Lung cancer associated with combustion particles and fine particulate matter (PM2.5) - The roles of polycyclic aromatic hydrocarbons (PAHs) and the aryl hydrocarbon receptor (AhR)

Abstract

Air pollution is the leading cause of lung cancer after tobacco smoking, contributing to 20% of all lung cancer deaths. Increased risk associated with living near trafficked roads, occupational exposure to diesel exhaust, indoor coal combustion and cigarette smoking, suggest that combustion components in ambient fine particulate matter (PM_2.5), such as polycyclic aromatic hydrocarbons (PAHs), may be central drivers of lung cancer. Activation of the aryl hydrocarbon receptor (AhR) induces expression of xenobiotic-metabolizing enzymes (XMEs) and increase PAH metabolism, formation of reactive metabolites, oxidative stress, DNA damage and mutagenesis. Lung cancer tissues from smokers and workers exposed to high combustion PM levels contain mutagenic signatures derived from PAHs. However, recent findings suggest that ambient air PM_2.5 exposure primarily induces lung cancer development through tumor promotion of cells harboring naturally acquired oncogenic mutations, thus lacking typical PAH-induced mutations. On this background, we discuss the role of AhR and PAHs in lung cancer development caused by air pollution focusing on the tumor promoting properties including metabolism, immune system, cell proliferation and survival, tumor microenvironment, cell-to-cell communication, tumor growth and metastasis. We suggest that the dichotomy in lung cancer patterns observed between smoking and outdoor air PM_2.5 represent the two ends of a dose-response continuum of combustion PM exposure, where tumor promotion in the peripheral lung appears to be the driving factor at the relatively low-dose exposures from ambient air PM_2.5, whereas genotoxicity in the central airways becomes increasingly more important at the higher combustion PM levels encountered through smoking and occupational exposure.

Keywords: Air pollution; Carcinogenesis; Diesel exhaust; Genotoxicity; Inflammation; Occupational exposure; Smoking; Tumor metastasis; Tumor microenvironment; Tumor promotion.

Fig. 1.

Overview of the main signaling pathways of AhR and the cancer-related responses regulated by these. AhR may induce effects through at least four different signaling modes. In the classical genomic pathway (1), inactive AhR resides in the cytosol bound to heat-shock protein 90 (HSP90), XAP2, and p23 proteins. Upon ligand activation, AhR translocates to the nucleus, dimerizes with its binding partner Arnt, and the AhR:Arnt dimer binds to dioxin response elements (DREs) in the regulatory region of target genes. The prototypical genes activated are the CYP1A1/−1B1 enzymes, which may metabolize PAHs into genotoxic metabolites. However, a number of genes express DRE sites and are affected by classical AhR signaling, including IL1B and other proinflammatory cytokines. AhR may also dimerize with other binding partners (X) such as NF-κB subunits through non-classical genomic signaling (2), activating alternative binding sites and regulate other genes including various immunomodulating factors. A subfraction of AhR appears to be localized in close connection interacting with caveolin-1 (Cav1) in caveolae, acting as a cytosolic signaling molecule in the so-called non-genomic pathway (3). Non-genomic AhR signaling regulates rapid activation of Ca2 + signaling from transient receptor potential (TRP) channels and intracellular stores, and Src-mediated activation of EGFR-RAS-ERK signaling which may regulate cell proliferation, cell survival, angiogenesis and immunomodulating responses. Importantly mutations in the KRAS (Ras) and EGFR genes are characteristic of lung cancers in smokers and never-smokers, respectively, underscoring the potential importance of the non-genomic pathway. Another subfraction of AhR has been localized in the inter-membrane space of mitochondria, mitochondrial AhR (4), and may regulate mitochondrial polarization, metabolic reprogramming, glycolysis and apoptosis, which is also associated with lung cancer development.

Fig. 2.. A framework for development of Adverse Outcome Pathways (AOPs) for AhR in lung cancer from air pollution and combustion PM.

The figure presents a framework for development of AOPs for the link between AhR activation in different lung cell types and development of lung cancer after exposure of low levels of combustion PM and PAHs from outdoor air (A) and high-level exposures from smoking or occupational settings (B). At low-level exposure (A), AhR activation is primarily suggested to induce lung cancer by tumor promotion, through release of proinflammatory IL-1 family cytokines and nongenomic activation of EGFR. At high-level exposure (B) AhR induced CYP1 expression with subsequent PAH metabolism, formation of genotoxic metabolites and mutations in TP53 and KRAS is believed to be a central, early key events. AhR induced tumor promotion likely also affects cancer development in the high-level exposure scenario, but the role is less clear and suppressive effects of AhR on KRAS-driven cancers have been reported. It should be noted that some of MIE like VEGF release resulting in increased angiogenesis are first of importance in the later stage of cancer development; while key events like release of immunomodulating factors, DNA damage/mutations, increased cell survival, disrupted cell-to-cell-communication are of importance during a much longer period of cancer development than indicated in the figures. Well documented connections between AhR activation as the molecular initiating event, different key events, and the adverse outcome (lung cancer) are highlighted by solid lines on green background. Dotted lines represent connections that are indicated in the literature but where more uncertainty still exists.