Medicine, Faculty of
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Medical Genetics, Department of
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International Journal of Molecular Sciences 24 (3): 2859 (2023)
BC Cancer Research Centre
Children's Hospital (Vancouver, B.C.). Research Institute
Forder, Aisling
Zhuang, Rebecca
Souza, Vanessa G. P.
Brockley, Liam J.
Pewarchuk, Michelle E.
Telkar, Nikita
Stewart, Greg L.
Benard, Katya
Marshall, Erin A.
Reis, Patricia P.
Lam, Wan
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.
Citation: Forder, A.; Zhuang, R.;Souza, V.G.P.; Brockley, L.J.;Pewarchuk, M.E.; Telkar, N.; Stewart,G.L.; Benard, K.; Marshall, E.A.; Reis,P.P.; et al. Mechanisms Contributingto the Comorbidity of COPD andLung Cancer. Int. J. Mol. Sci. 2023, 24,2859. https://doi.org/10.3390/ijms24032859Academic Editor: Paolo CameliReceived: 30 November 2022Revised: 18 January 2023Accepted: 22 January 2023Published: 2 February 2023Copyright: © 2023 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). International Journal of Molecular SciencesReviewMechanisms Contributing to the Comorbidity of COPD andLung CancerAisling Forder 1,2,*,†, Rebecca Zhuang 1,2,†, Vanessa G. P. Souza 1,3 , Liam J. Brockley 1,2,Michelle E. Pewarchuk 1,2, Nikita Telkar 1,2,4,5 , Greg L. Stewart 1,2, Katya Benard 1, Erin A. Marshall 1,2 ,Patricia P. Reis 3 and Wan L. Lam 1,21 British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada2 Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada3 Molecular Oncology Laboratory, Experimental Research Unit, School of Medicine,São Paulo State University (UNESP), Botucatu 18618-687, SP, Brazil4 Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada5 British Columbia Children’s Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada* Correspondence: aforder@bccrc.ca† These authors contributed equally to this work.Abstract: Lung cancer and chronic obstructive pulmonary disease (COPD) often co-occur, and indi-viduals with COPD are at a higher risk of developing lung cancer. While the underlying mechanismfor this risk is not well understood, its major contributing factors have been proposed to include ge-nomic, immune, and microenvironment dysregulation. Here, we review the evidence and significantstudies 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, predisposethe 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, promotingepithelial-mesenchymal-transition, and generating a chronic inflammatory environment. This leads toabnormal immune responses that promote cancer development, though not all smokers develop lungcancer. Sex differences in the metabolism of tobacco smoke predispose females to developing COPDand 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 areat a high risk for developing lung cancer. We evaluate possible novel and individualized screeningstrategies, 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 lungcancer. It is crucial that we optimize the current methods for the early detection and management oflung cancer and COPD in order to improve the health outcomes for a large affected population.Keywords: COPD; lung cancer; pathogenesis; microbiome; immune microenvironment; genomicalterations; epigenetics; lung cancer screening1. IntroductionLung cancer is the leading cause of cancer-related mortality worldwide and accountsfor almost 25% of all cancer fatalities. Despite recent advances in diagnosis and treatment,the five-year survival rate remains poor at 22%. Lung cancer is divided broadly into thecategories of small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), whichshow variable disease etiology, risk factors, and genomic variants associated with theonset of disease [1,2]. Largely, it has been shown that squamous cell carcinoma (SCC),a subtype of NSCLC, has a greater association with COPD (e.g., risk, decreased overallInt. J. Mol. Sci. 2023, 24, 2859. https://doi.org/10.3390/ijms24032859 https://www.mdpi.com/journal/ijmsInt. J. Mol. Sci. 2023, 24, 2859 2 of 20survival, severity), as well as an increased risk of SCLC with the presence of COPD inde-pendent of smoking status [3–7]. However, no biological link has been identified. Tobaccosmoking is a major cause of lung cancer, and other smoking-related conditions such ascardiovascular diseases and chronic obstructive pulmonary disease (COPD) often presentas comorbidities (Figure 1). In all, 40-70% of individuals with lung cancer show evidenceof airflow obstruction, indicative of COPD, which is commonly measured by the forcedexpired volume in one second (FEV1) (Figure 1B) [8]. Patients with COPD experience acontinual inflammation of the lung tissues, which has been shown to increase the riskof developing lung cancer two to seven fold, irrespective of smoking history [9–11]. Themechanisms accounting for this elevated risk are not understood; thus, deciphering suchmechanisms could yield targets for early intervention to prevent COPD-damaged airwaysfrom progressing to cancer [12]. Additionally, chronic inflammation is known to increasethe metastatic potential of cancer [13–15], and one study has linked a pathway active inCOPD to increased migration in the NSCLC cell lines [16]. There is also some evidence thatco-existing COPD can promote the metastasis of other primary tumors to the lungs [17–19].Furthermore, COPD in never-smokers was recently shown to be an independent predictorof lung cancer incidence [20]. Worsening airflow limitation is correlated with increasinglung cancer incidence, signifying that there is a linear relationship between increasingCOPD severity and cancer risk [21]. Lung cancer patients with COPD, compared to thosewithout COPD, show significantly worse clinical and surgical outcomes, indicating anurgent need for improved screening and early treatment options for lung cancer in theCOPD population. Considering the prevalence of COPD and the mortality rate of lungcancer, it is crucial to identify early intervention strategies to detect and prevent lung canceronset in this high-risk patient group. We review potential mechanisms associated with thetransition between COPD and lung cancer including genetic predisposition, epigeneticchanges, the alteration of non-coding RNAs (ncRNAs), oxidative stress-induced pathogen-esis, immune microenvironment and microbiome dysregulation, and sex differences inthe susceptibility to lung cancer and COPD [22]. We then highlight the application of thisknowledge in optimizing lung cancer screening and prevention in the context of COPD toimprove patient outcomes.Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 3 of 22 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 propor-tion (40–70%) of lung cancer patients have COPD. (C) COPD confers a 2-7x greater risk of devel-oping lung cancer, independent of smoking history. Possible shared mechanisms that may contrib-ute to this process are genetics, oxidative stress, and microenvironmental factors. 2. Genetic Mechanisms of Lung Cancer Development in Individuals with COPD Genetic alterations as well as the deregulated expression of protein-coding and non-coding RNA genes have been extensively reported for the subtypes of lung cancer [23–25]. While the genetic contribution to COPD is not fully understood [26], studies have linked the co-morbidity of lung cancer and COPD [12]. For example, two percent of COPD patients have an alpha-1 antitrypsin (A1AT) deficiency that results in unopposed proteo-lytic activity by neutrophil elastase (NE), which has been linked to increased lung cancer progression and metastasis [27,28]. Genome-wide association studies (GWAS) have also identified several genetic variants that might increase the susceptibility to developing both COPD and lung cancer (Figure 2A); however, the estimated heritability of both re-mains low [29,30]. Polygenic risk scores (PRSs) show a high association between genotype and the onset and severity of developing COPD, both in European and in non-European populations [31], with multi-ancestry PRS performing better than ancestry-specific ones [32]. Other variants include certain shared single nucleotide polymorphisms (SNPs) that also appear to increase the risk of both COPD and lung cancer development, particularly those found on chromosome 12q25 [33] and chromosome 6 [34]. Another cluster of genes, specifically the CHRNA5-CHRNA3-CHRNB4 loci on chromosome 15, encode the nicotinic Figure 1. COPD confers a greater isk for lung canc r developme t. (A) COPD and lung cancer areclosely linked diseases that affect the lung. (B) There is a large overlap between COPD and lungcancer 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 developinglung cancer, indep ndent of smoking history. Possible shared mechanisms that may contribute to thisprocess are genetics, oxidative stress, and microenvironmental factors.Int. J. Mol. Sci. 2023, 24, 2859 3 of 202. Genetic Mechanisms of Lung Cancer Development in Individuals with COPDGenetic alterations as well as the deregulated expression of protein-coding and non-coding RNA genes have been extensively reported for the subtypes of lung cancer [23–25].While the genetic contribution to COPD is not fully understood [26], studies have linked theco-morbidity of lung cancer and COPD [12]. For example, two percent of COPD patientshave an alpha-1 antitrypsin (A1AT) deficiency that results in unopposed proteolytic activityby neutrophil elastase (NE), which has been linked to increased lung cancer progressionand metastasis [27,28]. Genome-wide association studies (GWAS) have also identifiedseveral genetic variants that might increase the susceptibility to developing both COPDand lung cancer (Figure 2A); however, the estimated heritability of both remains low [29,30].Polygenic risk scores (PRSs) show a high association between genotype and the onset andseverity of developing COPD, both in European and in non-European populations [31],with multi-ancestry PRS performing better than ancestry-specific ones [32]. Other vari-ants include certain shared single nucleotide polymorphisms (SNPs) that also appear toincrease the risk of both COPD and lung cancer development, particularly those found onchromosome 12q25 [33] and chromosome 6 [34]. Another cluster of genes, specifically theCHRNA5-CHRNA3-CHRNB4 loci on chromosome 15, encode the nicotinic acetylcholinereceptor (nAChR) subunits that are expressed on lung epithelial cells, and variants in thisregion have been associated with a heightened COPD and lung cancer risk [35]. A recentprospective cohort study found that the CHRNA5 AA genotype variant was independentlyassociated not only with an increased risk of developing COPD and lung cancer, but alsowith increased smoking exposure, referred to as the ‘triple whammy effect’ [36]. Telomereshortening has also been linked to lung cancer subtypes and COPD [37], with the rs2736100variant of the telomerase reverse transcriptase (TERT) having been shown to be associ-ated with an increased risk of COPD [38]. The rs560191 allele variant of tumor proteinp53-binding protein 1 (TP53BP1) may increase the lung cancer risk depending on whichpolymorphism of the TERT allele is present, indicating a potential combinatorial effect [39].Other SNPs that have been linked to COPD and lung cancer susceptibility include thosefound in IREB2, FAM13A, and HHIP [40,41]; however, the majority of these seem to onlyconfer a small additive magnitude of effect. These shared genes imply shared pathways,and early interventions at the onset of COPD could depress the progression of COPDtowards lung cancer.Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 4 of 22 acetylcholine receptor (nAChR) subunits that are expressed on lung epithelial cells, and variants in this region have been associated with a heightened COPD and lung cancer risk [35]. A recent prospective cohort tudy found that the CHRNA5 AA genotype variant was independently associated not only with an increased risk of developing COPD and lung cancer, but also with increased smoking exposure, referred to as the ‘triple whammy ef-fect’ [36]. Telomere shortening has also been linked to lung cancer subtypes and COPD [37], with the rs2736100 variant of the telomerase reverse transcriptase (TERT) having been shown to be associated with an increased risk of COPD [38]. The rs560191 allele var-iant of tumor protein p53-binding protein 1 (TP53BP1) may increase the lung cancer risk depending on which polymorphism of the TERT allele is present, indicating a potential combinatorial effect [39]. Other SNPs that have been linked to COPD and lung cancer susceptibility include those found in IREB2, FAM13A, and HHIP [40,41]; however, the majority of these seem to only confer a small additive magnitude of effect. These shared genes imply shared pathways, and early interventions at the onset of COPD could depress the progression of COPD towards lung cancer. 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 mac-rophages leads to increased expression of pro-inflammatory mediators. 3. Epigenetic Mechanisms of Lung Cancer Development in Individuals with COPD Epigenetic mechanisms have also linked COPD and lung cancer development, and specific patterns of DNA methylation have been identified in both COPD and lung cancer patients. Genome-wide alterations in the methylation status of genes can be induced by tobacco smoking and may affect genes involved in cell-cycle regulation, airway remodel-ling, and wound healing, to name a few [42,43]. These abnormal patterns of promoter Figure 2. Shared genetic and epigenetic echanisms in COPD and lung cancer development.(A) Single nucleotide polymorphisms (SNPs) carries increased risk for the development of bothCOPD and l ng cancer. (B) Abnormal promoter methylation decr ases the expression of certaintumor suppressor and immune genes. (C) Histone acetylation of pro-inflammatory genes in alveolarmacrophages leads to increased expression of pro-inflammatory mediators.Int. J. Mol. Sci. 2023, 24, 2859 4 of 203. Epigenetic Mechanisms of Lung Cancer Development in Individuals with COPDEpigenetic mechanisms have also linked COPD and lung cancer development, andspecific patterns of DNA methylation have been identified in both COPD and lung cancerpatients. Genome-wide alterations in the methylation status of genes can be induced bytobacco smoking and may affect genes involved in cell-cycle regulation, airway remod-elling, and wound healing, to name a few [42,43]. These abnormal patterns of promotermethylation in COPD can also alter the expression of tumor suppressor or immune genesto promote carcinogenesis (Figure 2B), with global hypomethylation observed in wholeblood samples and modulated levels found in sputum samples by cell type [44,45]. Hy-permethylation leading to decreased expression levels of CDKN2A, MGMT, CCDC37, andMAP1B genes have been found in individuals with both COPD and lung cancer [46,47].Interestingly, the increased levels of methylation found in IL-12Rb2 and Wif-1 genes inCOPD patients were reported to contribute to COPD-related lung cancer [48]. Furthermore,a hypermethylation and underexpression of the tumour suppressor gene PTEN was seenin COPD patients [30]. PTEN is commonly found to be mutated in cancers, especially insmokers. If COPD patients have changes in the methylation status of tumour suppressorgenes that lead to their decreased expression, and subsequently acquire mutations in suchgenes, or vice versa, this could lead to the biallelic inactivation of these genes and thuspromote lung tumorigenesis.Hypomethylated cytosine-phosphate-guanine (CpG) sites within certain genes havebeen significantly associated with the presence and severity of COPD [49]. Gene ontologyanalysis based on these CpGs has identified several genes, especially in the gene coding foralpha1-antitrypsin (SERPINA1), involved in immune and inflammatory system pathwayswhich may further contribute to tumor proliferation, migration, and invasion, whereSERPINA1 hypomethylation has been linked to COPD and decreased lung function [49]. Arecent study reported that, in male patients with COPD, higher levels of serum SERPINA1methylation are associated with the development of lung cancer [50]. It has also beendemonstrated that IL-1β, an important inflammatory biomarker of COPD previouslyassociated with lung cancer, is positively correlated with the SERPINA1 methylationlevels. Interactions between SERPINA1 and IL-1β and their role in disease is not yet fullyunderstood. Aberrant DNA methylation has been recently reviewed in lung cancer [51],but it may also present therapeutically targetable drivers and biomarkers of lung cancer inpatients with COPD.The dysregulation of histone modifications can also contribute to COPD and lung can-cer development through the modification of pro-inflammatory gene expression (Figure 2C).In alveolar macrophages, the inflammation-induced histone acetylation of IL-8, IL-1b, IL-6,GM-CSF, and MIP-2 genes results in an elevated expression of these inflammatory medi-ators [52]. Increased histone acetyltransferase (HAT) and decreased histone deacetylase(HDAC) activity are also characteristic, contributing to an inflammatory environment thatpromotes cancer growth. Furthermore, as environmental influences affect the onset ofCOPD substantially, the epigenetic profiles of susceptible people might be prone to changedynamically over time.4. Alterations of Non-coding RNAs in COPD and Lung CancerNon-coding RNAs (ncRNAs) are a heterogeneous class of RNAs that are not translatedinto proteins and are involved in a wide variety of biological functions, including the regu-lation of gene expression, RNA processing, and translation [53]. They are divided into twobroad categories: small ncRNAs (sncRNAs; <200 nucleotides) and long ncRNAs (lncRNAs;>200 nucleotides) [54,55]. There are also multiple classes of small ncRNAs, including mi-croRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), small interfering RNAs (siRNAs),and small nucleolar RNAs (snoRNAs). NcRNAs have also been frequently implicated incancer and appear to show specific patterns of expression in COPD compared to non-COPDpatients. Some of these ncRNAs have also been previously linked to lung cancer.Int. J. Mol. Sci. 2023, 24, 2859 5 of 204.1. MicroRNAsCurrently, the majority of the studies on the role of ncRNAs in both COPD and lungcancer has focused on miRNAs. The dysregulated expression of miRNAs in COPD patientscontributes to known important mechanisms in the pathogenesis of lung cancer, such as air-way inflammation [56], angiogenesis [57], immune response [58], autophagy [59], oxidativestress [60], and cellular senescence [61], suggesting that miRNA alterations may precedethe development of lung cancer. From a clinical perspective, circulating miRNAs in theserum have shown promise as clinical markers for lung inflammatory disease and responseto treatment [62]. In COPD, miR-218-5p has been previously reported to be downregulatedin biopsies from patients with COPD and smokers, potentially indicating a protective rolein the pathogenesis of COPD and spurring an ongoing clinical trial evaluating circulatingmiRNAs in smokers and non-smokers with COPD [63,64]. In addition, several studieshave confirmed that alterations in the miRNA expression levels could increase the risk ofdeveloping cancer in COPD patients. For example, the downregulation of cancer-associatedmiRNAs, such as miR-548D-5p, miR-4695-3p, miR-517a-3p, miR-320E, miR-548ay-5p, miR-320c, and miR-519D-3p, was observed in COPD patients, and suppression of these miRNAwas associated with an increased lung cancer risk [65]. Another study evaluating bron-choalveolar lavage samples showed the miRNAs (miR-15b, miR-425, and miR-486-3p)commonly expressed by patients with COPD and those with adenocarcinoma, as well asby those with both COPD and adenocarcinoma [66]. An investigation by Fathinavid et al.observed four miRNAs (miR-15b, miR-106a, miR-17, miR-103, and miR-107) involved incommon pathways in both COPD and lung cancer [67]. According to pathway analyses,these miRNAs might be involved in the VEGF signaling, ERBB signaling, WNT signaling,and TGF beta signaling pathways; however, further validation via in vitro experiments willbe required [67]. Similarly, the comparison of the miRNA expression profiles of lung sam-ples from lung cancer patients with and without COPD identified four miRNAs (miR-21,miR-200b, miR-210, miR-let7c) that demonstrated greater expression in lung cancer patientswith COPD than in those without. Furthermore, these miRNAs appeared to regulate targetgenes related to lung carcinogenesis [68]. Several studies have shown that miR-21 is anoncogenic miRNA (oncomiR) involved in the growth, metastasis, and apoptosis of NSCLCcells through its control of various target molecules and signaling pathways [69–72]. InCOPD, an increase in miR-21 expression in airway epithelium and lung macrophagesis implicated in airway inflammation and fibrosis, and reduces lung function [73]. Onerecently reported method of modulating miRNA expression is the ketogenic diet, whichwas shown to normalize the levels of miRNAs controlling the metabolic network in obesity,showcasing the therapeutic potential of miRNAs in inflammatory disease [74]. Overall,this seems to indicate a potential role for miRNAs as biomarkers for COPD-associatedlung cancer. Additionally, it would be rational to explore whether the turnover of specificmiRNAs may be a new therapeutic strategy for these patients.4.2. Long Non-Coding RNAsStudies have also revealed an association between lncRNAs and the susceptibilityto both COPD and lung cancer [75,76]. Evidence shows that Metastasis-associated lungadenocarcinoma transcript 1 (MALAT1, also called nuclear enriched abundant transcript 2or NEAT2), an lncRNA highly abundant in lung tissues, is implicated in the pathogenesisof chronic lung diseases, including both COPD and lung cancer [76]. There is evidencethat, in NSCLC patients, MALAT1 can accelerate proliferation, migration, and invasion andimpede apoptosis through regulating the miR-185-5p/MDM4 axis, while promoting cellcarcinogenesis via the miR-515-5p/EEF2 axis [77,78]. In COPD, a high MALAT1 expressionmediated by a hypomethylated promoter elevates cyclooxygenase 2 (COX2) expressionvia inhibiting miR-146a, which can affect the pulmonary functions in COPD patients [79].Another investigation demonstrated that a high expression of MALAT1 can be used topredict the disease progression and acute exacerbation risk in COPD patients [80]. MALAT1has a well-established role in lung cancer progression and carcinogenesis [77,78,81], butInt. J. Mol. Sci. 2023, 24, 2859 6 of 20further research will be required to uncover common links between its mechanisms ofaction in COPD and lung cancer.The lncRNAs NNT Antisense RNA 1 (NNT-AS1) and growth arrest-specific 5 (GAS5)can also contribute to the increased risk for lung cancer in COPD patients. In comparisonwith NSCLC patients without COPD, the level of NNT-AS1 expression was enhanced inlung tissues from patients with COPD [82]. In vitro, NNT-AS1 promotes proliferation,apoptosis, inflammation, and airway remodeling by regulating the expression of the targetgene FBXO11 via sponging miR-582-5p [82]. In COPD, GAS5 promotes pyroptosis (awell-documented process in cancer [83]) by functioning as competing endogenous RNAsto regulate the miR-223-3p/NLRP3 axis [84].4.3. Small Nucleolar RNAsAlthough emerging evidence has also demonstrated that snoRNAs are essential factorsin lung cancer onset and dissemination, their roles in lung cancer susceptibility in COPDpatients remain unknown [85]. For instance, SNORD66 (Small Nucleolar RNA, C/D Box 66)were found at elevated levels in plasma samples in both COPD and NSCLC patients whencompared with healthy individuals [86]. The area under the receiver operating curve (AUC)for this snoRNA was 0.81 (lung cancer patients versus healthy controls) and 0.79 (lungcancer patients versus COPD patients), suggesting that snoRNAs provide potential markersfor differentiating between lung cancer and COPD. Further studies will be required todetermine the role of lncRNAs and snoRNAs in lung cancer susceptibility in COPD patientsto evaluate their contribution to pathogenesis and potential for use as biomarkers for lungcancer in the COPD population.5. Oxidative Stress Contributes to Pathogenesis in COPD and Lung CancerOxidative stress is a major mechanism underlying the pathogenesis of COPD andlung cancer, and it occurs when an exposure to reactive oxygen species (ROS) overwhelmsthe host’s antioxidant defenses. ROS are generated by tobacco smoke, a risk factor forboth diseases, but can also be produced by exposure to other pollutants and carcinogens(Figure 3). ROS and reactive nitrogen species (RNS) are both generated in the presenceof airway inflammation. Free radicals from ROS and RNS can oxidize and damage DNAand can post-translationally modify DNA repair proteins [87]. This is evident in the lungsof COPD patients, which have increased oxidative DNA damage and impaired DNArepair mechanisms compared to non-COPD smokers and non-smokers (Figure 3A) [88,89],resulting in an increased number of double strand breaks at abasic sites and a reducedexpression of DNA repair enzymes. ROS and RNS can also activate signaling moleculessuch as HIF1, the master regulator of angiogenesis and an important factor for tumourprogression [90]. Additionally, the by-products of ROS and inflammation have beenshown to inactivate PTEN, a commonly-altered tumour suppressor gene in lung cancer,through the formation of an intramolecular disulfide bond [91,92]. DNA damage, combinedwith impaired DNA repair mechanisms in COPD, can predispose lung epithelial cells toacquiring somatic mutations and progressing to malignancy.ROS also contributes to the cycle of inflammation, immune response, and oxida-tive stress by activating NF-kB, a transcription factor that promotes cellular prolifera-tion, suppresses apoptosis, and activates the epithelial-mesenchymal transition (EMT;Figure 3B) [93,94]. The lung epithelium of COPD patients and smokers has upregulatedmesenchymal markers, such as α-SMA, vimentin, and collagen type 1, and downregulatedepithelial markers (e.g., ZO-1, E-cadherin) compared to that of non-COPD non-smokers,likely due to cell turnover from repeated cycles of tissue injury and repair due to inflam-mation and oxidative stress (Figure 3C) [95,96]. Moreover, tobacco smoke extract loweredthe levels of zonula occludens-1 (ZO-1), an epithelial marker involved in tight junctionstructure, both in a normal lung cell line and in the airways of mice [97]. However, in situanalysis did not detect ZO-1 downregulation in the lung tissue of smokers [96]. This reduc-tion in epithelial attributes seen with airway repair can impair epithelial barrier function,Int. J. Mol. Sci. 2023, 24, 2859 7 of 20and has been correlated with subepithelial fibrosis and airway obstruction, key characteris-tics of COPD pathogenesis [96]. This also has implications for cancer, as increased airwaypermeability and EMT can promote the local invasion of cancer cells and thus the distantmetastasis of cancer cells through the blood vessels. Therefore, the presence of COPD couldpotentially contribute to carcinogenesis and worse outcomes in lung cancer. Collectively,the effects of oxidative stress can induce multiple pre-malignant fields of injury in therespiratory system that are at a higher risk of cancer formation.Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 8 of 22 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 pro-cess of epithelial-mesenchymal transition. ROS also contributes to the cycle of inflammation, immune response, and oxidative stress by activating NF-kB, a transcription factor that promotes cellular proliferation, sup-presses apoptosis, and activates the epithelial-mesenchymal transition (EMT; Figure 3B) [93,94]. The lung epithelium of COPD patients and smokers has upregulated mesenchy-mal markers, such as 𝛼-SMA, vimentin, and collagen type 1, and downregulated epithelial markers (e.g., ZO-1, E-cadherin) compared to that of non-COPD non-smokers, likely due to cell turnover from repeated cycles of tissue injury and repair due to inflammation and oxidative stress (Figure 3C) [95,96]. Moreover, tobacco smoke extract lowered the levels of zonula occludens-1 (ZO-1), an epithelial marker involved in tight junction structure, both in a normal lung cell line and in the airways of mice [97]. However, in situ analysis did not detect ZO-1 downregulation in the lung tissue of smokers [96]. This reduction in epithelial attributes seen with airway repair can impair epithelial barrier function, and has been correlated with subepithelial fibrosis and airway obstruction, key characteristics of COPD pathogenesis [96]. This also has implications for cancer, as increased airway per-meability and EMT can promote the local invasion of cancer cells and thus the distant metastasis of cancer cells through the blood vessels. Therefore, the presence of COPD could potentially contribute to carcinogenesis and worse outcomes in lung cancer. Collec-tively, the effects of oxidative stress can induce multiple pre-malignant fields of injury in the respiratory system that are at a higher risk of cancer formation. 6. Lung Immune Microenvironment Dysregulation Contributes to Both COPD and Lung Cancer Progression Figure 3. Oxidative stress is a common underlying mechanism in the pathogenesis of COPD andlung cancer. (A) It is generated in the presence of inflammation, tobacco smoke, pollutants, andcarcinogens. (B) Reactive oxygen species (ROS) directly causes DNA damage in lung epithelialcells. (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 theprocess of epithelial-mesenchymal transition.6. Lung Immune Microenvironment Dysregulation Contributes to Both COPD andLung Cancer ProgressionThe lung immune microenvironment has been well-researched in the field of COPDand lung cancer, and its dysregulation is known to play a role in the formation of atumour-promoting niche [98,99]. In COPD, the immune microenvironment encompassesthe states of both c ronic airway inflammation and emphysema, and the progression ofboth phenotypes has been linked to inhaled irrit nts, oxidative stress, and immune c llderegulation. Chronic inflammation has been established as a significant risk factor forthe development of various cancer types. Individuals with COPD have a higher degreeof airway and systemic inflammation compared to healthy individuals, and studies haveshown that this inflammation persists even after the cessation of smoking [100]. Chronicinflammation is common between COPD and lung cancer, and alterations of inflammatoryInt. J. Mol. Sci. 2023, 24, 2859 8 of 20mediators and of immune cell composition may play a major role in pathogenesis [101,102].The increased infiltration of neutrophils, alveolar macrophages, CD4+ and CD8+ T cells,and B cells is also associated with the severity and stage of COPD. Inflammation in COPD ischaracterized by a Th1 T cell phenotype, which can initiate or exacerbate lung inflammationby secreting IFNγ, IL-2, and TNFα (Figure 4A). Neutrophils and alveolar macrophagesare potent sources of oxidative stress and have various functions that can contribute to anincreased risk of lung cancer (Figure 4B).Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 9 of 22 The lung immune microenvironment has been well-researched in the field of COPD and lung cancer, and its dysregulation is known to play a role in the formation of a tu-mour-promoting niche [98,99]. In COPD, the immune microenvironment encompasses the states of both chronic airway inflammation and emphysema, and the progression of both phenotypes has been linked to inhaled irritants, oxidative stress, and immune cell deregulation. Chronic inflammation has been established as a significant risk factor for the development of various cancer types. Individuals with COPD have a higher degree of airway and systemic inflammation compared to healthy individuals, and studies have shown that this inflammation persists even after the cessation of smoking [100]. Chronic inflammation is common between COPD and lung cancer, and alterations of inflamma-tory mediators and of immune cell composition may play a major role in pathogenesis [101,102]. The increased infiltration of neutrophils, alveolar macrophages, CD4+ and CD8+ T cells, and B cells is also associated with the severity and stage of COPD. Inflam-mation in COPD is ch racterized by a Th1 T cell phenotype, which can initiate or exacer-bate lung inflammation by secre ing IFN𝛾, IL-2, and TNF𝛼 (Figure 4A). Neutrophils and alveolar macrophages are potent sources of oxidative stress and have various functions that can contribute to an increased risk of lung cancer (Figure 4B). Figure 4. Features of immune and microenvironment dysregulation in COPD that contribute to can-cer 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 Figure 4. Features of immune and microenvironment dysregulation in COPD that contribute tocancer risk. (A) A Th1 T cell polarization is characteristic of COPD. Th1 cells secrete pro-inflammatorycytokines that activate neighbouring immune cells and exacerbate the inflammatory response.(B) Macrophages and neutrophils release ROS, matrix metalloproteinases (MMPs), and neutrophilelastase (NE), which contributes to tissue injury and extracellular matrix (ECM) remodeling. (C) IL-17secreted by Th17 T cells and chemokines released by the lung epithelium promote increased neu-trophil and macrophage recruitment. (D) Dysbiosis of the lung microbiome is evident in both COPDand lung cancer and may play a role in promoting immune dysregulation.Int. J. Mol. Sci. 2023, 24, 2859 9 of 20Neutrophilic inflammation in COPD is associated with increased disease severityand exacerbations, and, in lung cancer, a high neutrophil to lymphocyte ratio (NLR) isassociated with poor prognosis and survival [103]. Both neutrophils and macrophages cancontribute to exacerbating emphysema in COPD, and they also support cancer growth andmetastasis by secreting NE and other metalloproteinases (MMPs). In particular, MMP-1and MMP-9 have both been linked to the development of emphysema and lung cancer.Higher amounts of IL-17A, primarily secreted by Th17 cells, are also found in individualswith COPD, compared to healthy smokers and non-smokers (Figure 4C) [104]. IL-17A isinvolved in the recruitment of neutrophils and macrophages to the lung, and increasedamounts are associated with COPD severity. Chronic NF-kB signalling may also provide animmunosuppressive tumor microenvironment in the lung favourable for the developmentof both COPD and lung cancer [105]. Further contributing to the oncogenic potential ofchronic inflammation is the fact that inflammation recruits myeloid-derived suppressorcells (MDSCs), which down-regulate immune surveillance and antitumor immunity, thus fa-cilitating tumor growth [106]. Overall, having COPD results in changes to the immune cellsthat infiltrate the lung, and their presence can alter components of the microenvironment,such as the ECM, and recruit more immune cells that are able to create a tumour-promotingmicroenvironment.7. The Lung Microbiome in COPD and Lung CancerAlthough once thought to be sterile, the airways of the lungs are now known to host adistinctive microbiome. The contribution of microbes to the microenvironment in diseasecontexts is significant; microbial dysbiosis has been implicated in cancer initiation throughthe promotion of inflammation and the generation of ROS, and by signalling epithelial cellsdirectly to activate oncogenes (Figure 4D) [107]. While normal lungs are hosts to a healthymicrobiome, there is evidence to suggest links between an abnormal lung microbiomecomposition, COPD, and the inception of lung cancer.Significant differences have been found between the microbial communities of healthyand diseased airways in COPD and lung cancer. Alpha diversity (the number of taxaand the evenness of their distribution in samples) tends to be higher in normal lung tis-sue than in lung cancer tissue [108]. The bacterial composition of diseased lungs canshift from the phylum Bacteroidetes towards the class Gammaproteobacteria, many mem-bers of which are gram-negative pathogens [109]. Comparing patients with COPD, lungcancer, or both, the proportion of gram-negative bacteria has been found to be signifi-cantly higher in those with both diseases [110]. One study found that patients with severeCOPD have larger populations of species from the Lactobacillus genus than those withless severe or absent COPD [111], and another study found that a high Lactobacillus pop-ulation was a good predictor of lung cancer [112]. Other studies have found increasesin the genera Veillonella, Streptococcus, and Granulicatella, the latter of which particularlyincreased in late-stage cancer [113,114]. Bacteria of the genus Acidovorax were found tobe abundant in the lung tissue of smokers with squamous cell carcinoma and TP53 muta-tions [115]. A meta-analysis has described a significant association between tuberculosisand the onset of lung adenocarcinoma, independent of smoking history, environmen-tal smoke exposure, or time of tuberculosis diagnosis [116]. These distinctive micro-biome compositional changes suggest that bacteria are sensitive to microenvironmentalchanges in the lung, which may be common between COPD and lung cancer and may eveninfluence them.Changes in the microenvironment of the airways during disease progression couldallow pathogenic microbiota to overtake commensal species. These pathogenic speciesmay in turn exacerbate conditions that are conducive to their survival. Dysbiosis, or thepathological imbalance of bacterial species, is thought to increase the amount of DNAdamage-associated ROS in the lungs [108]. The by-products of inflammation may pro-vide some Gammaproteobacteria with terminal electron acceptors for anaerobic respira-tion, allowing them to outcompete fermenting bacteria [109]. Some GammaproteobacteriaInt. J. Mol. Sci. 2023, 24, 2859 10 of 20also produce inflammation-promoting molecules, which could create a positive feedbackloop allowing them to thrive. Proportionally abundant species found in the lungs ofpatients with COPD and lung cancer were associated with oxidative stress, amino acidmetabolism, and glycolipid metabolism, which could influence cancer development [110].Bacterial metabolic by-products, such as acetaldehyde and deoxycholic acid, are notedcarcinogens [108]. Bacteria can also activate toll-like receptors (TLRs), which drive thecellular pathways associated with proliferation and survival. Tuberculosis is known toincrease TNF-α expression, which promotes inflammation and can thereby cause geneticdamage [108].There are limitations to the studies of COPD and lung cancer-associated microbiota,which include different sample collection methods between studies, a sampling bias to-wards those with lung disease, and the inherent difficulty in determining whether popu-lation shifts at a diseased site are opportunistic or causative [108,113,117]. However, theutility of the microbiome as a marker of disease is an attractive strategy and is currentlybeing explored. In fact, a recent study proposed that a classifier based on the lung mi-crobiome profile could be used to detect lung cancer in its early stages [112]. While theexact pathogenic role of bacteria in the airways has not yet been fully elucidated, there arecompositional changes in the tissue-resident microbiome which can be used to indicate thepresence of lung disease, and potentially to predict cancer development [112].8. Sex Differences in COPD and Lung Cancer RiskFemale sex is a known risk factor for the development of COPD in smokers; however,sex differences in lung cancer risk are controversial, and sex differences in non-smokersfor both COPD and lung cancer risks are topics for further research. It has been shownin large epidemiological studies that women who smoke are 50% more likely to developCOPD than men [118] and are two to three times more likely to die of COPD than menfor any given pack-year of smoking [119]. It has also been widely reported that womenare more susceptible to the harmful effects of smoking and are at a greater risk of devel-oping COPD [120]. One explanation is that the smaller lung size in women means thedamage caused by oxidative stress is more pronounced than in men with a comparablesmoking history [120]. Another is sex differences in tobacco metabolism: women havean increased activity of certain cytochrome P450 enzymes in the liver, such as CYP1A1and CYP1B1, which activate certain components of tobacco smoke to produce ROS [121].This increased CYP expression in females is due in part to the action of estrogen in in-ducing CYP enzyme-related pathways [122]. For example, a study of smokers with lungcancer demonstrated an increased expression of CYP1A1 in females and a correspondingincrease in DNA adducts even in non-tumor lung tissue [123]. Additionally, work per-formed in animal studies demonstrated that the injection of naphthalene (a component oftobacco smoke) into female mice caused greater airway injury, spurred by an increasedCYP enzyme expression and the production of a metabolites that initiated a more extremeinflammatory reaction in the airways and generated more ROS than in males [124]. Innon-smokers, indoor and outdoor air pollution exposure is also a significant risk factorfor the development COPD in women, who are more commonly exposed to biomasssmoke [125,126].The evidence that female smokers are at a higher risk for developing lung cancerrelative to male smokers has been inconclusive. On one hand, increased susceptibility tothe harmful effects of smoking via the increased expression of cytochrome P450s, mediatedpartially through estrogen signalling, has been reported [127], and early case-control studiesdemonstrated an increased risk of developing lung cancer in female smokers comparedto in males [128]. Epidemiological studies also found an increased odds ratio for thedevelopment of lung cancer in female smokers relative to male smokers [129,130]. Incontrast, it has also been reported that there is no difference in the risk of lung canceronce smoking history is accounted for [131], or that there is a potential slight increasein risk in male smokers compared to female smokers [132]. A general trend in the lastInt. J. Mol. Sci. 2023, 24, 2859 11 of 2050 years is that women have shown an increased risk of cancer relative to men, but thishas been attributed to rising rates of adenocarcinoma in younger women and in never-smokers [133]. Risk factors other than smoking that may be unique for women includeexogenous factors such as exposure to radiation from the treatment of prior cancers, such asbreast cancer, and biomass exposure from indoor cooking fumes, and endogenous factorssuch as exposure to hormone replacement therapy and the previously discussed increasein CYP450 enzyme expression, leading to increased ROS production [134]. Furthermore,for the same decrease in FEV1, female smokers are twice as likely to develop lung canceras men are [21], reinforcing a role for lung disease like COPD in the pathogenesis oflung cancer.There is evidence of an increased risk of COPD in female smokers, but an increasedrisk of lung cancer in this population has not been proven, despite the known mechanismsof female-specific increased DNA damage from tobacco smoke. The factors accounting forthe rise in lung cancer rates in younger females and never-smokers, including potentialassociations with COPD, have the potential to better inform screening guidelines forthese populations.9. Implications for Lung Cancer Screening and PreventionThe 2013 guidelines from the United States Preventive Services Taskforce (USPSTF)recommends annual lung cancer screening with low-dose computed tomography (CT)for adults 55–80 years old with a 30 pack-year history. However, several studies haveshown that these guidelines lack sensitivity and specificity. Approximately 60% of in-dividuals with lung cancer do not meet the screening criteria, and 96% of the nodulesidentified were false positives [135]. Females and non-smokers are particularly under-represented, and risk factors other than smoking history are not accounted for—50–80%of women diagnosed with lung cancer do not meet the USPSTF screening criteria [134].Although the USPSTF guidelines were updated in 2021 to expand eligibility since thesestatistics were published, lowering the minimum age to 50 and the pack-year history to20 [136], a substantial and rising proportion of the young female population will con-tinue to be excluded. Therefore, there is a need to better identify unique risk factors forunderdiagnosed populations in screening paradigms beyond simple age and smokingstatus. For example, COPD is vastly underdiagnosed in the population, and includingspirometry testing during lung cancer screenings may lead to the earlier detection ofundiagnosed COPD, thus expanding the window for intervention to prevent cancer devel-opment (Figure 5A). As up to 70% of individuals with lung cancer have COPD, offeringscreening to current and former smokers with COPD regardless of age or pack-years cantheoretically increase early lung cancer detection, but this is limited by the potential forover-diagnosis. Alternative methods to CT scans using biomarker identification may beused to screen for lung cancer in the future. Genetic tools, including the identification ofmethylation signatures and GWAS, have been used to assess the risk of lung cancer withmeasured success (Figure 5B) [137]. For instance, the hypermethylation of Prostaglandin EReceptor 4 (PTGER4) in the plasma was shown to distinguish patients with lung cancerfrom those with COPD or benign lung lesions [138]. Further, markers associated withoxidative stress and inflammation can be measured in exhaled breath condensate (EBC),and certain biomarkers have already been characterized for both COPD and lung cancer(Figure 5C) [139]. Another application for biomarkers is in prognosticating: for example, asignature of five genes was discovered that is overexpressed in lung cancer with comorbidCOPD and can be used to predict the survival of the lung cancer–COPD population [140].Stratifying patients using prognostic biomarkers may facilitate clinical decisions to improvepatient outcomes.Int. J. Mol. Sci. 2023, 24, 2859 12 of 20Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 13 of 22 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 pa-tients are at a higher risk of lung cancer development. (D) Smoking cessation and avoidance of sec-ond-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. Currently, the most well-established ways of preventing lung cancer in patients with COPD are smoking cessation and limiting exposure to second-hand smoke (Figure 5D). Some chemopreventive agents including inhaled corticosteroids (ICS), which are 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 andthose at high risk for COPD may improve early lung cancer detection. (B) Using genetic screening todetect SNPs and abnormal methylation patterns, or (C) analysis of biomarkers of oxidative stressand inflammation in exhaled breath condensate (EBC) may be used to determine which COPDpatients are at a higher risk of lung canc r development. (D) Smoki g ce sation and avoidance ofsecond-hand smoke exposure is currently the best method of cancer prevention in COPD. (E) Somechemopreventive agents, including inhaled corticosteroids (ICS) and statins, have shown limitedefficacy in preventing lung cancer in COPD.Currently, the most well-established ways of preventing lung cancer in patients withCOPD are smoking cessation and limiting exposure to second-hand smoke (Figure 5D).Some chemopreventive agents including inhaled corticosteroids (ICS), which are commonlyprescribed to COPD patients, and statins have been associated with reduced inflamma-tion and thus with a decreased cancer risk (Figure 5E). However, the evidence for theireffectiveness in lung cancer prevention is controversial, as several observational studieshave demonstrated a dose-dependent reduction in lung cancer risk with ICS or statinInt. J. Mol. Sci. 2023, 24, 2859 13 of 20use [141,142], while systematic reviews and meta-analyses found no significant bene-fit [143,144]. Statins have also been considered as a treatment for lung cancer, but, despitemultiple suggested mechanisms of action, the clinical evidence of efficacy is lacking [145].The inhibition of interleukin 1β, a mediator of chronic inflammation in the tumour mi-croenvironment that has been indirectly associated with COPD, with canakinumab inpatients with atherosclerosis was incidentally demonstrated in a randomized controlledtrial to reduce lung cancer incidence and mortality compared to placebo [146,147]. Thoughcanakinumab reduced lung cancer incidence, it had no effect on COPD incidence, sug-gesting a more prevalent role for interleukin 1β in the progression of lung cancer thanin COPD and highlighting the importance of studying the differences between COPD vs.non-COPD-related lung cancer. A recent retrospective cohort study reported that low-doseaspirin exposure in patients with COPD reduced the risk of lung cancer development by25%, although aspirin use was accompanied by an increased risk of the bleeding disorderhemoptysis [148]. A previous meta-analysis reported no association between lung can-cer risk and aspirin use [149], and a retrospective cohort study found that aspirin onlydecreased the lung cancer risk in combination with metformin and statins [150]. Thiscould potentially indicate a chemopreventive role for aspirin specifically in the contextof patients with COPD, though further research will be required to validate this finding.Further revision of the screening guidelines to better capture underdiagnosed cohorts(including females and non-smokers), incorporating novel biomarkers, and delineatingthe mechanisms linking COPD with lung cancer, will be essential for developing effectiveprevention strategies in the future.10. ConclusionsDespite the notably poor outcomes in individuals with both COPD and lung cancer,there are few available strategies for preventing the development of lung cancer in thecontext of COPD.Determining genetic variants and epigenetic alterations helps to stratify the COPDpopulation according to their risk of developing lung cancer. Delineating the temporalchanges in the tissue immune microenvironment and the microbiome of the pre-malignantlung is also a key step in developing treatment strategies to block progression. Investigatingthese factors with attention to sex-specific differences will be essential, as an increasedsusceptibility to COPD in females has been reported. A better understanding of thebiological factors that drive the progression from COPD to lung cancer, in addition to thedevelopment of screening tools to effectively detect which individuals with COPD are mostlikely to develop lung cancer, has the potential to identify and improve the outcomes for avery large at-risk population.Author Contributions: R.Z., E.A.M. and W.L.L. initiated the project. A.F., R.Z., M.E.P., N.T., V.G.P.S.,L.J.B., G.L.S., K.B. and E.A.M. designed, researched, analyzed, and wrote about the topics covered inthe article. R.Z. and E.A.M. designed the figures. P.P.R. and W.L.L. are the principal investigators.A.F., M.E.P., L.J.B., G.L.S. and W.L.L. revised the manuscript. All authors contributed to data interpre-tation and manuscript preparation. All authors have read and agreed to the published version ofthe manuscript.Funding: The present work was supported by funds from the Canadian Institutes for Health Re-search (grant CIHR, FRN-143345 and FRN-183775) and the BC Cancer Foundation. A.F., M.E.P., andG.L.S. were supported by the CIHR Frederick Banting and Charles Best Canada Graduate Scholar-ships. V.G.P.S. was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior(CAPES/Brazil, Finance code: 001), and E.A.M. by a Vanier Canada Graduate Scholarship. N.T. issupported by fellowships from The University of British Columbia.Institutional Review Board Statement: Not applicable.Informed Consent Statement: Not applicable.Data Availability Statement: Not applicable.Int. J. Mol. Sci. 2023, 24, 2859 14 of 20Acknowledgments: Figures were generated using Biorender.com.Conflicts of Interest: The authors declare that they have no conflict of interest.AbbreviationsCOPD Chronic Obstructive Pulmonary DiseaseCT Computed tomographyECM Extracellular matrixEMT Epithelial-mesenchymal transitionFEV Forced expiratory volumeGWAS Genome-wide association studiesICS Inhaled corticosteroidslncRNA Long non-coding RNAmiRNA MicroRNAMMP Matrix metalloproteinaseNE Neutrophil elastasencRNA Non-coding RNANLR Neutrophil to lymphocyte ratioNSCLC Non-small cell lung cancerPRS Polygenic risk scoreROS Reactive oxygen speciesSCLC Small cell lung cancerSNP Single nucleotide polymorphismUSPSTF United States Preventive Services Task ForceReferences1. Zhang, T.; Joubert, P.; Ansari-Pour, N.; Zhao, W.; Hoang, P.H.; Lokanga, R.; Moye, A.L.; Rosenbaum, J.; Gonzalez-Perez, A.;Martínez-Jiménez, F.; et al. Genomic and Evolutionary Classification of Lung Cancer in Never Smokers. Nat. 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COPD
lung cancer
pathogenesis
microbiome
immune microenvironment
genomic alterations
epigenetics
lung cancer screening
Mechanisms Contributing to the Comorbidity of COPD and Lung Cancer
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