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 Table of Contents  
Year : 2018  |  Volume : 9  |  Issue : 4  |  Page : 165-176

Biomarkers in chronic obstructive pulmonary disease patients for prediction of lung cancer development

1 Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra, India
2 Homi Bhabha National Institute, Mumbai, Maharashtra, India

Date of Web Publication12-Mar-2019

Correspondence Address:
Badri N Pandey
Homi Bhabha National Institute, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jrcr.jrcr_28_18

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According to the World Health Organization (2016), chronic obstructive pulmonary disease (COPD) and lung cancer (along with trachea and bronchial cancers) are third and sixth among 10 top causes of death globally. The association between lung cancer and COPD has been widely established owing to their common endogenous and exogenous risk factors. Mechanistically, lung cancer and COPD are interlinked diseases in many ways such as oxidative stress-associated DNA damage, inflammation, and telomere shortening. An increase in lung cancer has been well correlated with smoking, which is likely to occur up to five folds higher in smokers with COPD than normal lung function subjects. In majority of cases, lung cancer development, especially in COPD patients, is asymptomatic and only diagnosed at advanced stages with poor prognosis. The development of biomarkers for early prediction of lung cancer in both high- and low-risk COPD patients will help clinicians for their better follow-up, early diagnosis, and improved therapeutic management.

Keywords: Biomarkers, chronic obstructive pulmonary disease, lung cancer, predictive markers

How to cite this article:
S Balla MM, Melwani PK, Kumar A, Pandey BN. Biomarkers in chronic obstructive pulmonary disease patients for prediction of lung cancer development. J Radiat Cancer Res 2018;9:165-76

How to cite this URL:
S Balla MM, Melwani PK, Kumar A, Pandey BN. Biomarkers in chronic obstructive pulmonary disease patients for prediction of lung cancer development. J Radiat Cancer Res [serial online] 2018 [cited 2020 Dec 5];9:165-76. Available from: https://www.journalrcr.org/text.asp?2018/9/4/165/254001

  Introduction Top

Chronic obstructive pulmonary disease (COPD) is a progressive lung disorder, which may cause fatal deterioration of lung function over time. In general, COPD is defined as chronic minimally reversible airflow obstruction in the lungs. Spirometry test (a ratio of postbronchodilator forced expiratory volume in 1 s [FEV1] to forced vital capacity) <70% is indicative of COPD. COPD has now been recognized as a heterogeneous group of chronic lung diseases, including well-characterized features such as chronic inflammation, narrowing of bronchial tubes (chronic bronchitis), and progressive destruction of alveolar sacs (emphysema). During COPD, lung damage is caused by several reasons mainly associated with oxidative stress (smoking), release of inflammatory cytokines, and protease activity. These physiological damages result in airway narrowing, airflow limitation, and subsequent structural alterations of pulmonary airways and vessels. Systemic inflammation, increased angiogenesis, and vascular changes in the bronchial circulation are interlinked processes during the pathogenesis of COPD.

COPD is also recognized as one of the risk factors of lung cancer development. In 2016, COPD and lung cancer (along with trachea and bronchus cancers) claimed 3.0 million and 1.7 million lives globally, which make them third and sixth death-causing diseases, respectively, among ten top causes of death (WHO, 2016).[1] Taken together, these diseases account for ~8% of total deaths. In Indian population, among top 10 causes of death, even though COPD is the second highest cause of death (~11%, tolling ~1.1 million lives), it is very close to ischemic heart disease, the highest death-causing disease (~12.4%, ~1.2 million deaths) (WHO, 2012).[2] COPD and lung cancer show commonality for lung as disease site and smoking/air pollution as risk factors, in addition to strong clinical association with each other. These facts make this review further imperative and relevant in the research area.

  Linkage of Chronic Obstructive Pulmonary Disease With Lung Cancer and Its Development Top

The association between lung cancer and COPD has been widely established owing to their common endogenous and exogenous risk factors [Figure 1]. For instance, an increase in lung cancer has been well correlated with smoking,[3] which is likely to occur up to five folds more in smokers with COPD than normal lung function subjects.[4] COPD itself is an independent risk factor for lung carcinoma, especially for squamous cell carcinoma.[5] Pertaining to linkage with smoking, COPD, and small-cell lung cancer (SCLC), a pooled analysis in the International Lung Cancer Consortium showed that former smokers had significantly higher risk of SCLC than nonsmokers. In this study, a much higher risk of lung cancer development was observed among the current smokers than nonsmokers.[6] Furthermore, a statistically significant COPD-mediated SCLC risk was associated with smoking parameters such as current status, pack-years, intensity, duration, and time since quitting. Juvenile initiated cigarette smoking had ~15 folds higher risk of SCLC in the following years compared with nonsmokers. A steady decrease in SCLC risk with number of years since smoking cessation highlights the importance of quitting smoking toward the prevention of lung cancer incidence. However, the persistence of lung cancer even after smoking cessation suggests irreversible carcinogenic changes in lung tissue due to smoking.[6] Moreover, the damaged lung tissue and subsequent impaired lung mucociliary function during COPD result in poor removal of dust/smoke particles associated with pollution or smoking which further supports the lung cancer development in COPD patients.
Figure 1: Linkage of cellular/molecular and exogenous factors in the pathogenesis of chronic obstructive pulmonary disease and lung cancer

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Tobacco burning at high temperature while smoking generates thousands of chemicals. Hence, smokers inhale a highly toxic mixture of many known carcinogens and toxins, such as benzo[a] pyrene and other polycyclic aromatic hydrocarbons (PAHs), formaldehyde (an irritant), carbon monoxide, cyanide (asphyxiants), benzene, tobacco-specific nitrosamines (N-nitroso derivatives of nicotine and its metabolites), acrolein (an irritant), and Polonium (a radioisotope) (World Cancer Report 2014, IARC).[7] Once these carcinogens are inhaled through smoking, they are metabolized in the lung by xenobiotic-metabolizing enzymes including Phase I (microsomal epoxide hydrolases, flavin monooxygenases [e.g., heme oxygenase-1], myeloperoxidase, and cytochromesP[CYPs]), and Phase II enzymes (transferases, e.g., glutathione S-transferases [GSTs] and arylamine N-acetyltransferases).[8] Phase I enzymes metabolically activate xenobiotics; however, Phase II enzymes transform these activated entities into inactive hydrophilic compounds for their easy excretion. Several genetic polymorphisms in these enzymes that activate or detoxify the tobacco smoke carcinogens may modulate the risk of chronic smokers of developing COPD and squamous cell lung carcinoma.[9],[10] In this regard, it is important to mention that PAH is an important xenobiotic substrate for CYP enzymes in cigarette smoke. It is relatively harmless (in small doses) in native form but upon bioactivation by CYP enzymes can become genotoxic to the lung cells. Genetic factors such as polymorphism in DNA repair genes[11] may modulate the efficiency of DNA repair, which explains the variation in the magnitude of COPD and lung cancer in smokers.

Mechanistically, lung cancer and COPD are interlinked diseases in many ways such as oxidative stress-associated DNA damage, inflammation, and telomere shortening, which are investigated in the process of carcinogenesis induced by heavy metal radionuclides.[12] Moreover, these diseases share similar genetic predisposition and epigenetic changes as common causative agent/major risk factors. Smoking is one of the major causes of oxidative stress. Typically, every puff of cigarette contains ~1015 free radicals[13],[14] including reactive nitrogen and oxygen species (RNOS), which can cause cancer-associated DNA damage and mutation. In addition, RNOS can also alter protein structure and function by modifying amino acid residues, protein dimerization, etc., which are reported in COPD condition. Such condition may subsequently result in prolonged inflammatory phenotypes leading to severe lung damage. The damage of lung tissue during COPD results in higher cell division to restore tissue homeostasis, which when combined with exposure of carcinogen while smoking causes a higher possibility of cancer-causing DNA damage and malignant cellular transformation. In addition to the above factors, hypoxia generated due to the narrowing of airways during COPD stimulates the activation of hypoxia-inducible factor-1 alpha, which targets the genes responsible for the activation of glycolysis, deregulated cell proliferation, and inhibition of apoptosis.[15] A stepwise progression of premalignant changes (from basal cell hyperplasia to dysplasia and squamous cell carcinoma) due to smoking has been investigated in invasive lung carcinoma development.[16]

Chronic inflammation is known to mediate malignant transformation and cancer progression in many cancer types.[17],[18],[19],[20],[21] The higher incidence of lung cancer in COPD patients has been attributed mainly to chronic systemic inflammation. The inflammatory response in COPD is mainly mediated by macrophages, neutrophils, and T-lymphocytes.[22],[23],[24] The number of macrophages in lung tissues and sputum is significantly enhanced (5–10 folds) in COPD patients.[25],[26] Continuous insult to lung tissue due to smoking and pollutants in COPD patients stimulates macrophages to produce high level of pro-inflammatory cytokines and proteinases including matrix metalloproteinase (MMP)-2, MMP-9, and MMP-12.[27] Macrophages are more inflammatory and express a higher level of MMPs in smoking COPD patients than smokers with normal lung function.[28],[29] Macrophage is highly plastic and exists in different polarized states, i.e., pro-inflammatory M1 phenotype or healing M2 phenotype.[30] Both M1 and M2 macrophages are known to coexist in COPD lungs.[31] However, persistent oxidative stress leads to impaired phagocytic activity[32] and efferocytosis of apoptotic cells[32] for compromised M1 macrophages in COPD patients. Furthermore, excessive tissue damage and cytokine milieu in inflamed lung tissue skew macrophage polarity toward M2 phenotype,[33] which induces tissue remodeling and angiogenesis.[34] The presence of such complex milieu of M2 macrophage-derived tissue remodeling, cytokines, proteinases, and angiogenic growth factors in the lungs of COPD patients can promote epithelial-to-mesenchymal transition under oxidative stress leading to lung cancer and its metastasis. Under oxidative stress conditions, pulmonary epithelial cells and alveolar macrophages release chemokines, which mediate the recruitment of neutrophils and other inflammatory cells in the lungs of COPD patients.[35],[36],[37] Neutrophils are source of several cytokines such as interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α, and IL-6, which play an important role in lung cancer development.[38] In COPD patients, a dose-dependent decrease in the risk of lung cancer development after corticosteroid (a known immunosuppressive agent) inhalation was demonstrated in a multicenter cohort study[39] suggesting a prominent role of inflammation in driving lung cancer in COPD patients.

Several studies suggest linkage of telomere length shortening with COPD,[40] lung cancer incidence,[41] and its poor prognosis.[13],[14] There is also evidence of familial susceptibility for COPD development and lung cancer incidence, which is linked with chromosome 6.[42],[43] Furthermore, in a genome-wide association study, the same loci including hedgehog-interacting protein (4q31), family with sequence similarity 13 member A (4q24), and cholinergic receptor nicotinic alpha (CHRNA4/CHRNA5 (15q)) were found associated in COPD and lung cancer cohorts.[44] Studies also implicate a role of deficiency of α1-antitrypsin gene[45] in both COPD and lung cancer.

Even though the development of lung cancer in COPD patients has been studied/reported in animal models and human beings, the molecular alterations during sequential phases of lung carcinoma in COPD patients/animal models are yet not well established. DNA extracted from the microdissected bronchial epithelial cells showed widespread point mutation of TP53, suggesting that a single progenitor bronchial epithelial cell might have populated to broad areas of bronchial mucosa.[46] In murine models, pulmonary stem cell population is found at the bronchioalveolar duct junctions (bronchioalveolar stem cells [BASCs]). BASCs, which are resistant to alveolar damage, further proliferate during cell renewal and get transformed to adenocarcinoma.[47],[48],[49]

  Need to Develop Biomarkers for Lung Cancer Development Top

Based on several studies, common risk factors and pathways are well established in COPD and lung cancer, suggesting COPD as a potent driver for lung cancer pathogenesis. In majority of cases, lung cancer development, especially in COPD patients, is asymptomatic and only diagnosed at advanced stages with poor prognosis. The development of biomarkers for early prediction of lung cancer will help clinicians for better follow-up and early diagnosis of lung cancer in COPD patients.[50] In this regard, a range of strategies has been employed for early lung cancer surveillance by screening of patients. However, most of them were not focused for high-risk COPD patients. In the 1980s, chest radiography and sputum cytology have been performed for lung cancer screening; however, any decrease in mortality remains unproven.[51] Later on, in the 2000s, low-dose computed tomography (LDCT) was employed for early-stage detection and increased resectability rates; however, mortality benefit has not been proven.[51] The National Lung Screening Trial by the National Cancer Institute, USA, during 2000–2004 enrolled 54,454 persons at high risk of lung cancer. Almost equal number of participants was randomly assigned to undergo three annual screenings either with LDCT or with single-view posteroanterior chest radiography. The lung cancer incidence per 100,000 person-years was 645 cases (1060 cancers) in the LDCT group than 572 cases (941 cancers) in the radiography group. During follow-up for the death (per 1,00,000 person-years) associated with lung cancer showed 247 deaths in the LDCT group than 309 deaths in the radiography group, suggesting a relative reduction (20%) in mortality from lung cancer with LDCT screening.[52] However, it may be important to mention here that LDCT screening might have expected higher detection of lung cancer exclusively in very high-risk heavy smoking COPD patients.

  Biomarkers for Chronic Obstructive Pulmonary Disease and Lung Cancer Top

Review of literature for this section was done from PubMed with keywords “Biomarkers and COPD and Lung cancer” in October 2018. Out of total 326 publications, 55 review articles were not considered and 73 full-length research articles were considered for this review. However, wherever possible, emphasis has been given for the literature where biomarkers were studied for differentiating healthy controls, COPD and lung cancer subjects. For easy reference, these biomarkers were categorized based on sample types used for analysis.

Blood-based biomarkers

Various approaches have been used to study blood-based molecular, cellular and genetic biomarkers in COPD, and lung cancer patients. Leidinger et al. studied microRNA (miRNA) profile in blood samples in COPD and lung cancer patients, which were compared with healthy controls. Out of 14 miRNAs (hsa-miR-641, hsa-miR-662, hsa-miR-369-5p, hsa-miR-383, hsa-miR-636, hsa-miR-940, hsa-miR-26a, hsa-miR-92a, hsa-miR-328, hsa-let-7d, hsa-miR-1224-3p, hsa-miR-513b, hsa-miR-93, and hsa-miR-675), which were significantly different in COPD (n = 24) compared to lung cancer patients (n = 28), only hsa-miR-675 was differentially expressed in lung cancer patients, COPD patients and healthy controls (n = 19).[53] In another study, miRNA expression was compared between non-SCLC ( NSCLC) patients (n = 74), COPD patients (n = 26), and healthy controls (n = 20) using panel of 128 miRNA. Among these miRNAs, only hsa-miR-330-3p was found upregulated in comparison to healthy controls and downregulated when compared to COPD participants. Top 10 most significant miRNAs which were downregulated in NSCLC were hsa-miR-199a-3p, hsa-miR-26b-5p, hsa-let-7a-5p, hsa-miR-126-3p, hsa-let-7f-5p, hsa-let-7 g-5p, hsa-miR-720, hsa-let-7d-5p, hsa-let-7e-5p, and hsa-miR-27a-3p. Out of these, five are from let-7 family. Furthermore, this study highlighted that hsa-let-7a was one of the miRNAs, which essentially could be shown as lung cancer miRNA signature. However, authors discussed that based on these miRNAs, it is far more challenging to separate lung cancer and COPD patients than lung cancer with controls.[54] In a follow-up study in COPD patients (n = 534), miRNA analysis was done after 54 months, where miR-150-5p was downregulated in COPD patients which subsequently developed lung cancer.[55]

Epigenetic changes in blood samples were studied in terms of aryl-hydrocarbon receptor repressor [AHRR (cg05575921)] methylation. This marker was lower in smokers than nonsmokers and was inversely correlated with smoking intensity. AHRR (cg05575921) hypomethylation was predictive of high risk of COPD exacerbation. It was further shown that AHRR (cg05575921) methylation was suitable to separate the different risk grades in smokers for lung cancer.[56]

Using blood-based haplotype-tagging single-nucleotide polymorphism (SNPs), genetic variations in COPD with lung cancer (n = 423) and COPD alone (n = 108) were evaluated. It was found that a total of 21 SNPs in 12 genes were significantly (P < 0.01) associated with COPD risk. Out of 21 SNPs, 13 (ATP-binding cassette transporter subfamily C members [ABCC1] [rs16967755; rs215100], ABCC4 [rs7324283; rs1729786], ABCC3, ABCC2 [rs717620; rs2756109], glutamate–cysteine ligase [rs12524550; rs2100375; rs542914; rs4712035], glutathione synthetase, and GST Pi 1 [GSTP1]) were related to glutathione synthase pathway, 7 SNPs (MutS Homolog 3 (MSH3) [rs12513549; rs33013; rs12522132; rs2897298], xeroderma pigmentosum DNA repair protein [XPA], poly (ADP-ribose) polymerase 1, and excision repair cross-complementation Group 2 [ERCC2]) related to DNA repair pathway, and 1 SNP in prostaglandin-endoperoxide synthase 2 (PTGS2) related to inflammatory pathway. These results have indicated that ABCC4 and PTGS2 genes were commonly susceptible to COPD and lung cancer. Further, ABCC1, ABCC2, GSTP1, and MSH3 genes were independently susceptible for COPD. It was also shown that there is a strong association of the GST omega 2 gene (GSTO2) in COPD with lung cancer, which indicates that GSTO2 may be critical for developing cancer among patients with COPD. In DNA repair pathway, it was found that ERCC1 was significantly associated with COPD without lung cancer, suggesting that ERCC1 may have an important role in COPD than in lung cancer. In contrast, Ribonucleotide Reductase Catalytic Subunit M1 was significantly associated to COPD with and without cancer suggesting its involvement in COPD and lung cancer.[57] In another study, polymorphisms in the gene GSTP1 and ALA114Val were significantly higher in COPD patients (n = 108) than SCLC patients (n = 89). However, healthy controls have displayed identical variant genotype frequencies in the gene GSTP1. These results were interpreted that the polymorphism in GSTP1 gene has a protective action against SCLC. This study also highlighted that with exon 6 variant of GSTP1 genotype showed reduced exposure to cigarette smoke as compared to patients with the wild-type GSTP1 exon 6 genotype. This study has a limitation of small sample size, and hence, this genetic polymorphism needs to be validated in large sample size and multiethnic population to confirm the findings.[58] The patients carrying SNP exon variant c. 353T > C (p. Val118Ala) of Snail 1 gene correlated significantly (P < 0.05) in smoking COPD patients with lung cancer.[59] It was studied that the homozygosity for MMP3 (rs3025058 [5A/5A, 5A/6A, and 6A/6A]) and rs678815 (G/G, C/G, and C/C) polymorphisms is a potential marker of enhanced susceptibility to lung cancer in COPD patients (n = 53) compared to COPD subjects (n = 54).[60]

Fatty acid profile of total lipids from erythrocytes and platelets of patients from lung cancer (n = 50), COPD (n = 15), asthma (n = 15), and control participants (n = 50) were also analyzed. The decrease in linoleic acid-18:2n6 fatty acid was highly specific to the NSCLC patients and had high diagnostic accuracy in both erythrocytes and platelets analyzed.[61],[62] Role of IL-6 in COPD and lung cancer was studied in Collaborative cross CCSP(Cre)/LSL-K-ras(G12D) mouse model (CC-LR) mice strain. Genetically ablating the IL-6 resulted in inhibition of COPD-like airway inflammation and also lung cancer development.[63] In another study, superoxide anion, nitrotyrosine, and total protein carbonylation levels were significantly higher in lung cancer with COPD than without COPD patients.[64]

Plasma biomarkers

In plasma samples, the levels of ras p21 protein in COPD patients were higher than historical controls but lower than cancer patients. Authors suggested that the ras protein in plasma from lung cancer patients could be a possible prognostic marker for lung cancer.[65] Moreover, the cytogenetic damages (sister-chromatid exchanges [SCEs]/cell and high frequency of SCE cells) and ras oncoprotein tended to be significantly lower in controls than in COPD and cancer patients.[66]

Small nucleolar RNAs (snoRNAs) were also evaluated in lung cancer patients (n = 37), COPD patients (n = 26), and age-matched healthy controls (n = 22). It was observed that snoRNA SNORD66 expression was significantly higher in lung cancer patients compared to COPD patients and healthy controls. Area under the curve for this biomarker was found to be 0.81 (lung cancer patients versus healthy controls) and 0.79 (lung cancer patients versus COPD patients), suggesting it as a possible plasma biomarker for lung cancer developing in COPD patients.[67] Cell-free DNA in plasma samples of lung cancer patients (n = 50), COPD patients (n = 34), and healthy controls (n = 40) were evaluated. It is observed that even though plasma DNA is highest in lung cancer patients, it is not useful in discriminating COPD and healthy donors. However, plasma cfDNA is helpful in discriminating NSCLC from healthy individuals.[68] Furthermore, plasma DNA methylation was compared among lung cancer patients (n = 33), COPD patients (n = 42), and healthy controls (n = 61). In this study, authors suggested a four-marker model (homeobox DNA-binding domain [HOXD10], paired box [PAX9], receptor-type tyrosine-protein phosphatase N2 [PTPRN2], and stromal antigen 3 [STAG3]) and receiver operating characteristic curve analysis showed that this model is better in discriminating cancer from healthy with 87.8% sensitivity and 90.2% specificity. Moreover, the model also discriminated cancer from COPD with a specificity of 88%.[69] A higher level of pro-surfactant protein B was seen in patients with advanced COPD stages, which was also shown to be higher in the early stage of lung cancer.[70],[71] Plasma levels of vascular endothelial growth factor (VEGF) and IL-4 were significantly lower, whereas transforming growth factor (TGF-β) and IL-10 levels were higher in lung cancer with COPD than in only lung cancer patients.[72] Circulating caspase-4 was also evaluated in NSCLC (n = 125) and healthy participants (n = 79). Plasma levels of the circulating caspase-4 were higher in lung cancer patients compared to healthy participants. Furthermore, the levels of the circulating caspase-4 in COPD patients were three times higher than healthy subjects. Although these levels were still lower than those observed in lung cancer patients.[73]

  Serum Biomarkers Top

Serum high mobility group box protein 1 (HMGB1) was evaluated in serum samples of NSCLC patients (n = 145), COPD patients (n = 77), and healthy controls (n = 49), which was significantly different among NSCLC patients, COPD patients, and healthy controls. In addition, the serum HMGB1 level was notably increased in patients with distant metastasis than without distant metastasis. In addition, its serum level was significantly increased and correlated with increase in the size of tumor.[74] Serum C-reactive protein (CRP) level was higher in advanced lung cancer than early lung cancer patients. Further, the patients with early lung cancer had a significantly higher level of serum CRP than the patients with COPD and healthy individuals. However, serum CRP levels were in a similar range between male and female lung cancer patients (with or without COPD) and healthy individuals. In COPD group, serum CRP level was significantly higher in the male than in female patients. It was significantly higher in smoker and ex-smoker COPD patients than never-smoker COPD patients.[75] Levels of three serum proteins (CXCL16, endostatin, and CRP) were significantly elevated in lung cancer patients with COPD versus lung cancer patients without COPD.[76] Serum carbohydrate sulfotransferase 7 (CHST7) concentrations were lower in lung cancer alone (n = 71) than lung cancer with COPD (n = 23). In all lung cancers, SCLC showed the highest elevation of serum CHST7. In metastatic stage, where the cancer cells were infiltrated in large vessels or surrounding organs, there was significant release of CHST7 in serum.[77]

Nuclear magnetic resonance spectra were evaluated for serum samples of NSCLC and COPD patients. An increase in 3-methyl-2-oxovalerate, 3-hydroxybutyrate, isoleucine, valine, acetone, creatinine, acetoacetate, isobutyrate, lactate, α-glucose, lipids (L6), and an unidentified compound (with a resonance of 1.05 ppm) as well as reduced level of glutamine and trimethylamine N-oxide (TMA) were observed only in early NSCLC than COPD. However, high level of glycerol, N-acetylated glycoproteins (NAC2), and glycine and low level of glyceryl of lipids (L8) were found in advanced NSCLC than COPD.[78] In this study, it was also observed that advanced NSCLC patients (Stages III and IV) exhibited reduced levels of isoleucine, acetoacetate, lactate, glyceryl of lipids (L8), creatinine, acetone, valine, isobutyrate, and unidentified compounds (resonances of 1.05 and 1.41 ppm) compared with early NSCLC patients (Stages I and II). Simultaneously, creatine, NAC1, NAC2, and glycerol levels were elevated in advanced than early NSCLC patients. Finally, out of these biomarkers, only six metabolites could be considered as candidate biomarkers of lung cancer staging. It was found that during the progression of the pathological state, the levels of two metabolites (isoleucine and acetoacetate) were decreased, whereas the levels of creatine, NAC1, NAC2, and glycerol were increased.[78] Serum uric acid levels were evaluated in COPD (n = 3901) and lung cancer (n = 1015) patients. It was observed that the predicted incidence rates of lung cancer and COPD were 70% and 40% higher, respectively.[79]

Serum levels of tissue inhibitor MMP1 (TIMP1) levels were significantly (P < 0.01) higher in lung cancer with COPD (n = 53) than COPD-only group (n = 54).[60] Mean serum concentrations of cytokeratin-19 fragment (CYFRA 21-1) in healthy controls, COPD patients, and NSCLC patients were significantly (P < 0.05) different and will be one of the potential biomarkers to be further studied.[80] Our group has shown that serum VEGF was significantly higher in metastatic than nonmetastatic lung cancer patients. Furthermore, IL-8 was able to diagnose cancer in COPD patients and healthy subjects with Youden's index (YI) 0.35 and 0.55 and overall accuracy 71% and 83.3%, respectively. MMP9 and MMP2 did not show potential to predict cancer in COPD patients.[81] Another study has shown serum miRNAs (miR-200b, miR-429, miR-203, miR-125b, miR-34b, and miR-205) as promising biomarkers with a significantly higher abundance in NSCLC. However, authors alerted to screen in large number of cohort to confirm these findings.[82] It was observed that coenzyme Q10 levels in the subjects with lung cancer (n = 28) were significantly higher than COPD (n = 26), and further, the values of both were significantly different from healthy controls (n = 28).[83]

Oxidative stress is one of the key players in COPD and lung cancer development. Oxidative damage markers such as malondialdehyde and 8-oxo-7,8-dihydro-2'-deoxyguanosine were not significantly different in the groups.[83] Cathepsin-S degraded decorin in the serum of NSCLC was higher than healthy controls and COPD patients.[84] Eighteen markers of inflammation and fibrosis were evaluated in serum samples of COPD alone (n = 42) and lung cancer with (n = 115) or without COPD (n = 92). Levels of osteoprotegerin, pentraxin 3 (PTX3), receptor tyrosine kinase AXL, delta-like canonical Notch ligand 1 (DLL1), CD147, and activated leukocyte cell adhesion molecule (ALCAM) were significantly higher in COPD patients compared to lung cancer patients with and without COPD. sCD163 was significantly higher in COPD patients compared to lung cancer patients without COPD.[85]

Bronchoalveolar lavage fluid-based biomarkers

In a study, bronchoalveolar lavage fluid was evaluated for cytokines in patients with COPD alone (n = 15), lung cancer (n = 15), lung cancer with COPD (n = 15), and control group (n = 15). The cytokines that have shown significantly differential expression in the above groups are calcyphosin-2 (CAPS2) and cofilin-1 (CFL1). These proteins were also downregulated in the COPD group and upregulated in the lung cancer and lung cancer with COPD as compared to the control group.[86] Furthermore, another study was focused to evaluate redox regulative proteins differentially expressed in these disease conditions.[87] Peptidylprolyl isomerase A (PPIA) or cyclophilin A was shown to be upregulated between COPD group and lung cancer with or without COPD. Cathepsin D preprotein (CTSD) and ezrin (ERZ) proteins were found to be upregulated in lung cancer patients but not in COPD and lung cancer with COPD patients. Peroxiredoxins 1, 5, and 2a were shown to be upregulated in COPD and lung cancer with COPD but not in lung cancer without COPD patients.[87]

In a study, miRNAs evaluated in bronchoalveolar lavage samples showed upregulation of miR-132-212 cluster in COPD; however, other four miRNA clusters, namely miR-17-92, miR106a-363, miR106b-25, and miR-192-194), were upregulated in lung adenocarcinoma.[88] IL-11 and C-C motif chemokine ligand 1 (CCL-1) in bronchoalveolar lavage samples were shown to be specific for adenocarcinoma with or without COPD when compared with COPD alone and patients with squamous cell carcinoma with or without COPD.[89]

Tissue biomarkers

Signal transducer and activator of transcription 3 (Stat3) and their downstream signaling genes were evaluated in tissues of normal human lung (n = 13), human pulmonary adenocarcinoma (ACC; n = 26), human pulmonary squamous cell carcinoma (SCC; n = 26), nonsmoker COPD (n = 20), and smoker COPD (n = 30) patients. It was observed that the average mRNA expression of Stat3 was significantly higher in ACC and in SCC when compared to normal human lung tissues. Further, it was shown that Stat3 level was higher in nonsmoker COPD and smoker COPD patients. In addition, authors have evaluated the Stat3 upstream and downstream genes. In upstream genes (cerebellin 1 precursor [Cbln1], claudin-2 [Cldn2], fibrinogen-like protein 1 precursor [Fgl1], gap junction beta-1 protein [Gjb1], hepatic nuclear factor 4-alpha [HNF4α], and transmembrane protein 27 [Tmem27]) were significantly downregulated in SCC. In downstream genes, retinal short-chain dehydrogenase reductase 2 (RDH-E2) gene was decreased only in ACC and SCC but modestly upregulated in COPD. Rest of the evaluated genes were either modestly regulated or remain unchanged. Authors speculated that RDH-E2 may be useful to predict the COPD-adenocarcinoma transition.[90] Whole genome gene expression profiles from microdissected tissue of SCC patients with (n = 18) or without COPD (n = 17) were analyzed. It was observed that there is a more frequent loss of 5q in SCC tumors without COPD compared to tumors with COPD patients.[91] The expression level of muscarinic receptor 3 (M3R) was evaluated in paraffin-embedded sections of NSCLC patients with or without COPD. It was observed that in the NSCLC patients with COPD group (n = 60) where M3R was highly expressed, survival rate was significantly lower than patients with low level of M3R expression. In patients without COPD (n = 88), a high level of M3R also predicted a poorer 5-year survival rate than did a low level of M3R. Further, M3R expression was shown to be positively correlated with smoking history.[92] Lung tumors from COPD cases showed significantly higher prevalence for methylation of coiled-coil domain-containing protein 37 (CCDC37) and microtubule-associated protein 1B (MAP1B). CCDC37 was methylated in 54/71 (76%) lung tumors from COPD compared to 20/46 (43%) non-COPD cases while MAP1B was methylated in 48/71 (68%) tumors with COPD versus 17/46 (37%) non-COPD participants. The repression of these genes in COPD before lung cancer is likely predisposing for the increased methylation during lung carcinogenesis and may contribute to the increased risk of lung cancer observed in COPD patients. Future studies should investigate if this can be used as a biomarker that will improve the sensitivity and specificity of predicting lung cancer risk among COPD patients.[93] Inflammatory cytokines were evaluated in lung cancer with COPD group and it was compared with lung cancer patients without COPD. It was shown that in lung cancer patients with COPD, Th1 cytokines (tumor necrosis factor-α [TNF-α] and IL-2) and Th2 cytokines (TGF-β and IL-10) were increased systemically and those of VEGF and IL-4 were decreased compared with lung cancer without COPD. In lung cancer patients with COPD group, levels of VEGF, TNF-α, TGF-β, and IL-10 were higher in tumors than in nontumor lungs. Further, in tumor specimens, M1/M2 ratio of macrophages was significantly higher in the lung cancer with COPD than in the lung cancer patients.[72]

It was also shown that one of the related redox proteins, i.e., superoxide dismutase 1 (SOD1) expression level was significantly higher in tissue samples of lung cancer with COPD (both tumor and nontumor parts) than in lung cancer group.[64] Inflammatory responses play a key role in many pathogenesis of diseases, such as autoimmune, chronic, and cancer diseases. In a study, hexanal exposure was evaluated to see whether this causes an airway inflammatory response in relation to environmental pulmonary disease. It was shown that LEPTIN, IL-10, MCP-1, and VEGF cytokines were elevated and these cytokines are known to be associated with diverse lung diseases, such as lung fibrosis, COPD, and non-SCLC. It was suggested that the high levels of these four cytokines may be considered essential for the discovery of novel cytokine biomarkers for a screening of environmental exposure to hexanal and the pathologies of pulmonary diseases.[94] In a mutational analysis study of DNA samples from formalin-fixed paraffin-embedded lung cancer tissue with (n = 77) and without COPD (n = 120), it was observed that the frequency of phosphatidylinositol 3-kinase (PIK3CA) mutation was significantly higher in the COPD than in the non-COPD participants. In the multivariate logistic regression model (considering age, smoking dose, COPD status, and histopathological stage), significantly higher PIK3CA mutation was observed in COPD patients, and authors concluded that PIK3CA mutation is a distinctive genetic feature of NSCLC with COPD.[95] The levels of caspase-4 were significantly increased in NSCLC tissues compared to the lung tissues obtained from non-COPD patients. Authors observed that the survival rate of NSCLC patients with higher expression of tumor-associated caspase-4 was significantly lower than those who had lower levels of this marker.[73]

Expression of miR-21, miR-200b, miR-210, and miR-let7c and DNA methylation in lung tumor specimens was greater in lung cancer with COPD than of lung cancer patients without COPD. Expression of downstream markers such as phosphotensin homolog (PTEN), myristoylated alanine-rich protein kinase (MARCKs), tropomyosin-1, programmed cell death-4, sprouty homolog 2, ETS-1, zinc finger E-box-binding homeobox, fibroblast growth factor receptor-like 1 (FGFRL-1), ephrin A3, and K-RAS together with P53 was selectively downregulated in tumor samples of lung cancer with COPD patients. In these patients, tumor expression of miR-126 and miR-451 and that of the biomarkers PTEN, MARCKs, FGFRL-1, SNAIL-1, P63, and k-RAS were reduced.[96]

Sputum biomarkers

A panel of six genes (enolase 1, fragile histidine triad, hyaluronoglucosaminidase 2, S-phase kinase-associated protein 2, P16, and 14-3-3zeta) were evaluated in the sputum samples of a case–control study of NSCLC patients (n = 49), COPD patients (n = 49), and healthy smokers (n = 49). The authors then validated these genes in an independent cohort of NSCLC patients (n = 69) and noncancer participants (n = 65). This panel has distinguished Stage I NSCLC patients from noncancer individuals. Furthermore, the gene panel had higher sensitivity in identification of squamous cell carcinoma than adenocarcinoma of the lung.[97] In a study prospective sputum samples were collected from lung cancer (n = 53) and COPD (n = 47) patients. Gene promoter methylation status of Ras association domain family member 1 (RASSF1A), adenomatous polyposis coli, and cytoglobin (CYGB) was evaluated by quantitative methylation-specific PCR. Cumulative 6- or 9-day methylation analysis increases the chance of lung cancer identification. It was also observed that sensitivity of gene promoter hypermethylation analysis in sputum for lung cancer increases when sputum is sampled during more than 3 consecutive days.[98] Furthermore, RASSF1A hypermethylation in sputum along with exhaled breath analysis increased sensitivity for lung cancer diagnosis to 100%, suggesting complimentary nature of these methods to increase the sensitivity.[99]

Amount of DNA was evaluated in induced sputum samples from COPD patients (n = 23), lung carcinoma patients (n = 26), and healthy subjects (n = 33). Promoter methylation frequency of cyclin-dependent kinase inhibitor 2A (CDKN2A), E-cadherin (CDH1), and O6-methylguanine DNA methyltransferase (MGMT) was evaluated using methylation-specific polymerase chain reaction. Results showed that DNA concentration was more in lung cancer and COPD, respectively, compared to control individuals. Moreover, methylation status of CDKN2A and MGMT was significantly higher in COPD and lung cancer patients than control group. CDH1 methylation showed a statistically significant difference between lung cancer and healthy individuals. These results suggest that aberrant methylation of tumor suppressor genes in induced sputum samples could be a useful tool for the early diagnosis of lung diseases.[100] In an epigenome-wide association study, methylation of CCDC37 and MAP1B was found to be significantly higher in lung cancer patients with COPD than without COPD. Especially, CCDC37 methylation was more pronounced in sputum of COPD smokers than non-COPD smokers.[93]

Exhaled breath condensate biomarkers

In exhaled breath condensate (EBC), it was shown that there is a significant increase in angiogenic markers (basic fibroblast growth factor [bFGF], angiogenin, and VEGF), TNF-α, and IL-8. These analytes discriminated 74 individuals with or without NSCLC. Levels of angiogenic markers (such as bFGF, angiogenin, and VEGF) in EBC significantly demarcated 17 individuals with NSCLC having stable/exacerbated COPD patients and healthy volunteers. Especially, levels of IL-8 and TNF-α in EBC indicated for COPD but not lung cancer.[101] In EBC, the non-COPD group exhibited significantly higher levels of pulmonary surfactant protein A (SP-A) and pulmonary surfactant protein (SP-D) compared with COPD group. The results further showed that FEV1 was positively correlated with the level of SP-A (r = 0.494 and P < 0.05) and SP-D (r = 0.253 and P < 0.05) in EBC.[102] In proteome analysis of EBC of lung cancer, it was observed that cytokeratins such as KRT6A, KRT6B, and KRT6C isoforms were significantly higher and these proteins showed positive correlation with tumor size.[103] In another study, new volatile organic compounds were evaluated in exhaled breath to distinguish lung cancer from COPD patients and healthy participants using thermal desorption-gas chromatography-mass spectrometry. The compounds studied were nonanal, octanal, heptanal, hexanal, propanoic, and nonanoic acids. Among these compounds, nonanoic acid showed statistically significant differences in the EBC between lung cancer and control/COPD participants.[104]

  Conclusions and Future Directions Top

Most of the current research activities are directed to investigate biomarkers which have shown differential expression in lung cancer patients compared to healthy controls. However, majority of the studies have used limited number of sample size, which need to be extended with larger cohort to gain conclusive information. It would be more useful to evaluate the biomarkers which can predict the development of lung cancer in high-risk COPD patients like high age and smokers. Moreover, these biomarkers also need to have the ability to identify different stages of disease in COPD (e.g., exacerbation) and lung cancer (e.g., metastases and response to treatment), which are not well addressed in the literature. The development of biomarkers predicting risk of lung cancer development as well as pathogenic conditions of these diseases would help clinicians for better management and therapy of patients.

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Conflicts of interest

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