Air pollution can cause lung cancer, not because it causes genetic mutations, but because it causes an inflammation reaction around cells that have acquired mutations for other reasons. With adequate anti-inflammatory treatment, however, the appearance of cancer in tissues that have accumulated mutations can be prevented. This is demonstrated by international research led by the Francis Crick Institute in London that is presented today in the scientific journal Nature.
The results represent a paradigm shift in the understanding of some cancers, by relativizing the role of mutations and highlighting that of inflammation. In addition, they open the way to better prevention of cancers caused by pollution and possibly other types of cancer. And they provide new arguments to limit air pollution.
“Lung cancer in people who have never smoked is the eighth most common cause of cancer death in the UK,” Charles Swanton, the lead researcher, told a news conference on Tuesday. "A frequent question patients ask is 'Doctor, how come I have lung cancer?'" Finding the answer has required a nine-year investigation that has combined epidemiological analyses, experiments with mice, and patient studies.
Epidemiological data have detected that the areas with the highest levels of contamination by fine particles, less than 2.5 microns, coincide with the areas where there is a higher incidence of lung cancer in non-smokers. This phenomenon has been observed independently in the United Kingdom, Canada, South Korea, and Taiwan. Three years of exposure to a high level of air pollution is enough for the risk of lung cancer to increase significantly.
To clarify whether the relationship between pollution and lung cancer is cause-and-effect, researchers have studied mice prone to cancer. As expected, the fine contaminant particles have raised the likelihood that the animals would develop lung cancer. But surprisingly, unlike what happens with cancers caused by tobacco, there were no genetic mutations caused by the contamination that explained the appearance of the tumors.
"How can environmental pollution cause cancer without causing carcinogenic mutations?" Swanton asked at the press conference. The explanation was that fine particle pollution triggers an inflammatory reaction in the lungs. This reaction is characterized by the production of the protein interleukin-1 beta, against which there are several drugs already approved. Mice treated with one of these drugs, the antibody canakinumab, developed far fewer tumors.
Finally, genomic analysis of 295 non-smokers with lung cancer confirmed that they did not have a profile of genetic mutations that explained the disease. However, most had mutations hitherto considered cancer-promoting in their healthy lung tissue. Specifically, 53% had mutations in the KRAS gene in healthy tissues and 18% in the EGFR gene.
“I had always thought that oncogenic mutations were necessary and sufficient for cancer. What these data told me is that I had missed the inflammation," Swanton acknowledged at the press conference. "We need a new model" to explain how cancer starts.
The model that Swanton proposes is a two-phase process. First, genetic mutations accumulate in cells, something that inevitably occurs in all organs throughout life. Then an inflammatory reaction intervenes that, if it affects cells with oncogenic mutations, can initiate the disease.
This model explains a large part of the cases of lung cancer in non-smokers. Future studies should clarify which other types of cancer start in this way. Among the first candidates, Swanton cites mesothelioma and some head and neck tumors, as well as cancers related to obesity and alcohol, since they are factors that cause inflammation.
"The research is important because it shows that there is a relationship between exposure to pollution particles and the increased risk of lung cancer. In the future, the results open the door to prevention and also to early diagnosis," he highlights. Enriqueta Felip, specialist in lung cancer at the Vall d'Hebron Institute of Oncology (VHIO) in Barcelona and president of the Spanish Society of Medical Oncology.
Prevention could be based on a diet that limits the action of interleukin-1 beta and other inflammatory molecules involved in cancer, says Swanton. Also, "if we understand these phenomena a little better, I hope that one day pharmacological prevention will be possible."
For now, the researcher defends that "leaders do everything possible to reduce air pollution [because] citizens have no choice over the air they breathe." Air pollution, recalls Swanton, "is responsible for eight million deaths a year in the world, as many as tobacco."
