Lung adenocarcinoma promotion by air pollutants

Nature. 2023 Apr;616(7955):159-167. doi: 10.1038/s41586-023-05874-3. Epub 2023 Apr 5.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung* / chemically induced
  • Adenocarcinoma of Lung* / genetics
  • Air Pollutants* / adverse effects
  • Air Pollutants* / analysis
  • Air Pollution* / adverse effects
  • Air Pollution* / analysis
  • Alveolar Epithelial Cells / drug effects
  • Alveolar Epithelial Cells / pathology
  • Animals
  • Cell Transformation, Neoplastic* / chemically induced
  • Cell Transformation, Neoplastic* / drug effects
  • Cell Transformation, Neoplastic* / genetics
  • Cohort Studies
  • Environmental Exposure
  • ErbB Receptors / genetics
  • Lung Neoplasms* / chemically induced
  • Lung Neoplasms* / genetics
  • Macrophages, Alveolar / drug effects
  • Mice
  • Particle Size
  • Particulate Matter / adverse effects
  • Particulate Matter / analysis

Substances

  • Air Pollutants
  • ErbB Receptors
  • Particulate Matter
  • EGFR protein, human
  • IL1B protein, mouse