PARIS – Air pollution has been recognized as a risk factor for lung cancer for about 2 decades, and investigators in the UK have now identified a potential mechanism whereby the air we breathe may trigger driver mutations already present in normal lung cells to cause cancer.
Think of it as "smoking gun–level" evidence that may explain why many nonsmokers still develop non–small cell lung cancer, said Charles Swanton, PhD, from the Francis Crick Institute and Cancer Research UK Chief Clinician, London.
"What this work shows is that air pollution is directly causing lung cancer but through a slightly unexpected pathway," he said at a briefing prior to his presentation of the data in a presidential symposium held earlier this month in Paris at the European Society for Medical Oncology Congress 2022.
Importantly, he and his team also propose a mechanism for blocking the effects of air pollution with monoclonal antibodies directed against the inflammatory cytokine interleukein-1 beta.
Lung cancer in never-smokers has a low mutational burden, with about 5- to 10-fold fewer mutations in a nonsmoker, compared with an ever smoker or current smoker, Swanton noted.
"The other thing to say about never-smokers is that they don't have a clear environmental carcinogenic signature. So how do you square the circle? You've got the problem that you know that air pollution is associated with lung cancer – we don't know if it causes it – but we also see that we've got no DNA mutations due to an environmental carcinogen," he said during his symposium presentation.
The traditional model proposed to explain how carcinogens cause cancer holds that exposure to a carcinogen causes DNA mutations that lead to clonal expansion and tumor growth.
"But there are some major problems with this model," Swanton said.
For example, normal skin contains a "patchwork of mutant clones," but skin cancer is still uncommon, he said, and in studies in mice, 17 of 20 environmental carcinogens did not induce DNA mutations. He also noted that a common melanoma driver mutation, BRAF V600E, is not induced by exposure to a ultraviolet light.
"Any explanation for never-smoking lung cancer would have to fulfill three criteria: one, you have to explain why geographic variation exists; two, you have to prove causation; and three, you have to explain how cancers can be initiated without directly causing DNA mutations," he said.
Normal lung tissues in nonsmoking adults can harbor pre-existing mutations, with the number of mutations increasing likely as a consequence of aging. In fact, more than 50% of normal lung biopsy tissues have been shown to harbor driver KRAS and/or EGFR mutations, Swanton said.
"In our research, these mutations alone only weakly potentiated cancer in laboratory models. However, when lung cells with these mutations were exposed to air pollutants, we saw more cancers and these occurred more quickly than when lung cells with these mutations were not exposed to pollutants, suggesting that air pollution promotes the initiation of lung cancer in cells harboring driver gene mutations. The next step is to discover why some lung cells with mutations become cancerous when exposed to pollutants while others don't," he said.
Looking at data on 447,932 participants in the UK Biobank, the investigators found that increasing exposure to ambient air particles smaller than 2.5 mcm (PM2.5) was significantly associated with seven cancer types, including lung cancer. They also saw an association between PM2.5 exposure levels and EGFR-mutated lung cancer incidence in the United Kingdom, South Korea, and Taiwan.
And crucially, as Swanton and associates showed in mouse models, exposure of lung cells bearing somatic EGFR and KRAS mutations to PM2.5 causes recruitment of macrophages that in turn secrete IL-1B, resulting in a transdifferentiation of EGFR-mutated cells into a cancer stem cell state, and tumor formation.
Importantly, pollution-induced tumor formation can be blocked by antibodies directed against IL-1B, Swanton said.
"Elegant First Demonstration"
"This is a very meaningful demonstration, from epidemiological data to preclinical models of the role of PM2.5 air pollutants in the promotion of lung cancer, and it provides us with very important insights into the mechanism through which nonsmokers can get lung cancer," commented Suzette Delaloge, MD, from the cancer interception program at Institut Goustave Roussy in Villejuif, France, the invited discussant.
"But beyond that, it also has a great impact on our vision of carcinogenesis, with this very elegant first demonstration of the alternative nonmutagenic, carcinogenetic promotion hypothesis for fine particulate matter," she said.
Questions still to be answered include whether PM2.5 pollutants could also be mutagenic, is the oncogenic pathway ubiquitous in tissue, which components of PM2.5 might drive the effect, how long of an exposure is required to promote lung cancer, and why and how persons without cancer develop specific driver mutations such as EGFR, she said.
"This research is intriguing and exciting as it means that we can ask whether, in the future, it will be possible to use lung scans to look for precancerous lesions in the lungs and try to reverse them with medicines such as interleukin-1B inhibitors," said Tony Mok, MD, a lung cancer specialist at the Chinese University of Hong Kong, who was not involved in the study.
"We don't yet know whether it will be possible to use highly sensitive EGFR profiling on blood or other samples to find nonsmokers who are predisposed to lung cancer and may benefit from lung scanning, so discussions are still very speculative," he said in a statement.
The study was supported by Cancer Research UK, the Lung Cancer Research Foundations, Rosetrees Trust, the Mark Foundation for Cancer Research and the Ruth Strauss Foundation. Swanton disclosed grants/research support, honoraria, and stock ownership with multiple entities. Delaloge disclosed institutional financing and research funding from multiple companies. Mok disclosed stock ownership and honoraria with multiple companies.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
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Cite this: 'Smoking Gun–Level' Evidence Found Linking Air Pollution With Lung Cancer - Medscape - Sep 14, 2022.