Pathogenic link between chronic obstructive pulmonary disease and squamous cell lung cancer

Worldwide, lung cancer is the leading cause of death from cancer and tobacco smoking is associated with more than 90% of cases of lung cancer [1]. Cigarette smoking is also the most important risk factor for chronic obstructive pulmonary disease (COPD) [101]. Smoking-related lung diseases, such as COPD and lung cancer, are growing epidemics in women in the USA and elsewhere [2]. Interestingly, COPD, a chronic inflammation of the lower airways, is also a major independent risk factor for lung carcinoma among long-term smokers [3]. Lung cancer is also a leading cause of morbidity and mortality in patients with COPD [4]. This evidence emerges clearly from a large longitudinal study of asymptomatic patients with mild-to-moderate COPD, where after 14.5 years follow-up, 33% of these subjects died of lung cancer [4]. It is also known that smokers with COPD have a higher risk of developing a specific histological subtype of non-small-cell lung cancer (NSCLC) termed squamous cell carcinoma [5,6]. Importantly, squamous cell carcinoma still represents the most common lung cancer histological subtype in European men [7]. Despite significant advances in diagnostic techniques and understanding of the molecular biology, even the most recent therapeutic innovations for NSCLC have yielded little improvement in prognosis, with overall 5-year survival rates still less than 15% [1,8]. Lung cancer and COPD therefore share a common risk factor – tobacco smoking – through which they may also share similar pathogenic mechanisms. However, urban and house air pollution is also recognized as a strong risk factor for both COPD and lung cancer [9], and self-reported physician-diagnosed pulmonary emphysema represents a risk factor for lung cancer, even in lifelong nonsmokers [10].

Since more than 90% of all cases of COPD and lung cancer are related to tobacco smoking and only a proportion of lifelong smokers will develop COPD and/or squamous cell carcinoma, we focus here on the potential pathogenic molecular link between tobacco smoking-related COPD and squamous cell carcinoma.

A well-defined stepwise progression of smoking-associated pathological premalignant changes (from basal cell hyperplasia to dysplasia and in situ squamous cell carcinoma) occurs in the normal bronchial epithelium before the development of an invasive squamous cell lung carcinoma [11]. However, despite current data supporting a direct relationship between proximal airway basal progenitors and cells associated with carcinogenesis in murine models for human squamous cell lung carcinoma, the precise stem cell target of this process of carcinogenesis remains unknown [12].

Molecular genetic studies of squamous cell lung carcinoma have revealed that clinically evident squamous cell lung cancers have multiple genetic and epigenetic abnormalities, including DNA sequence alterations, copy number changes and aberrant promoter hypermethylation [13]. Together, these abnormalities result in the activation of oncogenes and inactivation of tumor-suppressor genes [13]. In many cases these abnormalities can be found in premalignant lesions and histologically normal lung bronchial epithelial cells [13].

It is conceivable that such a stepwise progression of the process of carcinogenesis could be facilitated in smokers who develop COPD owing to their impaired clearance of carcinogenic substances resulting from chronic airflow obstruction. Indeed, increased deposition of particulate matter in the major bronchi has been described recently in a computer model of the lungs of patients with COPD [14].

On the basis of the recent novel molecular findings in this field, we believe that the explanation of the link between COPD and squamous cell lung carcinoma is probably more complex than a simple mechanistic one. In fact, there are also many possible molecular links between tobacco smoking-related COPD and squamous cell lung carcinoma.

The human lung is a major target organ for all inhaled carcinogens contained in tobacco smoke. Many of these compounds require enzymatic activation to exert their deleterious effects on pulmonary cells [15]. Interindividual differences in in situ activation and inactivation of xenobiotics may contribute to the risk of developing both COPD and squamous cell lung carcinoma associated with these compounds. The major xenobiotic metabolizing enzymes, including both phase I cytochrome P450s (CYPs), epoxidehydrolases (EPHX), flavinmonooxygenases, such as hemeoxygenase (HMOX)1 and phase II enzymes (conjugation enzymes, including several transferases, such as glutathione S-transferases [GSTs]) are expressed in human lung tissues [15]. The combination of several genetic polymorphisms in the enzymes that activate or detoxify the tobacco smoke carcinogens, such as EPHX, GST and HMOX1, might modulate the risk of chronic smokers developing both COPD and squamous cell lung carcinoma [16].

Although cigarette smoke may be directly mutagenic, polymorphisms in the genes controlling acquired somatic mutations may also contribute, at least to some extent, to the observed differing susceptibilities to COPD and squamous cell lung carcinoma. Alterations in cell-cycle regulation and apoptosis leading to malignant transformation could be caused by common genetic variants in tumor-suppressor genes. A critical downstream mediator of the protein p53 is the tumor-suppressor gene p21, which is transcriptionally activated by p53 to induce cell-cycle arrest and DNA repair. One of the single-nucleotide polymorphisms in p21 results in an amino acid change in codon 31 from Ser to Arg. This polymorphism is located in a highly conserved region of p21 and is believed to affect its molecular function. The p21 Ser31Arg polymorphism is a moderate-risk allele for squamous cell carcinoma [17]. Lee and colleagues, in a case–control study involving 206 Taiwanese subjects with COPD and 210 healthy smokers as control subjects, reported that the distribution frequencies of genotypes of p21^WAP/CIP1 codon 31 were significantly different between the COPD and control groups [18]. Furthermore, higher odds ratios (ORs) for COPD were seen for individuals with p21^WAP/CIP1 R/R and R/S genotypes against S/S genotype (OR = 2.07) [18]. p21^WAP/CIP1 protein expression is increased in alveolar macrophages (a key cell in the pathogenesis of COPD [19]) and bronchial epithelial cells of patients with COPD [20] and, in vitro, hydrogen peroxide (an oxidative stress) induces cytoplasmic expression of p21^WAP/CIP1 in airway epithelial cells and fails to induce their apoptosis [20]. These data suggest that an increased expression of p21^WAP/CIP1 in the lower airways caused by chronic exposure to tobacco smoking may represent another potential molecular link between COPD and squamous cell lung carcinoma.

COPD is recognized as a chronic inflammation of the lower airways [101]. A causal relationship between inflammation and cancer had previously been proposed by Galen and later by Wirchow, who noticed the infiltration of leukocytes in malignant tissues and suggested that cancers arise at regions of chronic inflammation [21]. How exactly chronic airway inflammation is linked to lung carcinogenesis is still not completely understood [21,22]. However the transcription factor NF-κB could well be an important player in this process since it is activated in bronchial epithelium and in the inflammatory cells in the lower airways of COPD and in the premalignant lesions of the bronchial epithelium and neoplastic cells of squamous cell lung carcinoma [23–25].

NF-κB activation and subsequent transactivation of inflammation-related genes may play a central role in both COPD and squamous cell lung carcinoma. Indeed, in addition to its tumor-promoting role, which depends on the stimulation of cell proliferation and inhibition of cell death, NF-κB may also participate in tumor initiation [26]. For instance, NF-κB-activated macrophages in the bronchial tissues of COPD patients can release oxidants in the proximity of the basal bronchial epithelial cells to cause their DNA damage. Interestingly, in vitro inhibition of NF-κB using bortezomib or the compound BAY-11–7085 sensitizes squamous cell lung carcinoma cell lines to death induced by histone deacetylases inhibitors [27,28].

Interestingly, in vitro, nicotine acting on nicotinic receptors may stimulate MAPK (p44/42) and Akt-dependent proliferation and NF-κB-dependent survival of squamous cell lung cancer cell lines, conferring a survival advantage to these cells [29,30]. It also induces lung fibroblasts to produce fibronectin, a major component of the extracellular matrix [31].

Normal human bronchial epithelium and squamous cell lung cancer cell lines are able to produce acetylcholine [32,33], which has been shown to promote the proliferation of neoplastic cells acting on nicotinic receptors in vitro[33] and the proliferation of lung fibroblasts and myofibroblasts acting on muscarinic receptors [34]. There is a complete absence of studies on the potential effect of smoking or its components (such as nicotine) to modulate the release of acetylcholine from the non-neuronal cholinergic system in the airways. Notably, acetylcholinesterase activity in squamous cell carcinoma is 80% less than in its adjacent noncancerous tissue [35].

Theoretically, an increased release of acetylcholine in the lung of smokers, via an autocrine or paracrine loop, may cause both small airway fibrosis (a characteristic of the COPD lung [101]), thus contributing to the development of COPD, and enhanced cholinergic signaling on bronchial epithelium, contributing to carcinogenesis.

In this way, in long-term smokers, chronic nicotine inhalation and/or endogenous acetylcholine released locally in the lung might both play a role in COPD and squamous cell lung carcinoma development.

Tobacco smoking-related COPD is also associated with increased oxidative stress in the lower airways, which can cause DNA damage and carcinogenesis [36]. Damage to DNA induces several cellular responses that enable cells either to eliminate or cope with the damage or to activate a programmed cell death process, presumably to eliminate cells with potentially catastrophic mutations [37]. DNA repair mechanisms include direct, base excision, nucleotide excision, double-strand break and crosslink repair [37]. A lack of DNA repair may be another common mechanism linking both COPD and squamous cell lung carcinoma [38]. For example, one possibility is that heritable genetic polymorphisms influence the efficiency of both DNA repair damage in the bronchial epithelium and connective tissue damage repair. It is also likely that genetic factors modulating the quality of DNA repair explain the absence of both COPD and squamous cell lung cancer in most smokers [38]. Several polymorphisms in DNA repair genes have already been reported to be associated with squamous cell lung carcinoma risk [39]. Clearly, owing to the complexity and the inter-relationships of the many different pathways involved in the process of DNA repair in the lung, this area deserves to be fully explored in large ad hoc studies.

Recent molecular studies investigating gene expression in the bronchial epithelial cells of a control group of smokers with normal lung function compared with smokers with COPD using microarrays [40] are very useful and provide novel clues on the possible molecular links between COPD and squamous cell carcinoma of the lung. Among others, the protein AKR1B10 appears to be of particular interest since it is overexpressed in the bronchial epithelium of COPD patients and in the neoplastic cells of squamous cell carcinoma of the lung [40,41], suggesting its involvement in the multistep carcinogenesis of squamous cell carcinoma of the lung. Aldo–keto reductases are NADPH-dependent oxidoreductases that catalyze the reduction of a variety of carbonyl compounds. AKR1B10 is a member of this superfamily and reduces aromatic and aliphatic aldehyde substrates and has putative physiologic roles in steroid metabolism or detoxification of reactive aldehydes [41]. Data suggest that AKR1B10 translocates to the nucleus during the cell cycle and is involved in the regulation of the cell cycle in a fashion yet to be identified. Another possibility is that AKR1B10 promotes carcinogenesis of squamous cell lung carcinoma through its enzymatic activity, which counteracts the conversion of β-carotene to retinoic acid [41].

Many new compounds that target the molecular pathology of advanced squamous cell lung carcinoma are now undergoing clinical trials [42]; however, we believe that we need to promote more studies on the molecular biology of smokers with premalignant bronchial lesions of the squamous cell lung carcinoma compared with a control group of smokers with and without COPD to unravel the complex molecular interactions between COPD and early squamous cell lung carcinoma. These studies may allow the discovery of new molecular targets of the early carcinogenesis process that, in the foreseeable future, may render the prevention of invasive squamous cell lung carcinoma a reality.

Financial & competing interests disclosure

Supported by teh Associazione per la Ricerca e la Cura dell’Asma (ARCA, Padova, Italy), Fondo per Ricerca Scientifica di Interesse Locale 2007 of the University of Ferrara (ex60%), GlaxoSmithKline (UK) and Novartis (UK). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.