clarify the causality between air pollutants and lung function, chronic respiratory diseases, and the potential mediating effects of inflammatory proteins.MethodWe employed Mendelian Randomization (MR) analysis with comprehensive instrumental variables screening criteria to investigate the effects of air pollutants on lung function and chronic lung diseases. Our study incorporated genetic instruments for air pollutants, ensuring F-statistics above 20.86. A total of 18 MR analyses were conducted using the inverse-variance weighted approach, along with heterogeneity and pleiotropy tests to validate the results. Mediated MR analysis was utilized to evaluate the inflammatory proteins mediating the effects of air pollutants.ResultMR analysis demonstrated significant causal interactions of particulate matter 2.5 (PM2.5), PM10, and Nitrogen dioxide (NO2) with lung function decline. Specifically, PM10 negatively affected forced expiratory volume in one second (FEV1) (OR: 0.934, 95% CI: 0.904-0.965, p = 4.27 × 10-5), forced vital capacity (FVC) (OR: 0.941, 95% CI: 0.910-0.972, p = 2.86 × 10-4), and FEV1/FVC (OR: 0.965, 95% CI: 0.934-0.998, p = 0.036). PM2.5 and NO2 were identified as potential risk factors for impairing FEV1 (OR: 0.936, 95% CI: 0.879-0.998, p = 0.042) and FEV1/FVC (OR: 0.943, 95% CI: 0.896-0.992, p = 0.024), respectively. For chronic respiratory diseases, PM2.5 and NO2 were associated with increased COPD incidence (OR: 1.273, 95% CI: 1.053-1.541, p = 0.013 for PM2.5; OR: 1.357, 95% CI: 1.165-1.581, p = 8.74 × 10-5 for NO2). Sensitivity analyses confirmed the robustness of these findings, with no significant heterogeneity or horizontal pleiotropy detected.ConclusionOur study ascertained the causal correlations of air pollutants with lung function and COPD, emphasizing the importance of reducing air pollution. Interleukin-17A mediates the reduction of FEV1 and FVC by PM10, revealing potential therapeutic targets.

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Lung adenocarcinoma promotion by air pollutants.

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Lung adenocarcinoma promotion by air pollutants.

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