Mechanisms Contributing to the Comorbidity of COPD and Lung Cancer

Abstract

Lung cancer and chronic obstructive pulmonary disease (COPD) often co-occur, and individuals with COPD are at a higher risk of developing lung cancer. While the underlying mechanism for this risk is not well understood, its major contributing factors have been proposed to include genomic, immune, and microenvironment dysregulation. Here, we review the evidence and significant studies that explore the mechanisms underlying the heightened lung cancer risk in people with COPD. Genetic and epigenetic changes, as well as the aberrant expression of non-coding RNAs, predispose the lung epithelium to carcinogenesis by altering the expression of cancer- and immune-related genes. Oxidative stress generated by tobacco smoking plays a role in reducing genomic integrity, promoting epithelial-mesenchymal-transition, and generating a chronic inflammatory environment. This leads to abnormal immune responses that promote cancer development, though not all smokers develop lung cancer. Sex differences in the metabolism of tobacco smoke predispose females to developing COPD and accumulating damage from oxidative stress that poses a risk for the development of lung cancer. Dysregulation of the lung microenvironment and microbiome contributes to chronic inflammation, which is observed in COPD and known to facilitate cancer initiation in various tumor types. Further, there is a need to better characterize and identify the proportion of individuals with COPD who are at a high risk for developing lung cancer. We evaluate possible novel and individualized screening strategies, including biomarkers identified in genetic studies and exhaled breath condensate analysis. We also discuss the use of corticosteroids and statins as chemopreventive agents to prevent lung cancer. It is crucial that we optimize the current methods for the early detection and management of lung cancer and COPD in order to improve the health outcomes for a large affected population.

Keywords: COPD; epigenetics; genomic alterations; immune microenvironment; lung cancer; lung cancer screening; microbiome; pathogenesis.

Figure 1

COPD confers a greater risk for lung cancer development. (A) COPD and lung cancer are closely linked diseases that affect the lung. (B) There is a large overlap between COPD and lung cancer in smokers. While a subset of smokers develop COPD or lung cancer, a significant proportion (40–70%) of lung cancer patients have COPD. (C) COPD confers a 2-7x greater risk of developing lung cancer, independent of smoking history. Possible shared mechanisms that may contribute to this process are genetics, oxidative stress, and microenvironmental factors.

Figure 2

Shared genetic and epigenetic mechanisms in COPD and lung cancer development. (A) Single nucleotide polymorphisms (SNPs) carries increased risk for the development of both COPD and lung cancer. (B) Abnormal promoter methylation decreases the expression of certain tumor suppressor and immune genes. (C) Histone acetylation of pro-inflammatory genes in alveolar macrophages leads to increased expression of pro-inflammatory mediators.

Figure 3

Oxidative stress is a common underlying mechanism in the pathogenesis of COPD and lung cancer. (A) It is generated in the presence of inflammation, tobacco smoke, pollutants, and carcinogens. (B) Reactive oxygen species (ROS) directly causes DNA damage in lung epithelial cells. (C) ROS increases the expression of pro-inflammatory genes in a NK-kB-dependent manner. (D) Repeated cycles of tissue injury and repair occur due to damage from ROS, which involves the process of epithelial-mesenchymal transition.

Figure 4

Features of immune and microenvironment dysregulation in COPD that contribute to cancer risk. (A) A Th1 T cell polarization is characteristic of COPD. Th1 cells secrete pro-inflammatory cytokines that activate neighbouring immune cells and exacerbate the inflammatory response. (B) Macrophages and neutrophils release ROS, matrix metalloproteinases (MMPs), and neutrophil elastase (NE), which contributes to tissue injury and extracellular matrix (ECM) remodeling. (C) IL-17 secreted by Th17 T cells and chemokines released by the lung epithelium promote increased neutrophil and macrophage recruitment. (D) Dysbiosis of the lung microbiome is evident in both COPD and lung cancer and may play a role in promoting immune dysregulation.

Figure 5

Potential strategies for lung cancer screening and prevention in the COPD population. (A) Offering low-dose CT scans combined with spirometry testing to all individuals with COPD and those at high risk for COPD may improve early lung cancer detection. (B) Using genetic screening to detect SNPs and abnormal methylation patterns, or (C) analysis of biomarkers of oxidative stress and inflammation in exhaled breath condensate (EBC) may be used to determine which COPD patients are at a higher risk of lung cancer development. (D) Smoking cessation and avoidance of second-hand smoke exposure is currently the best method of cancer prevention in COPD. (E) Some chemopreventive agents, including inhaled corticosteroids (ICS) and statins, have shown limited efficacy in preventing lung cancer in COPD.