Lung Cancer in Chronic Obstructive Pulmonary Disease Patients, It Is Not Just the Cigarette Smoke

Pablo Sanchez-Salcedo; Javier J. Zulueta


Curr Opin Pulm Med. 2016;22(4):344-349. 

In This Article

Mechanisms Involved in Lung Cancer Development Among Patients With Chronic Obstructive Pulmonary Disease

Several mechanisms have been suggested to explain the link between these two diseases. These include inflammation and associated cytokines, oxidative stress, smoking, alterations in cell cycle regulation, and the presence of specific proteinases produced by immune cells and other stromal cells.[2] Genetic and epigenetic changes, including DNA methylation, and telomere shortening have also been described as potential mechanisms.[2,5–7] It is not the purpose of this review to thoroughly discuss these mechanisms, and the reader is encouraged to refer to the appropriate sources. We will discuss some of the mechanisms we believe are important.

'Oxidative stress' can be a key cause of both proliferation (lung cancer) and inflammation (COPD) in the lungs. It drives cancer initiation through DNA damage: point mutations, single and double-strand breaks, and DNA cross-linking.[7] These somatic mutations accumulate with age in part because of the continuous exposure to reactive nitrogen and oxygen species, caused by cigarette consumption.[7,8] Reactive nitrogen and oxygen species can also lead to degradation of tumor suppressors leading to decreased apoptosis and DNA repair,[9] and also stimulate the production of inflammatory mediators, alter protein structure, which at the end can inactivate histone deacetylase 2, resulting in a prolonged inflammatory status, as seen in patients with COPD.[7,10]

'Genetic susceptibility' has been well described in the development of COPD and/or lung cancer. Environmental factors, mainly tobacco, interact with multiple polymorphic genes to influence susceptibility.[5] Genetic mapping studies have also identified several single nucleotide polymorphisms that are associated with both diseases.[2] Genes, such as matrix metalloproteinase 1, cholinergic receptor, neuronal nicotinic, alpha polypeptide 3 and cholinergic receptor, neuronal nicotinic, alpha polypeptide 5, tumor protein 53, retinoblastoma 1, telomerase reverse transcriptase among others, have shown important associations between lung cancer and COPD.[2,5,7]

In addition to genetic changes, 'epigenetic changes', including DNA methylation, covalent histone modifications, microRNAs expression, and nucleosome remodeling have also been linked with COPD and lung cancer.[6,7] In a recent epigenome-wide association study, epigenetic-mediated repression of coiled-coil domain containing 37 and microtubule associated protein 1B was significantly associated with COPD and lung cancer.[11]

Telomeres are nucleoprotein complexes located at the end of chromosomes whose main job is to maintain normal chromosome structure and function, protecting chromosomes from degradation, end-to-end fusion, and atypical recombination.[12,13] 'Telomere shortening' is associated with cell aging and senescence. Several preliminary studies have described a link between short telomere length and lung cancer, as well as with COPD.[7,12,14,15] However, more recent evidence has shown the opposite. In a pooled analysis from three prospective cohort studies (the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, the Alpha-Tocoferol Beta-Carotene Cancer Prevention Trial, and the Shanghai Women's Health Study), longer telomere length was associated with increased lung cancer risk.[16] The effect of long telomere length occurred well in advance of lung cancer diagnosis (more than 6 years), suggesting that it is unlikely that the disease could influence the association, and it was particularly evident for adenocarcinoma, and especially among women.[16]