(A minor edit to this blog that should follow A Moving Picture)
You could call it ‘The Central Dogma of Cancer’ — the notion that over time cells accumulate mutations in key ‘driver’ genes and when they’ve collected enough they start to make more of themselves (proliferate) in an abnormal fashion. That’s a ‘neoplasm’ — something that could progress to spreading around the body, thereby becoming a malignant tumour. But we’ve known for many years that there’s more to cancer than that.
Back in the 18th century Percival Pott, the English surgeon and one of the founders of orthopaedics, concluded that boy chimney sweeps developed cancer as a result of soot lodging in the folds of skin. Looking back to this finding we would say it was consistent with something other than mutations being able to give cancer a helping hand. A further pointer came in a 1940s study showing that coal tar (actually the mutagens therein) gave rise to ‘dormant’ tumours in animals that could be ‘turned on’ to form growing tumours by a ‘tumour promoter’ — a chemical irritant (inflammatory agent) applied directly to the skin. From this has come the idea that environmental carcinogens can ‘promote’ dormant cells (carrying mutations) to become active tumours. We summarised these events in Don’t Read This!!, A Word From Cambridge University and on page 25 of Understanding Cancer.
These complementary ideas are illustrated in Allan Balmain’s scheme (below). The left-hand path shows environmental factors causing mutations in DNA that eventually drive malignancy. The factors include radiation, chemicals in tobacco and, the focus of this blog, particles in polluted air. Their action is shown in the right-hand path, in which immune cells are recruited — specifically macrophages — to the lung tumour environment where they release a cytokine (interleukin β: IL-1β), causing inflammation. The target is alveolar type 2 (AT2) cells that are stimulated from dormancy to become tumours. These AT2 cells carry mutated driver genes — typically in EGFR or KRAS.
Models of lung cancer development caused by air pollution. From Balmain 2023.
The term ‘environmental carcinogen’ includes the particles carried in polluted air and these have been studied by William Hill and colleagues in the latest report from the TRACERx Consortium. You may recall that we described this project in Intelligence: Of Birds, Men and Machines. TRACERx (TRAcking Cancer Evolution through therapy (Rx)) is a nine-year, multi-million pound research project run by the Institute of Cancer Research, London looking at what goes on within lung tumours (intratumour heterogeneity) and how that relates to clinical outcome. It’s also examining the impact of treatment regimens. The group recently showed that tumours with regions low in immune cells are more likely to relapse after surgery to remove tumour tissue or drug treatment (chemotherapy).
Now Hill, Charles Swanton and collaborators have turned their attention to the question of what gives rise to lung cancer in the 10% or so of cases not caused by tobacco. What they’ve shown for the first time is a molecular route by which particle pollution in air (also called particulate matter (PM)) can cause lung cancer. These particles are bits of solids (dust, soot, etc.) or liquid droplets carried in the air. Of these, the smaller particles, of diameter less than 2.5 micrometres, called PM2.5, are more dangerous because they can infiltrate deep into the lungs where they can act as an a inflammatory agent in a similar way to the chemical irritant described above.
They first did an epidemiological survey which showed that lung cancer incidence increased with levels of PM2.5 in the air. As you’d expect, the increase in risk was much higher for smokers but the key point was that PM levels also had a significant effect. An interesting corollary was that the sequences of tumour DNA from non-smokers living in polluted areas had few point mutations of the kind that can activate ‘driver’ genes. However, as expected, tumour DNA from smokers showed the distinct mutational signature caused by components of tobacco smoke. In other words exposure to irritants doesn’t cause mutations.
PM2.5 promotes lung tumourigenesis. Representative diagram of spatially segmented human EGFRL858R -positive clusters in lung lobes. Cluster size is proportional to EGFRL858R cell number at 10 weeks. EGFR is the epidermal growth factor receptor, a transmembrane signalling protein that frequently acquires a point mutation (L858R) in non‒small cell lung cancer. From Hill et al., 2023.
The authors then used a combination of lung cancer models in mice and human cells grown in 3D cultures (organoids) to show that PM2.5 does indeed act like a ‘promoter’ to turn on the growth of lung cells that already carry cancer-initiating mutations. Mutations were in the epidermal growth factor receptor (EGFR) or in the Kras gene — mutations commonly present in lung cancer. Lung cells with these mutations were promoted to rapidly growing tumours after just a few weeks of exposure to PM2.5 compared with mice lacking these mutations. But, given that these irritants don’t cause mutations, how do they promote cancer?
Seeking a mechanism, Hill and colleagues detected increased expression of the signalling protein interleukin-1β (IL-1β) during PM2.5-induced lung inflammation in mice. Moreover, an antibody that targets IL-1β reduced the incidence of lung cancer.
So the model is: sustained inflammation caused by PM2.5 signals the recruitment of immune cells — specifically macrophages — that release cytokines into the lungs. This contributes signalling molecules to the tumour microenvironment, including IL-1β, that can activate the growth of AT2 cells, those with EGFR mutations being particularly susceptible.
The message is that, as little can be done to prevent the acquisition of oncogenic mutations with age (apart, obviously, from not smoking, etc.), we need to identify environmental pollutants, including PM2.5, that have the potential to trigger the expansion of pre-existing, mutant lung cells via inflammation. You couldn’t ask for more compelling evidence to support a public health mandate to restrict particulate emissions, especially in urban areas.
References
Balmain A. Air pollution’s role in the promotion of lung cancer. Nature. 2023 Apr;616(7955):35-36. doi: 10.1038/d41586-023-00929-x. PMID: 37020001.
Hill W, Lim EL, Weeden CE, Lee C, Augustine M, Chen K, Kuan FC, Marongiu F, Evans EJ Jr, Moore DA, Rodrigues FS, Pich O, Bakker B, Cha H, Myers R, van Maldegem F, Boumelha J, Veeriah S, Rowan A, Naceur-Lombardelli C, Karasaki T, Sivakumar M, De S, Caswell DR, Nagano A, Black JRM, Martínez-Ruiz C, Ryu MH, Huff RD, Li S, Favé MJ, Magness A, Suárez-Bonnet A, Priestnall SL, Lüchtenborg M, Lavelle K, Pethick J, Hardy S, McRonald FE, Lin MH, Troccoli CI, Ghosh M, Miller YE, Merrick DT, Keith RL, Al Bakir M, Bailey C, Hill MS, Saal LH, Chen Y, George AM, Abbosh C, Kanu N, Lee SH, McGranahan N, Berg CD, Sasieni P, Houlston R, Turnbull C, Lam S, Awadalla P, Grönroos E, Downward J, Jacks T, Carlsten C, Malanchi I, Hackshaw A, Litchfield K; TRACERx Consortium; DeGregori J, Jamal-Hanjani M, Swanton C. Lung adenocarcinoma promotion by air pollutants. Nature. 2023 Apr;616(7955):159-167. doi: 10.1038/s41586-023-05874-3. Epub 2023 Apr 5. PMID: 37020004; PMCID: PMC7614604.