A Mechanism for How Air Pollution Kills, Nature: Lung adenocarcinoma promotion by air pollutants

[NNadir]

The paper to which I'll refer briefly is this one: Hill, W., Lim, E.L., Weeden, C.E. et al. Lung adenocarcinoma promotion by air pollutants. Nature 616, 159–167 (2023).

From the introduction:

Barrier organs such as the lung are directly affected by exposure to environmental challenges. Accordingly, more than 20 environmental and occupational agents are lung carcinogens2, and exposure to these are of particular relevance in understanding lung cancer in the never-smoking population. Lung cancer in never-smokers (LCINS) is the eighth most common cause of cancer death in the UK and has distinct clinical and molecular characteristics compared with lung cancer in smokers3. LCINS frequently harbour adenocarcinomas with oncogenic EGFR mutations and are more commonly observed in female individuals and in individuals with East Asian ancestry compared with patients with Western ancestry4. Several factors have been proposed to explain the observed sex and geographical disparities of lung cancer driven by EGFR mutations, including germline genetics5, ethnicity, radon exposure, occupational carcinogen exposure and air pollution6.

Air pollution accounts for 7?million deaths per year, with 99% of people living in areas that exceed World Health Organization guidelines (less than 5??g?m–3 annually)7. Particulate matter (PM) is a key constituent of air pollution and is classified by aerodynamic size. Fine particles ?2.5??m (PM2.5) are able to travel deep into the lung and are linked to multiple adverse health effects, including heart disease and lung cancer7...

EGFR is an abbreviation for epithelial growth factor receptor, an important receptor on the surface of cells that has functional implications. The Uniprot reference is here: P00533 · EGFR_HUMAN

The next paragraphs touch on a personal concern of mine, genetic disposition to esophageal cancer. I discussed this in a tiresome tangent in a post over in the Science forum (where perhaps this post belongs, but I seem to believe that air pollution is an important environmental issue) in which I discussed a happy recent development in the understanding of the biological effects of radiation, the use of molecular biology: A systematic "omics" (molecular biology) approach to the effects of radiation on living tissue.

To wit:

Traditionally, it is thought that carcinogens cause tumours by directly inducing DNA damage. However, recent data suggest that many carcinogens do not cause a detectable DNA mutational signature in tumours following exposure8,9. Genetic analyses of oesophageal cancer showed that mutational signatures do not fully explain the varied geographical incidence of this cancer10, and efforts that have profiled tumour genomes in LCINS failed to detect a dominant carcinogenic signal of mutations deriving from exogenous sources11,12,13.

We propose that air pollutants might promote inflammatory changes in the lung tissue microenvironment that permit pre-existing mutated clones to expand, consistent with the two-stage carcinogenesis model of initiation and promotion1. To address this hypothesis, we combined epidemiological evidence with functional preclinical models and clinical cohorts to decipher potential mechanisms of air-pollution-induced lung tumour promotion and actionable targets for molecular cancer prevention (Extended Data Fig. 1a).

As my life draws to a close, I suddenly find myself thinking a great deal about the implications of inflammatory responses. I am working on a project where inflammatory responses may be involved in a particular form of Alzheimer's disease, a rather novel hypothesis that seems to have considerable merit.

In particular, I am learning to appreciate the effects of cytokines, one of which mentioned in this paper, IL-1?, which plays an important role in inflammatory responses.

In any case, the authors posit that many healthy people do in fact, harbor specific mutations in the EGFR protein that are oncogenic, and go through life without developing this specific (EGFR based) lung cancer. These mutants are relatively rare:

The model of tumour initiation and promotion is contingent on histologically normal tissue cells harbouring oncogenic driver mutations1. In 15 reported studies involving deep sequencing of human histologically normal tissues from different anatomical sites (n?=?9,380 samples from 380 patients), an oncogenic EGFRL858R mutation was only reported in a single clone from a skin microbiopsy, which indicated that these mutations are rare (Supplementary Table 6). Using digital droplet PCR (ddPCR) and duplex sequencing (Duplex-seq), we sought for evidence of EGFR-driver mutations in non-cancerous lung tissue from patients with lung cancer or with cancers of other organs and from individuals with no evidence of cancer (Extended Data Figs. 7 and 8a and Supplementary Table 7).

The paper is rather cool, but regrettably, I will not have much time to spend with it.

The basic thesis is this as I understand it: PM2.5 particles of air pollution stimulate an immune response so that macrophages are recruited into the lung tissue, releasing proinflammatory IL-1? which acts to stimulate the oncogenic cells having mutant EGFR proteins that become cancer cells. Without this stimulation, tissue having these oncogenic mutations can exist in healthy tissue without ever inducing a cancer.

It appears that certain populations, in particular people of Asian origins may have a higher frequency of these problematic mutations, which is not to say that any population should feel immune.

Just a note...

The environmental point is that air pollution kills people.

If you're Jewish: Happy Passover.