Lung cancer has been linked to the changes in lung function characteristic of chronic obstructive pulmonary disease (COPD) and to the changes in lung morphology seen in emphysema. It seems that a common thread of smoking-induced lung injury can be traced to all three diseases. However, the association is not as straightforward as it may seem; for example, even never-smokers with emphysema have an increased risk of lung cancer. Whether lung cancer, COPD, and emphysema are linked by common genes, mechanisms, causes, or a combination thereof, understanding the associations between them has become a priority for research regarding tobacco-related illnesses. A better delineation of the relationships between these three entities may lead to significant improvements in the effectiveness of lung cancer screening programs, and to reductions in the morbidity and mortality associated with these deadly diseases.
Mechanisms That Might Explain the Association Between Lung Cancer and Alterations in Lung Function and Morphology
Certain mechanistic aspects of the association between COPD, lung cancer, and emphysema have been touched on in the previous section, but much more is suggested by existing evidence (Table 1). Current research has unveiled multiple avenues for future investigation, centered around several hypotheses. Chief among these postulated mechanisms are: a common genetic susceptibility to all three tobacco-related diseases, DNA damage and repair, chronic inflammation, and a favorable milieu.
The obvious argument in favor of a shared genetic susceptibility linking COPD, emphysema, and lung cancer is based on the facts that only a minority of smokers develop any of these diseases while most are spared, and that susceptibility runs in families. Patients who are genetically susceptible to the development of emphysema, such as individuals with α1-antitrypsin deficiency, also have a higher risk of lung cancer, probably due to an imbalance in elastase activity. Similarly, genome-wide association studies investigating the link between obstructive airway disease and lung cancer have identified a locus on chromosome 15q25, responsible for encoding nicotinic acetylcholine receptors, as a potential culprit, although the obvious link to nicotine dependence clouds the significance of this finding.[33-36]
Shortened telomeres have also been implicated in the development of lung cancer, emphysema, and COPD[37-39] and may be associated with a worse lung cancer prognosis. Telomere length is controlled by a group of specialized enzymes known collectively as telomerase reverse transcriptases, or TERTs. A TERT gene polymorphism, rs2736100, was linked in a recent meta-analysis with the risk for lung cancer.
Vascular endothelial growth factor receptor 1 (VEGFR1), which promotes inflammation and tumor progression and is one of several promising targets for novel lung cancer treatments, has been implicated in both COPD and lung cancer. VEGFR1 is encoded by FLT1, an oncogene instrumental in the control of cell differentiation and proliferation. Not surprisingly, genetic alterations in mediators of inflammation such as interleukin (IL)-7R, IL-1α, and IL-10 have also been the focus of attention. Interestingly, cytokine alterations in lung cancer may vary by altered lung function, as well as by race, gender, and smoking history. Genetic variants of the FAM13A gene, heavily expressed in the lung, have also been implicated in the common susceptibility to both COPD and lung cancer, although the mechanism by which this family of genes is involved is uncertain, with tumor suppressor activity being the most likely.
DNA damage and repair
Further evidence linking COPD and lung cancer can be found in epigenetics, an important mediator between genetic variation and environmental exposure. DNA methylation profiles associated with smoking and COPD have been described in seemingly normal lung tissue from patients with lung cancer and may have prognostic implications. A recently published study of methylation profiles for two well-defined cohorts of COPD patients identified 349 CpG sites (regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide) significantly associated with the presence and severity of altered lung function. Several of the sites linked to COPD in that study have also been implicated in lung tumorigenesis. A subsequent epigenetic study identified 2 genes, CCDC37 and MAP1B, with methylation patterns associated with both COPD and lung cancer susceptibility. In COPD, reduced expression of CCDC37, which is expressed by bronchial epithelium, and of MAP1B, a microtubule assembly mediator, might predispose the CCDC37 and MAP1B genes to hypermethylation and ultimately to involvement in lung cancer tumorigenesis through as yet unknown mechanisms.
Finally, common messenger RNA profiles have also been studied in this regard. The similarities found between patterns in patients with COPD and lung cancer are noteworthy when compared with patterns in a control group of healthy individuals.
Chronic inflammation has been implicated in a host of human cancers. A number of inflammation-related mediators, including nuclear factor kappa B (NF-κB), oxygen and nitrogen radicals, cytokines, prostaglandins, and microRNAs, may be responsible for this well-known association. Because COPD and emphysema are also related to inflammation, it is only logical to postulate that proinflammatory mediators play a pivotal role in the link between all three tobacco-related diseases. Genetic alterations in cytokines implicated in the pathogenesis of both COPD and lung cancer have already been mentioned, but other cytokines also play a role. For example, proinflammatory IL-17 may contribute to disease progression in patients with severe COPD. In lung cancer, however, its role is confusing: mechanisms that have been proposed include protumoral cell proliferation, angiogenesis, metastasis, immune system evasion, and chemotherapy resistance.[50,51] Human non–small-cell lung cancer cells have been shown to produce type 2 cytokines, which contribute to an oncogenic stroma. IL-4, for example, has been linked to tumor growth and the appearance of metastasis in lung cancer.[52,53] While COPD has been traditionally considered a type 1 cytokine–producing disease, recent evidence suggests that protumoral type 2 inflammatory cytokines may play a crucial role as well, providing further evidence in favor of a mechanistic link between COPD and lung cancer. This is a key finding because Th1 cell infiltration is associated with a better prognosis in non–small-cell lung cancer, while infiltration by type 2 cytokines favors tumor progression.
NF-κB, a regulator of genes that control cell proliferation and cell survival, and a modifier of Th2 proinflammatory cytokines, has been implicated in the development of both lung cancer and COPD. NF-κB expression is stimulated by smoking, and has been linked to COPD pathogenesis, as well as to chronic inflammation–related carcinogenesis and muscle wasting in smokers.[57-59] It may also induce carcinogenesis by a p53-related mechanism.
Another mediator of inflammation implicated in both COPD and lung cancer is the phosphatidylinositol 3-kinase (PI3K) pathway, a key promoter of tumorigenesis, as well as tumor proliferation and survival. Interestingly, inhaled PI3K inhibitors have been developed as promising new therapies for COPD.
Aberrant expression of the epidermal growth factor receptor (EGFR) and Wnts may also be involved in a common pathway leading to both COPD and lung cancer. The EGFR signaling pathway is a key regulator of airway mucus production and secretions, a salient feature of the chronic bronchitis phenotype of COPD. A possible role for EGFR in connecting the dots between COPD and lung cancer is intriguing, since, as most clinicians know, lung cancers in smokers with COPD rarely manifest EGFR mutations amenable to tyrosine kinase inhibitor treatment. EGFR may play an indirect role, since the proinflammatory mediators that induce EGFR expression in diseased airways are most likely type 2 protumoral cytokines.
The Wnt–β-catenin pathway has been linked to both COPD and lung cancer in animal models.[65,66] Wnt–β-catenin alterations are prominent in human malignancies. Furthermore, decreased Wnt signaling is involved in parenchymal tissue destruction and impaired repair capacity in emphysema.
Finally, chronic inflammation has been indirectly linked to both COPD and lung cancer by the repair mechanisms it triggers, notably epithelial-mesenchymal transitions (EMTs).[69,70] Five major EMT regulatory genes have been identified: SNAI1, SLUG, ZEB1, ZEB2, and TWIST1. A recent study investigating the role of one of them (SNAI1) in the common origins of lung cancer and COPD found a clear association. SNAI1 has been implicated in the promotion of EMT-like changes, cell migration, and invasion. In that study of more than 7,000 persons, including patients with lung cancer, patients with COPD, and controls, an exon variant of SNAI1 was associated with a decreased risk for both lung cancer and COPD. Interestingly, the effect on lung cancer risk appeared to be mediated indirectly by COPD.
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