How air pollution causes lung cancer in non-smokers

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Two experimental models are currently recognized as being responsible for carcinogenesis (cancer formation and development process): the classic mutation model and the tumor promotion model.

In the classic mutation model, exposure to environmental carcinogens results in mutations in DNA, which in turn result in driver genes that lead to tumor growth, as in exposure to tobacco, which promotes mutations of the KRAS gene.

In the tumor promotion model, there are two stages for the initiation of a tumor: the initiating event, promoted by a mutation, and another event, called the promoter.

In mice, potential driver mutations in pre-existing tumors have been shown to be caused by an endogenous mutation-generating process. Upon exposure to carcinogens, pre-existing mutations expand through clonal growth, resulting in the onset and proliferation of cancer.

However, a new mechanism has been identified by which very small polluting particles in the air can trigger lung cancer in people who have never smoked, paving the way for new prevention approaches and the development of new therapies. , according to recent data reported recently by Charles Swanton and colleagues at the European Society for Medical Oncology (ESMO) Congress 2022.

Particulates, commonly found in vehicle exhaust and fossil fuel smoke, are associated with the risk of non-small cell lung cancer (NSCLC), accounting for more than 250,000 lung cancer deaths in the world every year.

The same particles in the air that derive from burning fossil fuels, exacerbating climate change, are directly impacting human health through an important and hitherto overlooked mechanism that causes lung cell cancer.

The risk of lung cancer from air pollution is lower than from smoking, but we have no control over what we all breathe. Globally, more people are exposed to dangerous levels of air pollution than the toxic chemicals found in cigarette smoke, and this new data links the importance of climate health and improving human health.

Effect on EGFR and KRAS mutations

The new findings are based on human and laboratory research into mutations in the EGFR (epithelial growth factor receptor) gene, which are seen in about half of people with lung cancer who have never smoked.

In a study of almost half a million people living in England, South Korea and Taiwan, exposure to increasing concentrations of airborne particles (PM) of 2.5 μm from diameter has been associated with an increased risk of NSCLC with EGFR mutations. .

In laboratory studies, scientists from the Francis Crick Institute have shown that the same polluting particles (PM2.5) that promote rapid changes in airway cells with EGFR mutations also affect those that had mutations in the KRAS gene, leading to cell-cancer stem.

They also found that air pollution leads to the influx of macrophages that release the inflammatory mediator, interleukin-1β, causing cells with EGFR mutations to expand in response to PM2 exposure. ,5, and that blocking interleukin-1β inhibits the development of lung cancer. .

These results were consistent with data from a previous large clinical trial published by Ridker et al in the prestigious scientific journal The Lancet, showing a dose-dependent reduction in the incidence of lung cancer when people were treated with the antibody. anti-IL1β canakinumab.

In a final series of experiments, Francis Crick’s team used ultra-deep mutational profiling of small samples of normal lung tissue and found EGFR and KRAS driver mutations in 18% and 33% of normal lung samples, respectively.

The researchers found that mutations in the EGFR and KRAS genes, which are commonly found in lung cancer, are actually present in normal lung tissue and are likely a consequence of aging.

In research, these mutations alone potentiated cancer only weakly in laboratory models. However, when lung cells carrying these mutations were exposed to air pollutants, more cancers were detected, and these occurred more rapidly than when lung cells carrying these mutations were not exposed to pollutants, suggesting that air pollution promotes the development of lung cancer in cells carrying mutations in the driver gene.

The next step now is to find out why some lung cells with mutations become cancerous when exposed to pollutants, while others do not.

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