A new mechanism by which very small airborne pollutants can trigger lung cancer in people who have never smoked has been identified, opening the way to new prevention approaches and the development of therapies, according to data reported at the 2022 ESMO Congress by the science from the Francis Crick Institute and University College London, funded by Cancer Research UK.

Particulate matter, commonly found in car exhaust and fossil fuel smoke, is associated with lung cancer risk, responsible for more than 250,000 lung cancer deaths worldwide each year.

“The same airborne particles that come from burning fossil fuels, exacerbating climate change, directly impact human health through an important and hitherto ignored mechanism that causes cancer in lung cells. The risk of lung cancer from air pollution is lower than that from smoking, but we have no control over what we all breathe. “Globally, more people are exposed to unsafe levels of air pollution than to the toxic chemicals in cigarette smoke, and this new data links the importance of addressing climate health to improving human health,” said Charles Swanton, MD head of the Francis Crick Institute, right EurekAlert.

New approaches to prevention and development of therapies

The new findings are based on human and laboratory research on mutations in a gene called EGFR, 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 particulate matter (PM) with a diameter of 2.5 micrometers was linked to a risk grown by mutated cells.

In laboratory studies, scientists at the Francis Crick Institute showed that the same pollutant particles (PM2.5) promoted rapid changes in airway cells that also had mutations in another gene linked to lung cancer, called KRAS. leading them to a cancer stem cell-like state.

They also found that air pollution causes an influx of macrophages that release the inflammatory mediator interleukin-1β, which causes the expansion of mutated cells, in response to PM2.5 exposure, and that blocking interleukin-1β inhibited the initiation of lung cancer.

How did the mutations come about?

In a final series of experiments, the team used state-of-the-art ultra-deep mutational profiling of small samples of normal lung tissue and found EGFR and KRAS motor mutations in 18% and 33% of normal lung samples, respectively.

“We found that mutations in the EGFR and KRAS genes, commonly found in lung cancers, are actually present in normal lung tissue and are a likely consequence of aging. 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 they appeared faster than when lung cells with these mutations were not exposed to the pollutants, suggesting that air pollution favors the initiation of lung cancer in cells containing gene mutations. “The next step is to discover why some lung cells with mutations become cancerous when exposed to pollutants, while others do not,” said Swanton.

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