Abundant scientific information upholds the existence of a relationship between inflammation and the initiation and progression of various types of cancer, among these bronchial cancer.1 It is also known that chronic obstructive pulmonary disease (COPD) and bronchial cancer are closely related with smoking. Tobacco use could be the link that would explain this association, as it is considered as the common denominator responsible for both processes. Several studies, however, have shown that the severity of the bronchial obstruction, evaluated by measuring forced expiratory volume in one second (FEV1), is an independent factor for the development of bronchial cancer in smokers.2–4 This observation suggests that there is a connection between the two diseases, which could be independent from the action of tobacco. Given that the onset of cancer is associated with chronic inflammation and COPD is an inflammatory disease of the airways, it is possible that the inflammatory process present in smokers that develop bronchial obstruction is the link between COPD and cancer. Several studies point to lipid inflammatory mediators among the possible factors responsible for the relationship between inflammation and cancer.

Lipid mediators are formed in inflammatory processes from arachidonic acid (AA). AA is released from the deposits of phospholipids by the action of phospholipase A2, which can be activated by different stimuli, among which are cytokines, microorganisms, and different types of cell lesions. AA can be metabolized by three main pathways: that of cyclooxygenase (COX), that of lipoxygenase and that of the chromosome P450, by means of which a family of products called eicosanoids is formed. The family of the eicosanoids includes prostaglandins (PG) made by the action of the COX. There are two types of COX that participate in the synthesis of PG: COX-1 and COX-2. COX-1 is normally present in the cells and is in charge of physiological functions; in contrast, COX-2 is usually undetectable in normal situations, but it is rapidly induced in the cells when they are subject to inflammatory stimuli.5

The prostaglandins generated by the two COX enzymes are PGD2, PGE2, and PGF2α. Each one participates in the regulation of the inflammatory responses.5

The expression of COX-2 is higher in several human cancers, including bronchial cancer. The increased expression of COX-2 leads to an increase in the production of PGE2, a fact that has been demonstrated in colorectal, pancreatic, and lung cancers.6 PGE2 stimulates angiogenesis, cell invasion, the formation of metastasis and cell survival, the latter inhibiting apoptosis.6,7

Previous studies have demonstrated in COPD patients an increase in the production of PGE2 associated with the up-regulation of COX-2.8,9 Another interesting observation is that smoking also increases the expression of COX-2 and the production of PGE2.10,11

Taking all these data into account and associating them with the known interdependence, which is among smoking, COPD, and bronchial cancer, it is possible that the induction of COX-2, together with the increased production of PGE2, could be the common denominator for all of them.

In this study, we establish the hypothesis that, in smokers who are present with bronchial inflammation associated with COPD, the increased production of PGE2 makes them prone to developing bronchial cancer. Given that the increase in PGE2 is associated with higher COX-2 expression, we decided to study the expression of this enzyme in the tumor tissue, the bronchial mucosa adjacent to the tumor and in the pulmonary parenchyma distal to the area of the tumor invasion.

The specific objectives of the study are: (a) to evaluate and compare the expression of COX-2 in the lungs of COPD patients and subjects not affected by COPD; (b) to evaluate and compare the expression of COX-2 in the lung parenchyma, the airways, and the lung tissue of patients with COPD and bronchial cancer; (c) to analyze and compare the expression of COX-2 depending on the histologic type of the bronchial cancer, as well as its relationship with the degree of extension of the process.

Given that COX-2 seems to be involved in the regulation of various cell processes that are important in the development of cancer, such as angiogenesis, tumor progression, metastases and resistance to anti-neoplastic chemotherapy,16,17 the objective of this study was to research the expression of COX-2 in the lungs of COPD patients affected by bronchial cancer with the aim of analyzing the relationship between the expression of COX-2 in the lung tissue unaffected by the cancer and the neoplastic tissue.

The most relevant findings of our study have been: (a) the expression of COX-1 and COX-2 is up-regulated in the parenchyma of COPD patients; (b) COX-2 mRNA expression is higher in the parenchyma than in the tumor tissue, both from adenocarcinomas as well as squamous carcinomas; (c) The expression of the COX-2 protein is higher in tumor tissue, particularly in the adenocarcinoma samples.

This study confirms that COPD is a disease characterized by the presence of an increase in the activity of the COX pathway of AA metabolism. The higher expression of COX-2 in COPD was described for the first time by our group8 and later confirmed by other researchers.9 These studies demonstrated for the first time that, like COX-2, COX-1 also has a higher expression in COPD. This observation should not be considered exceptional because, although COX-1 is an enzyme that is usually involved in physiological functions, the truth is that in inflammatory processes small changes can be produced in their expression.10,11,18,19 Therefore, it is possible that the increase in the lung production of PGE2 in patients with COPD is in part due to the increase in the metabolic activity of COX-1.

Unlike what happened with mRNA, it was not possible to demonstrate differences in the expression of the COX-1 protein between the pulmonary parenchyma of the control subjects and of the COPD patients. This fact is not exceptional and, when it happens, it is usually due to the differences in the precision and sensitivity of the methods used to measure mRNA and the protein synthesized by the cell ribosomes. PCR is a technique that can detect small changes in mRNA synthesis, while Western blot, which is the technique used to evaluate the quantity of synthesized protein, presents a much lower precision and sensitivity for evaluating slight differences. Other possible reasons, although unlikely, such as the presence of alterations in protein synthesis or alterations in the half life of the proteins generated, could explain the difference in the results obtained with the COX-1 mRNA and protein.

In comparing the expression levels of COX-2 in the tumor tissues, two observations stand out: (a) the protein levels were markedly higher, while the mRNA levels were not as high; (b) The protein levels were much higher in the tissue from adenocarcinoma than from the tissue of squamous carcinoma. These observations suggest that, quite probably, the increased transcription of the COX-2 gene (mRNA) has a less relevant role than the processes of translation (protein synthesis) and post-translation (regulation of the protein half-life) in the increased expression of the COX-2 protein in bronchial tumors.

It is widely accepted that COX-2 plays a relevant role in inflammatory processes, and it is also assumed that the increased expression of this enzyme is mainly responsible for the increased production of PGE2 detected in COPD patients.9 Given the ability of PGE2 to promote oncogenesis, one may be led to think that the increased production of PGE2 as a consequence of the inflammatory response could contribute to the development of cancer in COPD patients.20 One possible sequence in the events that leads to the development of cancer in smokers could be the following: smoking starts up an inflammatory process in the lungs, and the tobacco and the inflammation cause increased COX-2 expression that entails increased production of PGE2, which, with its known capability for inducing oncogenesis and in association with other pro-neoplastic factors, finally promotes the development of cancer situated on an inflamed lung.

If this hypothesis were true, any therapy capable of reducing the synthesis of PGE2 should have a preventive effect on the development of bronchial cancer. Recent studies have shown that low doses of acetylsalicylic acid prevent the development of various cancers, among these bronchial cancer.21,22 Given that one of the actions of acetylsalicylic acid is to inhibit both COX enzymes, thus drastically reducing the synthesis of PGE2, these observations reinforce the hypothesis that indicates the COX pathway as the connection between the inflammation present in COPD and the predisposition of these patients to develop bronchial neoplasms.

One curious fact of this study is the varying degree of COX-2 expression depending on the histologic type. The greater abundance of COX-2 in adenocarcinoma compared with squamous carcinoma has been reported in previous studies.16,23 Given the capacity of low doses of acetylsalicylic acid for preventing the development of cancer, the fact that there are large differences in the levels of COX-2 between squamous and adenocarcinoma emphasize the need to carry out studies in order to know whether the antineoplastic effects of acetylsalicylic are related with the dose of the drug, the histologic type of the tumor or its relationship with the degree of expression of COX-2. The majority of the studies have been done in patients who were receiving treatment with low doses of acetylsalicylic acid with the aim of preventing cardiovascular diseases.21 There exists the possibility that higher doses than those indicated would have greater capacity for cancer prevention, particularly in adenocarcinoma, in which, as demonstrated by this and by other studies, the expression of the COX-2 protein is very high.

It is worth mentioning that the degree of COX expression can have a prognostic value. Previous studies have demonstrated that the up-regulation in the expression of COX-2 is associated with a poorer evolution of bronchial cancer.19,24,25 On the other hand, the inhibition of COX-2 can have not only preventive but also therapeutic effects, a fact supported by the results of studies, which have observed that the inhibition of COX-2 with acetylsalicylic acid or the selective inhibitors of COX-2 (coxibs) improve the therapeutic results when associated with antineoplastic therapies.26,27

In this study, we evaluate the degree COX-2 expression in the bronchial mucosa near the tumor. Our hypothesis established that there should be a relationship between the inflammation present in the airways—with the resulting increase in PGE2 production due to an increase in COX-2 expression—and the later development of cancer on this inflamed area. In accordance with this hypothesis, the bronchial mucosa should be the area of the lungs with a greater expression of COX-2. Surprisingly, the greater expression of COX-2 is found in the parenchyma. The reasons that can explain this finding are unknown for now. Nevertheless, it should be pointed out that the degree of COX-2 expression could not be compared in the bronchial mucosa of the COPD patients with cancer and the control subjects as, although samples were available from the parenchyma of subjects without COPD (affected by pneumothorax), for obvious reasons it was not able to obtain samples of the bronchial tissue of these same individuals. However, previous studies have demonstrated that the COX-2 expression levels are directly related with the degree of malignancy of the bronchial histologic lesions.28

In short, this study demonstrates that COPD is characterized by showing an increase in the activity of the cyclooxygenase pathway, a fact that is associated with an increase in the expression of COX-2 in the tumor tissue, especially in the tissue of adenocarcinoma. As a whole, these data reinforce the idea that inflammation and cancer can be related, and that in this relationship the lipid mediators generated by the COX pathway can play a relevant role. The importance that the inhibition of COX-2 may have in preventing and treating bronchial cancer in COPD patients deserve to be evaluated in prospective studies designed specifically in order to learn their true impact.

Authors have no conflict of interests to declare.