Molecular pathology selected abstracts

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Contribution of air pollutants to lung adenocarcinoma

Lung cancer is a leading cause of cancer death. Although traditionally associated with smoking, a large proportion of patients with lung cancer are nonsmokers, and lung cancer epidemiology, histology, and mutational profiles differ between smokers and nonsmokers. Risk factors for lung cancer include environmental exposures, radiation exposure, endocrine factors, personal history of lung disease, and family history of lung cancer. Environmental particulate matter (PM) measuring 2.5 µm (PM_2.5) or less is an established risk factor for lung cancer. However, the cellular mechanisms involved in this specific lung cancer pathogenesis are only beginning to be understood. The authors explored the association between particulate matter and lung cancer through epidemiological studies and in vivo and in vitro studies to provide a mechanistic explanation of how air pollution contributes to lung cancer. Epidemiological studies were performed using datasets of PM_2.5 air pollution from England, South Korea, and Taiwan, and these were correlated with the estimated incidence of EGFR-mutated lung carcinomas. (EGFR is the most common driver mutation in nonsmoker lung cancer.) The data showed a consistent relationship between PM_2.5 and estimated EGFR-driven lung cancer, with high PM_2.5 exposure being a significant risk factor for such cancer. To explore the biology of how particulate matter contributes to lung cancer, mouse models of lung cancer with doxycycline-inducible EGFR mutations were exposed to particulate matter or saline, and tumor growth was assessed for the cell types involved, gene expression profiles, and biomarker expression. Mice exposed to particulate matter had increased inflammatory response, increased influx of macrophages, alveolar type II epithelial cells, and tumor cell burden, as compared to control mice. The immune response was shown to be an important factor in developing particulate matter-mediated EGFR-mutated lung carcinoma, as immune-deficient mice did not develop cancer to the same extent as immune-competent mice. Mouse lung epithelial cells exposed to PM_2.5 showed different gene-expression patterns than epithelial cells from control mice exposed to only saline. Moreover, functional studies using a three-dimensional lung-organoid model showed that particulate matter exposure in the context of a genetically susceptible background (EGFR driver mutation) can reprogram cells to a lung progenitor state. Finally, the authors investigated whether driver mutations in EGFR and KRAS genes could be found in noncancerous human lung tissue, as advances in the mutational profiling of various cancers have occasionally identified low-level incidental pathogenic driver mutations in the genes of patients who were not diagnosed with cancer. Driver mutations in EGFR and KRAS were seen in 18 and 53 percent of noncancerous lung tissue samples, respectively, and a significant correlation in mutation count and age was also seen. The presence of mutations in noncancerous tissue suggests a genetically altered state susceptible to further tumorigenesis and progression. The authors provided epidemiological data that showed increased EGFR-mutant lung cancer incidences with increased PM_2.5 levels and a cellular basis for how air pollution particulate matter alters the host environment. In a genetically susceptible host (that is, one with an EGFR mutation), particulate matter-induced inflammatory changes due to increased macrophages, cytokine activity, and transcriptional alteration of alveolar epithelial cells promote clonal growth and proliferation. These studies provide support for clinically targetable treatment options and reducing air pollutants to improve public health.

Hill W, Lim EL, Weeden CE, et al. Lung adenocarcinoma promotion by air pollutants. Nature. 2023;​616:159–167.

Correspondence: Dr. Charles Swanton at charles.swanton@crick.ac.uk