In what has been described as a "wake-up call" about the damaging impact of pollution on human health, scientists have uncovered how fine particulates in car fumes “awaken” dormant mutations in lung cells and tip them into a cancerous state, reports MedicalBrief.
The work helps explain why so many non-smokers develop lung cancer and illustrates the health risk posed by the tiny particles produced by burning fossil fuels, sparking fresh calls for more urgent action to combat climate change.
“The risk of lung cancer from air pollution is lower than from smoking, but we have no control over what we all breathe,” said Professor Charles Swanton of the Francis Crick Institute, who presented the findings at the European Society for Medical Oncology conference (ESMO) in Paris at the weekend.
“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.”
Smoking remains the biggest cause of lung cancer, but outdoor air pollution causes about one in 10 cases in the UK: an estimated 6 000 people who have never smoked die of lung cancer every year, reports The Guardian. Worldwide, about 300 000 lung cancer deaths in 2019 were attributed to exposure to fine particulate matter, known as PM2.5, contained in air pollution.
However, the biological basis for how air pollution causes cancer has remained unclear. Unlike smoking or sun exposure, which directly cause DNA mutations linked to lung and skin cancer, air pollution does not cause cancer by triggering such genetic changes.
Instead, those with non-smoking lung cancer tend to carry mutations that are also seen in healthy lung tissue – small errors that we accumulate in our DNA throughout life and which normally remain innocuous.
“Clearly these patients are getting cancer without having mutations, so there’s got to be something else going on,” said Swanton, who is also Cancer Research UK’s chief clinician. “Air pollution is associated with lung cancer but people have largely ignored it because the mechanisms behind it were unclear.”
The latest work unveils this mechanism through a series of meticulous experiments showing that cells carrying dormant mutations can turn cancerous when exposed to PM2.5 particles. The pollutant is the equivalent of the ignition spark on a gas hob.
After analysing the health data of more than 460 000 people in England, South Korea and Taiwan, the team from the Francis Crick Institute and University College London found that exposure to the tiny PM2.5 pollution particles (which are less than 2.5 microns across) led to an increased risk of mutations in the EGFR gene.
In laboratory studies on mice, the team showed that the particles caused changes not just in the EGFR gene but also to the KRAS gene, both of which have been linked to lung cancer. Finally, they analysed nearly 250 samples of human lung tissue never exposed to carcinogens from smoking or heavy pollution.
Even though the lungs were healthy, they found DNA mutations in 18% of EGFR genes and 33% of KRAS genes, reports MedicalXpress.
“They’re just sitting there,” Swanton said, adding that the mutations seem to increase with age. “On their own, they probably are insufficient to drive cancer, but when a cell is exposed to pollution it can trigger a wound-healing response that causes inflammation,” he added. If that cell “harbours a mutation, it will then form a cancer”.
“We’ve provided a biological mechanism behind what was previously an enigma,” he said.
In another experiment on mice, the researchers showed that an antibody could block the mediator – called interleukin 1 beta – which sparks the inflammation, stopping cancer from getting started in the first place.
Swanton said he hoped the finding would “provide fruitful grounds for a future of what might be molecular cancer prevention, where we can offer people a pill, perhaps every day, to reduce the risk of cancer”.
'Revolutionary'
Suzette Delaloge, who heads the cancer prevention programme at France’s Gustave Roussy Institute, said the research was “quite revolutionary, because we had practically no prior demonstration of this alternative way of cancer forming”.
“This opens a huge door, both for knowledge but also for new ways to prevent cancer from developing,” said Delaloge, who was not involved in the research but discussed it at the conference on Saturday. “This level of demonstration must force authorities to act on an international scale.”
Swanton called air pollution a “hidden killer”, pointing to research estimating it is linked to the deaths of more than 8m people a year – around the same number as tobacco.
“It’s a wake-up call on the impact of pollution on human health,” he said. “You cannot ignore climate health. If you want to address human health, you have to address climate health first.”
Professor Tony Mok, of the Chinese University of Hong Kong and who was not involved in the research, said: “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.”
Professor Allan Balmain, a cancer geneticist at the University of California, San Francisco, said the findings also had implications for our understanding of how smoking causes cancer. “Both air pollution and cigarette smoke contain lots of promoting substances. This has been known since the early 1960s but has essentially been ignored, as everyone was focused on mutations,” he said.
“The tobacco companies are now saying that smokers should switch to vaping as this reduces exposure to mutagens, and therefore the cancer risk is going to go away. This is not true, as our cells get mutations anyway, and there is evidence that vaping can induce lung disease and cause inflammation similar to promoters.”
Study details
Mechanism of action and an actionable inflammatory axis for air pollution induced non-small cell lung cancer: Towards molecular cancer prevention
C. Swanton, W. Hill, E. Lim, C. Lee, C.E. Weeden, M. Augustine, K. Chen, F. Kuan, F. Marongiu, F. Rodrigues, H. Cha, T. Jacks, M. Luchtenborg, I. Malanchi, J. Downward, C. Carlsten, A. Hackshaw, K.R. Litchfield, J. DeGregori, M. Jamal-Hanjani.
Presented at ESMO on 10 September 2022
Abstract
Background
A mechanistic basis for non-small cell lung cancer (NSCLC) initiation in never smokers, a disease with a high frequency of EGFR mutations (EGFRm), is unknown. The air pollutant, particulate matter (PM), is known to be associated with the risk of NSCLC, however a direct cause and mechanism remain elusive.
Methods
We analysed 463,679 individuals to address the associations of increasing 2.5um PM (PM2.5) concentrations with cancer risk. We performed ultra-deep profiling of 247 normal lung tissue samples, analysed normal lung tissue from humans and mice following exposures to PM, and investigated the consequences of PM on tumour promotion in mouse lung cancer models.
Results
Increasing PM2.5 levels were associated with increased risk of EGFRm NSCLC in England, S.Korea and Taiwan and with increased risk of mesothelioma (HR=1.19), lung (HR=1.16), anal (HR=1.23), small intestine (HR=1.30), GBM (HR=1.19), lip, oral cavity and pharynx (HR: 1.15) and laryngeal carcinomas (HR=1.26) in UK Biobank; HR for each 1ug/m3 PM2.5 increment. 18-33% of normal lung tissue samples harbour driver mutations in EGFR and KRAS in the absence of malignancy. PM promotes a macrophage response and a progenitor-like state in lung epithelium harbouring mutant EGFR. Consistent with PM promoting NSCLC in at-risk epithelium harbouring driver mutations, PM increased tumour burden in three EGFR or KRAS driven lung cancer models in a dose-dependent manner. Finally, we uncover an actionable inflammatory axis driven by IL1B in response to PM, with anti-IL1B therapy preventing PM-induced mouse tumour formation, consistent with reductions in human lung cancer incidence with anti-IL1B therapy.
Conclusions
These results shed light on the aetiology of EGFRm lung cancer, particularly in never-smokers, and suggest that oncogenic mutations may be necessary but insufficient for tumour formation. These data reveal a mechanistic basis for PM driven lung cancer in the absence of classical carcinogen-driven mutagenesis, reminiscent of models of tumour initiation and promotion proposed 70 years ago, providing evidence to limit air pollution and opportunities for molecular targeted cancer prevention.
MedicalXpress article – Scientists discover how air pollution triggers lung cancer
ESMO presentation (Restricted access)
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