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A study published in Nature looks at lung adenocarcinoma promotion by air pollutants.
This Roundup accompanied an SMC Briefing.
The following comment was provided by our colleagues at SMC Germany:
Prof. Dr. Martin Göttlicher, Director of the Institute of Molecular Toxicology and Pharmacology, Helmholtz Centre Munich – German Research Center for Environmental Health, Munich, and Professor at the Department of Toxicology and Environmental Hygiene, Technical University Munich, said:
“First of all, I would like to congratulate the large international team for carrying out, completing and publishing such a complex study. The question of how ubiquitous man-made environmental pollution affects our health to varying degrees is highly relevant. Understanding these connections is essential for decisions on limiting exposure and preventing damage, and above all understanding what can be expected at what levels of exposure – the technical term is the expected dose-response relationship. The current publication presents the combination of a broad spectrum of methodological approaches including environmental epidemiological cohort studies on the incidence of a certain relatively common form of lung cancer in people who have never smoked, elaborate models in mice, cells and organoids in culture, as well as the study of mutation frequencies in the human population. This combination of complementary approaches makes the study exceptional, but appropriate given the complexity of the question.
“There has been evidence for some time that exposure to common urban air pollutants, including PM2.5 particulate matter, can promote the development of lung cancer in addition to asthma and cardiovascular disease. The current study aims to find out the underlying mechanism for this promotion of tumour development. This is being investigated in a type of tumour that is precisely defined in terms of central genetic alteration in the receptor for epidermal growth factor (EGFR). This genetically defined form of tumour is a relatively common variant among lung tumours in people who have never smoked. For the experimental studies in mouse models and cell or organ cultures, a standardised particle preparation that corresponds to an aerosol from urban air pollution is used. PM2.5 here indicates that the fraction of particles used behave like spheres of 2.5 micrometres or smaller in the air stream. These particles are so small that they can penetrate deep into the respiratory tract.
“The starting point of the present study are large epidemiological studies in population cohorts from England, South Korea and Taiwan, which show an association between the frequency of occurrence of a specific form of lung cancer and PM2.5 exposure at the place of residence of the study participants. The association is clearest in the cohort from Taiwan, where the highest PM2.5 exposures are recorded, though it is still statistically detectable in the cohort from England with the lowest exposure. However, the presentation of the data from the relatively low-exposure English cohort, in contrast to the other studies with higher exposures, suggests that the association between tumour incidence and particle exposure only exists for the highest exposures of the English study participants. It does not occur for the large proportion of those with lower exposures. The highest exposures in the English cohort with 14 micrograms per cubic metre (µg/m³) are still below the lowest exposures in the two Asian cohorts (20 µg/m³). For these studies, a specific form of lung tumours was considered, which is genetically characterised on a molecular level by mutations in the gene for the receptor for the epidermal growth factor (EGFR) and which, by selection of the affected individuals considered, cannot be attributed to smoking. Despite the significance of the correlation, it must not be disregarded that the effect of individual self-inflicted smoking is significantly higher on the development of lung tumours than the effect of the exposure to air pollutants imposed on everyone. Smokers have an approximately ten times higher risk than non-smokers. In contrast, there were about ten percent more cases in the relatively low-exposure English cohort and a doubling to tripling of the specific tumour type in the highest-exposure cohort from Taiwan. The epidemiological studies raise a question central to the current publication: whether PM2.5 exposure induces the development of the driving mutations in the EGFR gene itself (that is, whether PM2.5 is mutagenic) or whether PM2.5 exposure promotes the development of pre-existing or otherwise originating mutations in the EGFR gene into tumours (that is, acts as a tumour promoter).
“To answer this question, the authors translated the observations from the population into mouse models or into cells and organoids in the petri dish. A central element of their experimental approach is the very precise use of state-of-the-art techniques in genetics, which allow the simultaneous expression of the mutant EGFR in most cells of the respiratory tract at a desired time. Although this mutation is present in almost all cells, unlike in humans, there are only a few early tumour forms visible under the microscope within the observation period of ten weeks. The treatment of these genetically modified animals with PM2.5 for three weeks leads to a significant increase in these early tumour forms detectable under the microscope. But without the prior introduction of the mutation in the EGFR gene, PM2.5 would not cause any tumours.
“The series of the following experiments proves,
“The third approach of the publication addresses the question of whether the principles observed in the model systems can also be found in humans. Obviously, experimental mutations cannot be triggered in this case. It was possible, however, to carry out analyses showing whether pre-existing critical mutations in the EGFR gene or other genes critical for the development of lung cancer also exist in healthy human lung tissue. In fact, such mutations could be found in more than half of the people examined but always only at one spot in their lungs. The frequency of such mutations was correlated.
“In summary, the current study provides strong arguments that exposure to PM2.5 in the air we breathe can promote the development of lung cancer – albeit to a lesser extent than cigarette consumption. This is the basis of the authors’ call for further efforts to reduce air pollutants in urban areas. Only time will tell whether the study and the mechanistic understanding developed could provide approaches to protect people from the effects of particles described here through lifestyle factors, food supplements or even medication. However, it seems difficult to imagine treating many people preventively over years or decades to prevent the occurrence of few cases of lung cancer. However, in addition to the basic demand for reducing exposure, the study provides another important indication that there may be a plausible aim as to how far exposure to PM2.5 should be reduced, or how much PM2.5 in the air would be tolerable in terms of promoting tumour development. If the effect were mediated via the triggering of mutations by PM2.5, then the goal should be to reduce air pollution as much as possible, because every single additional mutation could be the decisive one that ultimately triggers the development of a tumour – although with a very low probability. Here, however, a different mode of action is demonstrated that depends on PM2.5-induced inflammatory reactions and does not lead to mutations itself. For such modes of action, it can be assumed that there is a low dose above which the pollutant no longer has a biologically relevant effect: If inflammatory reactions are no longer triggered, then according to the results presented in the current study, the development of pre-existing mutations to tumour disease shouldn’t start either. The comparison of the cohorts of this study from England, South Korea and Taiwan (Figure 1) suggests that the comparatively low exposures in England could already be close to a tolerable limit – at least with regard to promoting the development of lung cancer in people who have never smoked. In Germany, the annual mean values in 2022 for PM2.5 were between 5.2 and 15 µg/m³, depending on the measuring station [1]. This was below the currently valid limit value and in the range that was also measured for the English cohort.”
“How the results of the current study will be transferable to genetically other types of lung tumours and whether approaches for further understanding of other diseases promoted by particulate matter will emerge is an open question. It will be interesting to see how the results presented here will find their way into the regulatory framework for air pollution control – both by supporting claims to reduce air pollution as well as with justified concepts for defining still tolerable particle amounts that are too low to trigger inflammatory reactions and thus should no longer have any relevant effect on human health.”
[1] Umweltbundesamt. Luftdaten. Retrieved on: 01/30/2023.
Prof Zongbo Shi, Professor of Atmospheric Biogeochemistry, University of Birmingham, said:
Does the press release accurately reflect the science?
“Yes. Though care should be taken with the term here presented in the press release:
““Increased exposure to pollution is associated with a higher incidence of lung cancer.”
“The paper provides no evidence of a general association between pollution and lung cancer incidents. This can be problematic if taken out of context. Pollution refers to all sorts – water, air etc. Even for air pollution, it can refer to PM2.5, PM10, NO2, O3, SO2, etc. So, I think this needs to be more precise in the press release, for example:
“Increased exposure to PM2.5 pollution is associated with a higher incidence of lung cancer.”
“In the final sentence of the press release it would be more precise to say these results could be used “to address PM2.5 pollution”, not “address air quality”. Air quality does not need to be addressed. It is the air pollution that needs to be addressed.”
Is this good quality research? Are the conclusions backed up by solid data?
“This is high quality research drawing on multiple sources of evidence. It is particularly good to see the general epidemiological associations are backed up by laboratory-based mechanistic understanding.”
How does this work fit with the existing evidence?
“It strengthens existing evidence between the increased incidence of lung cancer with PM2.5 by providing mechanistical understanding.”
Have the authors accounted for confounders?
“Lifelong exposure to PM2.5 is hard to predict and therefore, there is always uncertainty in the relationship between diseases burden and air pollution. However, the overall relationship does seem to provide a robust association between the two. The research also used carefully selected data from Canada to indicate that high exposure could lead to EGFR-driven lung cancers.”
Are there important limitations to be aware of?
“As mentioned above, the PM2.5 exposure is hard to predict, and the association does not provide causal relationship. The research also used aggregate data instead of patient level data. But the conclusion is carefully phrased and supported by the evidence.”
What are the implications in the real world? Is there any overspeculation?
“This research provides further evidence to reduce PM2.5 exposure to protect public health.”
Prof Terry Tetley, Professor of Lung Cell Biology at the National Heart and Lung Institute, Imperial College London, said:
“This is a fascinating study which brings together large-scale clinical data with basic science in animal models. It indicates that exposure to PM2.5 can induce an inflammatory response that in turn induces pulmonary alveolar Type II epithelial cells which carry a specific genetic mutation to trigger tumour growth unrelated to cigarette smoking.
“We know that fine particulate matter (PM2.5) in the air can be inhaled and reach deep into the lungs; this study shows how PM2.5 can alter their microenvironment once they reach the alveoli of the lungs – specifically targeting pre-cancerous EGFR mutant Type II cells.
“These findings indicate that in people with mutations of the EGFR gene, following inhalation of small particles in the air, these cells are driven down a pathway towards rapid proliferation and tumour formation.
“It is estimated that a fairly low percentage of the population may carry such EGFR mutations yet the impact can be devastating for those who develop these types of cancers, and for their families.
“More work is needed to understand the mechanisms further, as well as identifying who may be at risk and ways to mitigate this.”
Dr Peter Chan, Oxford BHF CRE Intermediate Transition Research Fellow, Nuffield Department of Population Health, University of Oxford, said:
“This is a fascinating multi-disciplinary study that combines observational epidemiology in humans and controlled experiments in mice. The resulting evidence sheds light on possible mechanisms by which PM2.5 pollution may promote (but not initiate) certain types of lung cancer (e.g. those with EGFR mutation) that are more common in never-smokers. This definitely adds an interesting angle to the unresolved debate on whether ambient PM2.5 “causes” lung cancer.
“However, there are several limitations worth highlighting. As the authors rightly noted in the paper, the epidemiological analyses mostly used population-aggregated data, and the findings are prone to biases and residual confounding. The analysis of the UK Biobank cohort used individual-level confounders but approximated ambient PM2.5 levels near participants’ home address, a conventional method that omits how people spend most of their time indoors and do not stay outside of their home 24/7.
“It is somewhat counterintuitive to see the contrasting findings of a higher risk of EGFR lung cancer associated with 3-year cumulative mean exposure to PM2.5, but not with 20-year cumulative exposure in the small Canadian cohort of 228 non-smoking females with lung cancer. If the hypothesized mechanism is true, one would expect a larger amount of cumulative exposure (20 vs 3 years) to be associated with a greater risk of EGFR lung cancer, but that doesn’t seem to be the case. The ambiguity may be due to the rather small sample size, use of relatively crude (10 x 10km) address-based, area-level PM2.5 data, and residual confounding.
“In contrast, EGFR mutant lung cell proliferation in mice was not observed at the end of the 3-week PM2.5 exposure period but only after a further 7 weeks of no-exposure follow-up. This seems to suggest certain delayed effects in mice, which is also supported by the findings on sustained local inflammatory response (for up to 10 weeks). If possible, it would be interesting to conduct similar controlled experiments or pseudo-experiments (using observational causal inference approaches) in healthy humans to confirm the findings, as animal studies do not always translate to humans. One may raise ethical concerns about doing human intervention studies like such, but if the present study findings are true, the amount of PM2.5 exposure required would not be dis-similar to people’s daily exposure?”
‘Lung adenocarcinoma promotion by air pollutants’ by Charles Swanton et al. was published in Nature at 16:00 UK Time Wednesday 05 April 2023.
DOI: 10.1038/s41586-023-05874-3
Declared interests
Prof. Dr. Martin Göttlicher: “I have no conflicts of interest.”
Prof Zongbo Shi: “I declare no conflict of interest.”
Prof Terry Tetley: “No conflicts.”
Dr Peter Chan: “I declare no competing interest.”