Lung adenocarcinoma promotion by air pollutants.
William HillEmilia L LimClare E WeedenClaudia S Y LeeMarcellus AugustineKezhong ChenFeng-Che KuanFabio MarongiuEdward J EvansDavid Allan MooreFelipe S RodriguesOriol PichBjorn BakkerHongui ChaRenelle MyersFebe van MaldegemJesse BoumelhaSelvaraju VeeriahAndrew RowanCristina Naceur-LombardelliTakahiro KarasakiMonica SivakumarSwapnanil DeDeborah R CaswellAi NaganoJames R M BlackCarlos Martínez-RuizMin Hyung RyuRyan D HuffShijia LiMarie-Julie FavéAlastair MagnessAlejandro Suarez-BonnetSimon Lawrence PriestnallMargreet LüchtenborgKatrina LavelleJoanna PethickSteven HardyFiona E McRonaldMeng-Hung LinClara I TroccoliMoumita GhoshYork E MillerDaniel T MerrickRobert L KeithMaise Al BakirChris BaileyMark S HillLao H SaalYilun ChenAnthony M GeorgeChristopher AbboshNnennaya KanuSe-Hoon LeeNicholas McGranahanChristine D BergPeter D SasieniRichard S HoulstonClare TurnbullStephen LamPhillip AwadallaEva GrönroosJulian DownwardTyler JacksChristopher CarlstenIlaria MalanchiAllan HackshawKevin Litchfieldnull nullJames DeGregoriMariam Jamal-HanjaniCharles SwantonPublished in: Nature (2023)
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 1 . 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.
Keyphrases
- particulate matter
- air pollution
- small cell lung cancer
- public health
- epidermal growth factor receptor
- tyrosine kinase
- single cell
- induced apoptosis
- heavy metals
- papillary thyroid
- lung function
- transcription factor
- cell cycle arrest
- gene expression
- healthcare
- dna methylation
- mental health
- polycyclic aromatic hydrocarbons
- cell proliferation
- squamous cell carcinoma
- risk assessment
- cell death
- human health
- smoking cessation
- stem cells
- lymph node metastasis