The team at the Francis Crick Institute in London showed that rather than causing damage, air pollution was waking up old damaged cells. One of the world’s leading experts, Prof Charles Swanton, said the breakthrough marked a “new era”. And it may now be possible to develop drugs that stop cancers forming. The findings could explain how hundreds of cancer-causing substances act on the body.
The classical view of cancer starts with a healthy cell. It acquires more and more mutations in its genetic code, or DNA, until it reaches a tipping point. Then it becomes a cancer and grows uncontrollably. But there are problems with this idea: cancerous mutations are found in seemingly healthy tissue, and many substances known to cause cancer – including air pollution – don’t seem to damage people’s DNA.
So what is going on?
The researchers who also work at University College London, have produced evidence of a different idea. The damage is already there in our cell’s DNA, picked up as we grow and age, but something needs to pull the trigger that actually makes it cancerous.
The discovery came from exploring why non-smokers get lung cancer. The overwhelming majority of lung cancers are caused by smoking but still, one in 10 cases in the UK is down to air pollution. The Crick scientists focused on a form of pollution called particulate matter 2.5 (known as PM2.5), which is far smaller than the diameter of a human hair.
Through a series of detailed human and animal experiments they showed:
- Places with higher levels of air pollution had more lung cancers not caused by smoking
- Breathing in PM2.5 leads to the release of a chemical alarm – interleukin-1-beta – in the lungs
- This causes inflammation and activates cells in the lungs to help repair any damage
- But around one in every 600,000 cells in the lungs of a 50-year-old already contains potentially cancerous mutations
- These are acquired as we age but appear completely healthy until they are activated by the chemical alarm and become cancerous
Dr Emilia Lim, one of the researchers who is based at the Crick and UCL, said people who had never smoked but developed lung cancer often had no idea why. “To give them some clues about how this might work is really, really important,” she said. “It’s super-important – 99% of people in the world live in places where air pollution exceeds the WHO guidelines so it really impacts all of us.”
But the results also showed mutations alone are not always enough to cause cancer. It can need an extra element. Prof Swanton said this was the most exciting finding his lab had come across, as it “actually rethinks our understanding of how tumours are initiated”. He said it would lead to a “new era” of molecular cancer prevention.
The idea of taking a cancer-blocking pill if you live in a heavily polluted area is not completely fanciful. Doctors have already trialled an interleukin-1-beta drug in cardiovascular disease and found, by complete accident, they cut the risk of lung cancer. The latest findings are being presented to scientists at a conference of the European Society for Medical Oncology.
Speaking to the BBC from the conference, Prof Swanton said: “Pollution is a lovely example, but there are going to be 200 other examples of this over the next 10 years.”
And he said we needed to rethink how even smoking causes cancer – is it just the known DNA damage caused by the chemicals in tobacco or is the smoke causing inflammation, too? Curiously, the idea that mutated DNA is not enough and cancers need another trigger to grow was first proposed by scientist Isaac Berenblum in 1947.
“Philosophically, it’s fascinating. These incredible biologists have done this work 75 years ago and it’s largely been ignored,” said Dr Lim. Michelle Mitchell, chief executive of Cancer Research UK, stressed that “smoking remains the biggest cause of lung cancer”.
But she added: “Science, which takes years of painstaking work, is changing our thinking around how cancer develops. We now have a much better understanding of the driving forces behind lung cancer.”
By: James Gallagher
Critics by ESMO
A new mechanism has been identified through which very small pollutant particles in the air may trigger lung cancer in people who have never smoked, paving the way to new prevention approaches and development of therapies, according to late-breaking data [to be] reported at the ESMO Congress 2022 by scientists of the Francis Crick Institute and University College London, funded by Cancer Research UK.
The particles, which are typically found in vehicle exhaust and smoke from fossil fuels, are associated with non-small cell lung cancer (NSCLC) risk, accounting for over 250,000 lung cancer deaths globally per year. “The same particles in the air that derive from the combustion of fossil fuels, exacerbating climate change, are directly impacting human health via an important and previously overlooked cancer-causing mechanism in lung cells.
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 unsafe levels of air pollution than to toxic chemicals in cigarette smoke, and these new data link the importance of addressing climate health to improving human health,” said Charles Swanton, the Francis Crick Institute and Cancer Research UK Chief Clinician, London, UK, who will present the research results at the ESMO 2022 Presidential Symposium on Saturday, 10 September.
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 nearly half a million people living in England, South Korea and Taiwan, exposure to increasing concentrations of airborne particulate matter (PM) 2.5 micrometres (μm) in diameter was linked to increased risk of NSCLC with EGFR mutations.
In the laboratory studies, the Francis Crick Institute scientists showed that the same pollutant particles (PM2.5) promoted rapid changes in airway cells which had mutations in EGFR and in another gene linked to lung cancer called KRAS, driving them towards a cancer stem cell like state. They also found that air pollution drives the influx of macrophages which release the inflammatory mediator, interleukin-1β, driving the expansion of cells with the EGFR mutations in response to exposure to PM2.5, and that blockade of interleukin-1β inhibited lung cancer initiation.
These findings were consistent with data from a previous large clinical trial showing a dose dependent reduction in lung cancer incidence when people were treated with the anti-IL1β antibody, canakinumab. In a final series of experiments, the Francis Crick team used state-of-the-art, ultradeep 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.
“We found that driver mutations in EGFR and KRAS genes, commonly found in lung cancers, are actually present in normal lung tissue and are a likely consequence of ageing. 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 harbouring 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,” said Swanton. Commenting on the results, Tony Mok, Chinese University of Hong Kong, not involved in the study, 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 pre-cancerous lesions in the lungs and try to reverse them with medicines such as interleukin-1β inhibitors.
We don’t yet know whether it will be possible to use highly sensitive EGFR profiling on blood or other samples to find non-smokers who are predisposed to lung cancer and may benefit from lung scanning, so discussions are still very speculative.” Like Swanton, he stresses the importance of reducing air pollution to lower the risk of lung diseases, including cancer.
“We have known about the link between pollution and lung cancer for a long time, and we now have a possible explanation for it. As consumption of fossil fuels goes hand in hand with pollution and carbon emissions, we have a strong mandate for tackling these issues – for both environmental and health reasons,” Mok concluded.