| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
Correspondence and requests for reprints should be addressed to Jerome S. Brody, M.D., Pulmonary Center, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118. E-mail: jbrody{at}bu.edu
ABSTRACT
Both lung cancer and chronic obstructive pulmonary disease (COPD) are associated with cigarette smoking, which, by generating reactive oxidant species, induces a chronic inflammatory state in the lung. Activation, particularly of nuclear factor-
B, occurs in both cancer and COPD, and expression of a number of genes is altered in both diseases. In lung cancer, DNA damage, lack of DNA repair, and genomic instability predominate, whereas matrix degradation, lack of repair, and an intense immune response predominate in COPD. The reasons for the different responses to a common inflammatory response induced by smoking remain to be determined, but likely lie in genetic polymorphisms in genes that regulate genome integrity in cancer and that regulate the immune response to tissue destruction in COPD.
Key Words: genomic instability • inflammation • lung immune response • reactive oxygen species
It has long been known that cigarette smoke plays a causal role in both chronic obstructive pulmonary disease (COPD) and lung cancer. In addition, smokers who have COPD appear to be at increased risk for developing lung cancer, suggesting that there is some link between the processes that induce COPD and those that induce lung cancer (1–3). The odds ratio, or relative risk for developing lung cancer, increases 1.4- to 2.7-fold with moderate COPD and 2.8- to 4.9-fold with severe COPD. The likelihood of developing lung cancer within 10 yr is threefold greater in subjects with mild to moderate COPD versus smokers with normal lung function and close to 10-fold greater in subjects with severe COPD (1). Although cumulative smoking history increases the risk for developing both diseases, it is important to recognize that the majority of smokers develop neither COPD nor lung cancer.
CHRONIC INFLAMMATION
Cigarette smoke contains an extremely high concentration of oxidants together with a number of known carcinogens (4). The reactive oxidant species (ROS) generated by smoking induce inflammation in the lung and its airways as well as cause mutations in airway epithelial cell DNA. The risk of developing lung cancer does not disappear after smoking has been discontinued. In the United States, lung cancer now occurs in as many former smokers as current smokers (5). We have recently shown that expression of a large number of genes is altered in the airway epithelial cells of smokers (6). Expression of many of these genes, especially antioxidant and drug-metabolizing genes, returns to normal within 2 yr of smoking cessation, but expression of a number of putative oncogenes and tumor suppressor genes remains altered for decades after smoking has been discontinued. These genes may be in part responsible for the occurrence of lung cancer years after individuals have stopped smoking. In a similar fashion, the local lung inflammation initiated by ROS in cigarette smoke, persists in subjects with COPD after they have stopped smoking, generating smoking-independent oxidant stress and explaining the persistence and progression of the disease after smoking has been discontinued (7).
Chronic inflammation has been shown to lead to cancer in a number of organs. Reflux esophagitis, Helicobacter pylori gastric inflammation, viral hepatitis, ulcerative colitis, and cigarette smoking are all associated with chronic inflammation and an increased incidence of local cancers (8). In ulcerative colitis, DNA mutational "fingerprints" of dysplastic and normal colonic crypts show that DNA mutations spread by clonal expansion of proliferating cells and by fusion of adjacent crypts moderated in part by crypt cell turnover and cell death (9). The clonal expansion of crypt cells occurs because of the growth advantage and apoptosis resistance of cells that have been induced by continued inflammation and generation of ROS.
There is considerable evidence that links chronic inflammation, and the transcription factor nuclear factor (NF)-B, to cancer (10). Recent studies have also demonstrated the synergistic interaction of the classic mediator of inflammation, NF-B, and the classic tumor suppressor gene, p53, which acts as a general inhibitor of inflammation (10). p53 acts as an inhibitor of transcription of a number of genes with NF-B–dependent promoters. As a result, cytokines, macrophage activation, and markers of inflammation are increased in mice with absent p53 who are injected with lipopolysaccharide compared with wild-type mice with functional p53. Because p53 is often mutated by cigarette smoke, in COPD and in lung cancer, one might expect that oxidant activation of NF-B–mediated inflammation might be excessive, absent the suppressive effect of p53.
The genetic link between chronic lung inflammation and lung cancer has recently been reviewed by comparing QTL (quantitative trait loci, or chromosomal locations of putative susceptibility genes) in mouse models of chronic lung inflammation and mouse models of lung cancer (11). Combined susceptibility loci have been identified at eight chromosomal sites for genes such as Kras, TNF
, and so forth. The authors also point out that a number of animal studies demonstrate the antitumor effects of both steroidal and nonsteroidal antiinflammatory drugs.
GENE EXPRESSION PROFILING
One way to explore the relation between COPD and lung cancer is to compare global gene expression in resected cancerous and emphysematous lung tissue using high-density gene expression arrays. A number of articles have detailed patterns of gene expression in various lung cancer cell types and stages of lung cancer (12). Similar studies from other types of cancer and many in vitro studies have been summarized in a now classic "Hallmarks of Cancer" article (13) (see Table 1). Until recently, there have been no such studies of lung tissue from subjects with COPD. Three studies using different gene expression platforms in different COPD populations have generated somewhat similar findings in terms of functional categories of genes altered in emphysema (although individual genes significantly vary due to differences in study design and data mining) (14–16). Together with previous studies reporting expression of specific genes and proteins in lungs and bronchial biopsies of subjects with COPD (17), a "Hallmarks of COPD" can be constructed (see Table 1). Despite the common inciting agent, cigarette smoke, which generates ROS and inflammation in both COPD and lung cancer, the resulting biological processes differ considerably. In cancer, uncontrolled cell proliferation, lack of cellular apoptosis, tissue invasion, and angiogenesis predominate. In COPD, apoptosis, matrix degradation, inflammation, and local and systemic immune responses predominate. The reasons for these rather different responses to a common causal agent, cigarette smoke, which presumably generates ROS and inflammation in all smokers, remain unclear.
|
We have since extended these studies to current and former smokers with lung cancer and have begun to study current and former smokers with COPD. It is clear that subjects with lung cancer have a unique gene expression profile in airway epithelial cells that distinguishes them from comparable subjects without lung cancer and this profile may have value as a diagnostic tool. Preliminary studies of subjects with COPD suggest that there may also be a gene expression profile that is characteristic of COPD. We have already identified a number of genes whose expression levels correlate in a negative or positive fashion with FEV1 and are not altered in subjects with lung cancer.
Although our cancer studies may provide new tools for the early diagnosis of lung cancer, gene expression profiles will not replace the FEV1 or chest computed tomographic scans for the diagnosis of COPD. We believe that the ultimate value of such studies lies in the integrative analysis of expression data using increasingly sophisticated bioinformatic approaches for defining transcriptional activation and protein–protein interaction networks and signaling pathways. It is this parsing of expression data that will begin to provide fundamental biological insights into disease pathogenesis and will ultimately identify potential therapeutic targets for preventing or treating disease.
PATHWAYS TO LUNG CANCER AND COPD
Despite all of the studies noted above, the reason that some smokers develop COPD, some develop lung cancer, some develop both diseases, and some are free of disease remains unclear. Figure 1 depicts similarities and differences in the major biological and molecular events that lead to each disease and provides some ideas about pathogenetic differences between COPD and lung cancer. Smoke contains high concentrations of oxidants and free radicals (ROS) together with thousands of particulates. Local antioxidant and metabolizing enzymes inactivate many potentially toxic species and in the process often generate more ROS. As noted earlier, NF-B activation and subsequent transactivation of inflammation-related genes appear to play a central role in both COPD and cancer. These events occur to some extent in all smokers, even those without evident lung disease. Which genes are activated and which are suppressed in smokers may be a major determinant of whether a smoker remains disease free, or develops cancer and/or COPD. In COPD, matrix degradation and excessive apoptosis, with loss of blood vessels and incomplete tissue repair, predominate. In lung cancer, excessive DNA damage and incomplete DNA repair predominate. The diseases diverge further, with genomic instability causing further chromosomal abnormalities that result in clonal expansion of cells that have a growth advantage occurring in cancer, whereas an intense immune response and further inflammation predominate in COPD. The process by which these events diverge is unclear; it may be a consequence of random mutations in DNA. More likely, heritable genetic polymorphisms influence susceptibility to DNA or connective tissue damage, efficiency of DNA or connective tissue repair, the intensity of immune responses to constituents of tobacco smoke or genomic instability, determine the disease pathway taken. It is also likely that genetic factors explain the absence of either disease in most smokers. We can certainly learn as much from studying the genomics and genetics of individuals who have substantial smoking histories and no evidence of either COPD or cancer as we can from studying smokers with cancer or COPD.
|
FOOTNOTES
Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form March 20, 2006; accepted in final form April 26, 2006)
REFERENCES
This article has been cited by other articles:
|
|
 |
|
  S. M. Dubinett, D. R. Aberle, D. P. Tashkin, and J. T. Mao The Partners--Airflow Obstruction, Emphysema, and Lung Cancer Am. J. Respir. Crit. Care Med., October 1, 2008; 178(7): 665 - 666. [Full Text] [PDF]
|
|
|
|
|
|
D. O. Wilson, J. L. Weissfeld, A. Balkan, J. G. Schragin, C. R. Fuhrman, S. N. Fisher, J. Wilson, J. K. Leader, J. M. Siegfried, S. D. Shapiro, et al. Association of Radiographic Emphysema and Airflow Obstruction with Lung Cancer Am. J. Respir. Crit. Care Med., October 1, 2008; 178(7): 738 - 744. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Punturieri, T. L. Croxton, G. G. Weinmann, and J. P. Kiley Chronic Obstructive Pulmonary Disease: A View from the NHLBI Am. J. Respir. Crit. Care Med., September 1, 2008; 178(5): 441 - 443. [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Fabbri, F. Luppi, B. Beghe, and K. F. Rabe Complex chronic comorbidities of COPD Eur. Respir. J., January 1, 2008; 31(1): 204 - 212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P. de Torres, G. Bastarrika, J. P. Wisnivesky, A. B. Alcaide, A. Campo, L. M. Seijo, J. C. Pueyo, A. Villanueva, M. D. Lozano, U. Montes, et al. Assessing the Relationship Between Lung Cancer Risk and Emphysema Detected on Low-Dose CT of the Chest Chest, December 1, 2007; 132(6): 1932 - 1938. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
