New research elucidates how air pollution causes lung cancer in never-smokers
Research presented at the European Society of Medical Oncology (ESMO) Congress 2022 has uncovered a non-mutagenic mechanism by which air pollution promotes the development of lung cancer in people who have never smoked.1
Whilst smoking remains the greatest risk for lung cancer, an estimated 6,000 people in the United Kingdom who have never smoked die from lung cancer each year. 2,3 In 2019, approximately 300,000 lung cancer deaths were attributed to particulate matter (PM2.5) exposure worldwide.4
Although the association between increased lung cancer risk and PM2.5 in air pollution is well established, the mechanism has remained unclear. The current research has shown that preexisting latent mutant clones present in normal tissue can be activated in never-smokers through exposure to PM2.5, leading to the development of cancer. 5 This mechanism differs to the traditional model of carcinogenesis which follows cancer development is caused by a mutagenic mechanism where carcinogens lead to the direct induction of DNA damage.6 Alternatively, the present findings are in congruence with a model proposed by Isaac Berenblum in 1947 requiring two stages for the induction of cancer: tumor initiation and tumor promotion.7
These findings were demonstrated through a series of comprehensive human and animal experiments.8 Samples from over 400,000 individuals were analyzed from England, South Korea and Taiwan to investigate the association between the risk of cancer and increasing concentrations of PM2.5, confirming a positive correlation between high levels of PM2.5 and the incidence of epidermal growth factor (EGFR)-mutant lung cancer, as well as several other types of cancer. 9 Indeed, it is well established that mutations found in the EGFR gene are common in individuals with lung cancer who have never smoked.10
To further investigate, EGFR mutations were induced into the lung epithelium of mice which were then exposed to PM2.5 or control over several weeks. A dose-dependent increase in the number of tumors found in the mice exposed to PM was observed.11
The transcriptional data from the mouse models was then compared with data from the COPA (NCT02236039) trial, which included never-smokers being exposed to either PM2.5 or filtered air for 2 hours. The inflammatory cytokine, interleukin-1 beta (IL-1β) was found to be upregulated in both humans and mice. 11 Notably, when EGFR-mutant mice exposed to PM2.5 were simultaneously treated with an anti–IL-1β antibody, tumor growth did not occur. 12 These results are consistent with findings from the Phase III cardiovascular prevention CANTOS (NCT01327846) trial, which observed a reduction in the rate of lung cancer cases in individuals treated with the anti-IL-1β antibody, canakinumab.13
Lead study Charles Swanton, MD, PhD, of the Francis Crick Institute comments that:
“This may be a more common mechanism of tumor initiation than perhaps we once thought, and it’s interesting to note that Isaac did these experiments in 1947, and to some extent perhaps we have been slightly distracted by the tobacco/carcinogen/DNA mutation origins of cancer, and ignored some of these earlier experiments which might be more applicable to the majority of environmental carcinogens.”
Overall, the findings propose a model of cancer development that may be driven by environmental/inflammatory stimuli, such as PM2.5 in air pollution triggering IL-1β activation and inflammation, thereby acting on cells that harbor oncogenic mutations in normal tissue which are otherwise restrained. The results show mutations alone are not always sufficient for the development of cancer and present a new understanding of how lung cancer could be prevented in never-smokers through blocking the tumor promoting stage of carcinogenesis.
- Scientists Discover How Air Pollution May Trigger Lung Cancer in Never-Smokers [ESMO Congress 2022 Press Release. Esmo.org. 2022. Available from: https://www.esmo.org/newsroom/press-releases/scientists-discover-how-air-pollution-may-trigger-lung-cancer-in-never-smokers#:~:text=In%20the%20laboratory%20studies%2C%20the,cancer%20stem%20cell%20like%20state.
- Jyoti Malhotra, Matteo Malvezzi, Eva Negri, et al. Risk factors for lung cancer worldwide. European Respiratory Journal Sep 2016, 48 (3) 889-902.
- Bhopal A, Peake M, Gilligan D, Cosford P. Lung cancer in never-smokers: a hidden disease. Journal of the Royal Society of Medicine. 2019;112(7):269-271.
- Collaborators GBDRF. Global burden of 87 risk factors in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. (2020) 396:1223–49
- Cunningham M. Pathway Elucidated in Lung Cancer Caused by Air Pollution. Dailynews.ascopubs.org. 2022. Available from: https://dailynews.ascopubs.org/do/10.1200/ADN.22.201114/full/
- Balmain A. The critical roles of somatic mutations and environmental tumor-promoting agents in cancer risk. Nat Genet. 2020;52(11):1139-1143
- Sidharthan, Chinta. Study uncovers how air pollution can trigger lung cancer in individuals with no history of smoking. 2022 News-Medical. Available from: https://www.news-medical.net/news/20220913/Study-uncovers-how-air-pollution-can-trigger-lung-cancer-in-individuals-with-no-history-of-smoking.aspx.
- Cancer rules rewritten by air-pollution discovery. BBC News. 2022. Available from: https://www.bbc.co.uk/news/health-62797777
- Gourd E. New evidence that air pollution contributes substantially to lung cancer. The Lancet Oncology. 2022;23(10):e448.
- Sonobe M, Manabe T, Wada H, et al. Mutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma. British Journal of Cancer. 2005;93(3):355-363.
- Moore V. Research May Explain How Air Pollution Causes Lung Cancer in Never-Smokers. Cancer Therapy Advisor. 2022. Available from: https://www.cancertherapyadvisor.com/home/news/conference-coverage/esmo-2022/lung-cancer-air-pollution-research-may-explain-treatment-risk/
- Swanton C, Hill W, Lim E, Lee C, Weeden C, Augustine M et al. LBA1 Mechanism of action and an actionable inflammatory axis for air pollution induced non-small cell lung cancer: Towards molecular cancer prevention. Annals of Oncology. 2022;33:S1413.
- Wong C, Baum J, Silvestro A, Beste M, Bharani-Dharan B, Xu S et al. Inhibition of IL1β by Canakinumab May Be Effective against Diverse Molecular Subtypes of Lung Cancer: An Exploratory Analysis of the CANTOS Trial. Cancer Research. 2020;80(24):5597-5605.
Written by Ellie Jackson