How air pollution can cause lung cancer in people who have never smoked

Research supported by the UCLH Biomedical Research Centre has revealed how air pollution can cause lung cancer in people who have never smoked.

The research at UCL and the Francis Crick Institute, funded by Cancer Research UK, was first presented at the ESMO Congress in September last year. Led by Professor Charles Swanton, the research found found that exposure to tiny pollutant particles that are 3% of the width of a human hair, called PM_2.5, promotes the growth of cells carrying cancer-causing mutations in the lungs.

Examining data from over 400,000 people, the scientists also found higher rates of other types of cancer in areas with high levels of PM_2.5.

The research published in Nature is part of the TRACERx Lung Study, a £14 million programme to understand how lung cancer starts and evolves over time, in the hope of finding new treatments for the disease.

Although smoking remains the biggest risk factor for lung cancer, outdoor air pollution causes roughly 1 in 10 cases of lung cancer in the UK. An estimated 6,000 people who have never smoked die of lung cancer every year in the UK, some of which may be due to air pollution exposure. Globally, around 300,000 lung cancer deaths in 2019 were attributed to exposure to PM_2.5.

UCLH consultant Professor Swanton, who is lead investigator for TRACERx at the Francis Crick Institute and UCL and CRUK Chief Clinician, said:

Lead investigator for the TRACERx Lung study, Professor Charles Swanton, said: “Our study has fundamentally changed how we view lung cancer in people who have never smoked.

“Cells with cancer-causing mutations accumulate naturally as we age, but they are normally inactive. We’ve demonstrated that air pollution wakes these cells up in the lungs, encouraging them to grow and potentially form tumours.

“The mechanism we’ve identified could ultimately help us to find better ways to prevent and treat lung cancer in never smokers. If we can stop cells from growing in response to air pollution, we can reduce the risk of lung cancer.”

Air pollution has been linked to variety of health problems, including asthma, chronic obstructive pulmonary disease (COPD), heart disease and dementia. But how it causes cancer to start in people who have never smoked has been a mystery up to now.

Many environmental agents, such as UV light and tobacco smoke, cause damage to the structure of DNA, creating mutations which cause cancer to start and grow. But no evidence could be found that air pollution directly mutates DNA, so scientists looked for a different explanation.

They investigated the theory that PM_2.5 causes inflammation in the lungs which can lead to cancer. Inflammation wakes up normally inactive cells in the lungs which carry cancer-causing mutations. The combination of cancer-causing mutations and inflammation can trigger these cells to grow uncontrollably, forming tumours.

The scientists examined a type of lung cancer called epidermal growth factor receptor (EGFR) mutant lung cancer. Mutations in the EGFR gene are commonly found in lung cancer in people who have never smoked.

They examined data taken from over 400,000 people from the UK and Asian countries, comparing rates of EGFR mutant lung cancer in areas with different levels of PM_2.5 pollution. They found higher rates of EGFR mutant lung cancer, as well as higher rates of other types of cancer, in people living in areas with higher levels of PM_2.5 pollution.

Co-first author and postdoctoral researcher at UCL and the Francis Crick Institute, Dr Emilia Lim, said:

“According to our analysis, increasing air pollution levels increases the risk of lung cancer. Even small changes in air pollution levels can affect human health. 99% of the world’s population lives in areas which exceed annual WHO limits for PM_2.5, underlining the public health challenges posed by air pollution across the globe.”

The team then – in work without BRC involvement – exposed mice with cells carrying EGFR mutations in their lungs to air pollution at levels normally found in cities. They found cancers were more likely to start from cells carrying EGFR mutations, compared with those mice not exposed to air pollution. The researchers showed that blocking a molecule called IL-1β, which normally causes inflammation and is released in response to PM_2.5 exposure, prevents cancers from forming in these mice.

The research team think that the model presented in their study could be responsible for the early stages of many different types of cancer, where environmental triggers awaken cells carrying cancer-causing mutations in different parts of the body.

Funding for the study was provided by Cancer Research UK, The European Research Council,The Francis Crick Institute, the Mark Foundation, Lung Cancer Research Foundation, Rosetrees Trust and the Ruth Strauss Foundation.

Image: Professor Charles Swanton