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Lung adenocarcinoma promotion by air pollutants

Hill, William ; Saal, Lao H LU orcid ; Chen, Yilun LU ; George, Anthony M LU ; Litchfield, Kevin LU and Swanton, Charles (2023) In Nature 616(7955). p.159-167
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 (PM2.5), 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 PM2.5 levels and the incidence of lung cancer for 32,957... (More)

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 (PM2.5), 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 PM2.5 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 PM2.5 air pollutants and provide impetus for public health policy initiatives to address air pollution to reduce disease burden.

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published
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keywords
Animals, Mice, Adenocarcinoma of Lung/chemically induced, Air Pollutants/adverse effects, Air Pollution/adverse effects, Cell Transformation, Neoplastic/chemically induced, Environmental Exposure, ErbB Receptors/genetics, Lung Neoplasms/chemically induced, Particulate Matter/adverse effects, Particle Size, Cohort Studies, Macrophages, Alveolar/drug effects, Alveolar Epithelial Cells/drug effects
in
Nature
volume
616
issue
7955
pages
159 - 167
publisher
Nature Publishing Group
external identifiers
  • scopus:85151530286
  • pmid:37020004
ISSN
0028-0836
DOI
10.1038/s41586-023-05874-3
language
English
LU publication?
yes
additional info
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.
id
28256500-e9f6-4a58-88e4-67b255966841
date added to LUP
2023-04-14 12:10:54
date last changed
2024-04-05 18:23:38
@article{28256500-e9f6-4a58-88e4-67b255966841,
  abstract     = {{<p>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 (PM2.5), 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 PM2.5 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 PM2.5 air pollutants and provide impetus for public health policy initiatives to address air pollution to reduce disease burden.</p>}},
  author       = {{Hill, William and Saal, Lao H and Chen, Yilun and George, Anthony M and Litchfield, Kevin and Swanton, Charles}},
  issn         = {{0028-0836}},
  keywords     = {{Animals; Mice; Adenocarcinoma of Lung/chemically induced; Air Pollutants/adverse effects; Air Pollution/adverse effects; Cell Transformation, Neoplastic/chemically induced; Environmental Exposure; ErbB Receptors/genetics; Lung Neoplasms/chemically induced; Particulate Matter/adverse effects; Particle Size; Cohort Studies; Macrophages, Alveolar/drug effects; Alveolar Epithelial Cells/drug effects}},
  language     = {{eng}},
  number       = {{7955}},
  pages        = {{159--167}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature}},
  title        = {{Lung adenocarcinoma promotion by air pollutants}},
  url          = {{http://dx.doi.org/10.1038/s41586-023-05874-3}},
  doi          = {{10.1038/s41586-023-05874-3}},
  volume       = {{616}},
  year         = {{2023}},
}