Common Pathogenesis, Shared Clinical Challenges
Bartolome R. Celli1
1Pulmonary and Critical Care Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
(Received in original form July 9, 2011; accepted in final form October 6, 2011)
Correspondence and requests for reprints should be addressed to Bartolome R. Celli, M.D., 75 Francis Street, Boston, MA 02115. E-mail: email@example.com
Proc Am Thorac Soc Vol 9, Iss. 2, pp 74–79, May 1, 2012 Copyright 2012 by the American Thoracic Society DOI: 10.1513/pats.201107-039MS
Internet address: www.atsjournals.org
Environmental inhaled noxious particles have been known to play a role in several lung diseases, including chronic obstructive pulmonary disease (COPD) and lung cancer, the deadliest malignancy in the world in both sexes. Of the known noxious agents, tobacco smoking is the leading preventable cause of death worldwide and is a recognized risk for the development of both diseases. The association between COPD and lung cancer has been demonstrated in population-based studies, lung cancer screening programs, epidemiological surveys, and case control and biological mechanistic studies. There is evidence that cumulative smoking history is associated with the risk of developing lung cancer and COPD; however, the majority of smokers do not develop clinicalCOPDor lung cancer. This suggests the presence of one or several factors that modulate the responses to the offending agents and define the final risk for disease development. The 54th Aspen Lung Conference was convened to provide a forum for a systematic dissection of the potential mechanisms by which persons exposed to the causative agents are able to handleand control the process or, in the case of dysfunctional response, the mechanisms that take off in different directions and result in injury and disease. This summary reviews the themes presented and attempts to integrate them for those clinicians and researchers interested in these topics. The challenges and future directions emanating from the discussions may help frame future conferences and hopefully inspire the interest of young researchers.
Keywords: COPD; lung cancer; smoke-related diseases
It is a privilege to be the summarizer of the 54th Thomas L. Petty Aspen Lung Conference. I have attended four such conferences, first as a fellow in Pulmonary Diseases, then as a young mentor to Fernando J. Martinez, the third time as the Roger Mitchell Lecturer on the important topic of “Phenotypes of COPD,” and today as a summarizer for the conference. To “summarize” is a process to which I will try to adhere, that is “to express the most important facts or ideas about something or someone in a short and clear way.” To summarize this year’s conference is at first sight an overwhelming task because instead of one central topic there were two—chronic obstructive pulmonary disease (COPD) and lung cancer—and because, in spite of putatively similar environmental causes, there has been surprisingly little systematic effort to study them jointly. Credit has to be given to Rubin M. Tuder, York E. Miller, and Jeffrey A. Kern for attempting to fill the need by gathering a group of excellent researchers in an attempt to close the gap and chart the future.
Environmental inhaled noxious particles play a role in several lung diseases, including COPD and lung cancer. Of the known noxious agents, tobacco smoking is the leading preventable cause of death worldwide and is a recognized risk for both diseases (1, 2). The association between COPD and lung cancer has been demonstrated in population-based studies, lung cancer screening programs, epidemiological surveys, and case control and biological mechanistic studies (2–10). The reported incidence ratios for lung cancer range between 0.64 per 1,000 personyears (11) and 4.2 per 1,000 person-years (12, 13). The prevalence of COPD has been much better mapped, ranging between 9 and 18% (14, 15). There is evidence that cumulative smoking history is associated with increased risk of developing lung cancer and COPD; however, the majority of smokers do not develop clinical COPD or lung cancer. This suggests the presence of one or several factors that modulate the response to the offending agents and define the risk for specific disease development (Figure 1). A systematic dissection of the potential mechanisms by which persons exposed to the causative agents are able to handle and control the process or, in the case of dysfunctional response, the mechanisms that take off in different directions and result in injury and disease should provide information that can be used to modify the abnormal responses so that uncontrolled disease is never reached.
GENETICS AND EPIGENETICS IN COPD AND LUNG CANCER
There is ample evidence for familial aggregation of COPD (16– 20) and lung cancer (21–23), but for many years it was argued that this was mostly due to common exposure to offending agents. As summarized by Anne Schwartz, Ph.D. (24), genetic studies, particularly those using genome-wide association and whole genome/exome sequencing, have identified potential genes candidates for lung cancer and COPD. The evidence supports an association between lung cancer and COPD with the genes CHRNA3, CHRNA5 (acetylcholine receptor) located in chromosome 15 (25, 26). However, before we deposit all of our hope in the studies of genetics of these two diseases, Dr. Schwartz reminded us that even in the best scenario, the reported gene associations can only account for 5 to 10% of the explanation for development of lung cancer and or COPD because gene expression is modulated by many factors including environmental and racial background.
The field of epigenetics, defined as the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequence, offers great promise because if gene expression is modifiable, it may also be amenable to therapeutic interventions (27–32). Stephen Baylin, M.D., reviewed the evidence that aberrant gene function and altered patterns of gene expression are key features of cancer (33, 34). The best studied changes are those induced by methylation of bases that result in structural and functional changes in the native DNA (32). The fact that gene expression can be modulated by changing DNA methylation has potential implications for the management of cancer and COPD because drugs could be used to demethylate the base and return the original shape and function of the DNA.
MECHANISMS RESPONSIBLE FOR DISEASE DEVELOPMENT
The mechanisms by which the cells, organs, or the whole body respond to external agents are limited, and these mechanisms may singly or in combination contribute to the development of clinical disease (Figure 1) (35, 36).
INFLAMMATION AND OXIDATIVE STRESS
COPD is understood as a disease of the lung with airway inflammation at the center of the process (37, 38). However, patients with COPD usually develop important systemic manifestations that could also result from systemic inflammation (39). Alvar Agusti, M.D., Ph.D., reminded us that the prevalence and role of systemic inflammation in COPD is not well known. The largest prospective study addressing this knowledge gap is the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points or ECLIPSE, an observational cohort study that is meant to help understand the course of COPD (40). In ECLIPSE there is a higher prevalence of comorbidities (angina, arrhythmia, stroke, hypertension, osteoporosis, rheumatoid arthritis, diabetes, gastroesophageal reflux, anemia, and anxiety) in patients with COPD than in nonsmokers and smokers without COPD. Although in ECLIPSE there was no higher prevalence of comorbidity in the more obstructed patients compared with the less obstructed ones, previous evidence from large database cohorts indicate that the relative risk of dying over 5 years from comorbid conditions is higher the more severe the airflow obstruction (41). In the ECLIPSE study, persistent elevation (baseline and 1 yr) of white blood cell count and IL-6 and IL-1 was present in close to 30% of patients with COPD, whereas this was not seen in smokers and nonsmoking control subjects. Those patients had worse clinical outcomes, including exacerbation rate and mortality, compared with patients without elevated biomarkers, thus supporting the presence of a subgroup of patients with COPD who are persistently inflamed and at risk for poor outcomes. Similar to the association between systemic inflammation and COPD, there appears to be a relationship between inflammation and lung cancer. A. McGarry Houghton, M.D., reviewed the evidence that the relationship seems stronger between the development of lung cancer with emphysema than with the degree of obstruction (42). It has been shown that tumors secrete proteins that cause an influx of neutrophils and therefore act as proinflammatory agents (43), suggesting that inflammation may be the common link between COPD and lung cancer. Shyam Biswal, Ph.D, M.S., explored the potential role of oxidative stress in the COPD/cancer continuum (44–46). Excessive reactive oxygen species generation is associated with oncogenic DNA mutation, supporting the concept of a link between oxidative stress COPD and lung cancer. The nuclear factor (erythroid-derived)-like 2, also known as NFE2L2 or Nrf2, is a transcription factor that in humans is encoded by the NFE2L2 gene and is central to the modulation of the antioxidant response. Because Nrf2 is able to induce genes that are important in combating oxidative stress, thereby activating the body’s own protective response, it is able to protect from a variety of oxidative stress related complications, including cancer.
CELL INJURY AND REPAIR
Airways Progenitor Cells in COPD and Lung Cancer Exposure to certain agents, through inflammation, oxidative stress, or a combination of these and other factors, results in cell injury. This injury needs to be repaired if we are to maintain organ function. This central concept of basic biology was addressed by Susan D. Reynolds, Ph.D. Healing, defined as restoring to health soundness and cure, is achieved through the regenerative lineage, which in turn is based on tissue-specific stem cells. Effective regeneration results in total restoration of the injury with normal frequency and function of the daughter cells. Cells can also heal through repair, where replacement of the cells occurs but results in altered cell frequency or function. This is the most frequent form of response to injury, as has been documented in the naphthaline injury of the trachea model in rats, which is characterized by a repair process that results in different proportions of cells than those originally present (47). If instead of repair the tissue truly regenerated, there would be replication of the stem cells resulting in equal number and function of the original tissue. For stem cells to be effective, they must reside in a protective niche. This constitutes the “seed and soil” concept that states that stem cells need to reside in the appropriate niche if they are to function properly. Recent evidence suggests the presence of resident stem cells capable of regenerating effective lung units after injury (48), thereby providing hope that the lung may be able to regenerate itself if provided with the appropriate milieu and stimulus.
Cellular Senescence and Lung Disease
Judith Campisi, Ph.D., noted that the propensity for memory loss, osteoporosis, vascular disease, sarcopenia, diabetes, renal failure, respiratory failure, and multiple other organ function (49–53) increases exponentially after age 50. The incidence of cancer also increases; however, whereas most diseases are characterized by loss of cell number and function, only in cancer do the cells increase in number and function. The best explanation for this paradox is the development of oncogenic mutations occurring as replication increases as tissues attempt to induce repair (54, 55). During early life, humans remain relatively cancer free, likely due to the presence of tumor suppressor genes, also known as longevity assurance genes. A second class, the gate keeper genes, works through apoptosis to eliminate and arrest damaged mutant genes acting within the cell. Accelerated cell replication increases the chance of cancerigenic cell mutation and is characterized by telomere shortening, a finding that has been reported in lung cancer and COPD and that may be used as a potential marker of accelerated ageing in these diseases (56–59). On the other hand, cellular senescence is a process that converts a cell with mitosis potential into one that is postmitotic and cannot duplicate. In contrast to common belief, senescent cells are metabolically actively and secrete pathobiologically important cytokines (60, 61). One of the crucial regulators of cell cycle, which functions as a tumor suppressor protein, is protein 53 or tumor protein 53 encoded by the TP53 gene. Tumor protein 53 seems to help control senescence and or tissue repair (62). In contrast to the genes associated with senescence, there are some genes for which mutations extend the lifespan. One of these is the mammalian target of rapamycin (mTOR). Inhibiting mTOR with rapamycin prolongs life in mice by 30 to 40% (63). Indeed, the mTOR appears also to be an important mediator of cell injury and repair in COPD (64). These observations taken together suggest some potential therapeutic avenues for COPD and cancer whereby accelerated senescence may play a role. Using transgenic mice, Jack Elias and his laboratory have induced protein production of IL-13, which results in massive inflammation, eosinophilia, and in the deposition of tissue crystal chitinase, the 18 glycosyl hydrolase that has been shown to be present in mice and humans (65–67). Chitinase is meant to dissolve chitin, the constituent of shells present in lower species such as plants, worms, and shellfish. The human circulating version is YKL-40 chitinase-like protein. The levels are increased in patients with asthma and in patients with inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, diabetes mellitus type II, and cancer (68– 71). In mice, the protein is the BRP-39 (66). The mechanisms by which chitinases are involved in cancer generation and COPD remain poorly understood but potentially important if they could be modified.
LUNG CANCER CHEMOPREVENTION AND PERSONALIZED TREATMENT
Robert L. Keith, M.D., advanced the concept of early chemoprevention for lung cancer (72). He reviewed several historical trials using b-carotene, antioxidants, and selenium, all of which were negative. However, experimental chemoprevention treatment using iloprost prevented lung cancer development in mice (73), providing the rational to implement a trial of this agent in patients with atypical cytology in the sputum with cancer prevention as the outcome. In spite of this optimistic information, Ignacio A. Wistuba, M.D., brought to our attention that we may have reached a ceiling treatment effect with the use of surgery and chemotherapy because of a selection of resistant cancer cell clones that do not respond to the usual conventional therapeutic regimes. This sense of lack of effectiveness has spearheaded the need for personalized approach based on molecular profiling of cancer cells. However, the current knowledge of molecular profiling is limited to surgically resected lung tissue from lung cancer patients that have been healthy enough to undergo resection, thereby limiting the applicability of the findings to other patients. In squamous cell lung cancer, there is a progression of changes in the lungs that go through well described stages from dysplasia to metaplasia to squamous cell pathology (74, 75). The same may be true for adenocarcinoma, even though the evidence is less clear. As we move across the pathological progression of lung cancer, there are more gene mutations (76, 77) that can be evaluated in the tissue located just around the tumor (78) or at sites distant from the tumor (79). These findings are exciting because one could use tissue from proximal sites to evaluate potential changes in distant nonaccessible sites. Unfortunately, data from some groups suggest that gene expression may differ at different sites (80). These considerations make a uniform approach to gene mutation studies difficult to recommend and justify the need for the large studies that are being conducted to gain a better understanding of lung cancer pathobiology.
William Pao, M.D., Ph.D., expanded on the concept of targeted therapy, which attempts to deprive tumors of their growth potential. This is done by tailoring cancer therapy on the basis of knowledge of the gene mutation associated with the cancer (81, 82). The typical example is the endothelial growth factor receptor (EGFR) mutation that is associated with sensitivity to the chemotherapeutic agent gefitinib (83, 84). That study showed that the presence of an EGFR1 mutation was associated with a 71% response rate that was not seen in the EGFR2 group. Based on this and several other studies, the group at Vanderbilt University has developed a resource that can be accessed via www.mycancer.com that provides information about gene mutations in lung cancer and how therapies may be tailored to patients with those mutations.
EQUILIBRIA OF HUMANS AND OUR INDIGENOUS MICROBIOTA AFFECTING INFLAMMATION AND NEOPLASIA
We exist in equilibrium with living organisms (bacteria), and this relationship is becoming more important in the development of disease. This relevant topic was addressed by Martin J. Blaser, M.D., who reminded us that there are 1013 human cells in a human being and that coexisting with the same being there are 100 times more bacterial cells. The combination of this genome and microbiome has profound influence on who we are and how we react to environmental changes. As an example of the importance of the microbiome–genome interaction, he elaborated on the observed relationship between Helicobacter pylori (HP) and stomach cancer. HP has been present in humans’ stomachs at least for 58,000 years (85). There is a relationship between the presence of HP in the stomach and the risk of developing gastric cancer. However, the prevalence of HP has decreased to single digits in the Western World due to treatment of HP (86, 87). Over the last few decades, the incidence of gastric cancer has also decreased, but the incidence of esophageal cancer has increased. How this can be related to lung diseases is highlighted by the known relationship between gastroesophageal reflux disease and asthma. There is an inverse association between the prevalence of asthma at younger age and the presence of HP. The hypothesis has been put forth that the administration of antibiotics may have decreased the prevalence of HP and indirectly facilitated asthma increase (88–90). There is little information about the microbiome in COPD (91) and lung cancer, but a recent study of cigarettes using microarray technology followed by cloning and sequencing (92) showed the presence of Acinetobacter, Bacillus burkholderia, Clostridium, Klebsiella, Pseudomonas aeruginosa, and Serratia in > 90% of all cigarette samples tested. Bacteria and their products can be inhaled, and it is thus possible that the presence of clinical disease may be modulated at least in part by the microbiome prevalent in a subject at any given time.
CONCLUSIONS AND FUTURE DIRECTIONS
Great advances have been made in the areas of COPD and lung cancer. Environmental exposure, particularly to cigarette smoke in the Western World and to biomass residues in the Developing World, have fueled the epidemic that is now affecting the whole planet. Genetic studies seem to point to shared susceptibility genes that are common to COPD and lung cancer. The facts that gene function can be modified by epigenetic events and that these events can be measured provide researchers with powerful tools to investigate causative factors and potential therapeutic interventions that can modify initiation and progression of disease. The reasons why some subjects develop lung cancer and some develop COPD when exposed to similar environmental challenges remain unresolved and should be the subject of intense research. That there is an association between these complex diseases is evident through many lines of epidemiological and clinical studies, but how to use this information to the benefit of individual patients remains unsolved. It is likely that a balance between inflammation and its resolution, the capacity to regenerate or repair injured tissue, and the development of long-term changes in immunological response or senescence determines the path that individuals follow. Future studies should integrate resources from the field of COPD and lung cancer to maximize our understanding of these related pathologies. Below are a series of areas that require our attention:
1. Better characterization of exposure to environmental agents including smoking pattern and intensity.
2. As it was in 1959, when the first Aspen Lung Conference took place, there is a need to more comprehensively phenotype patients who are included in studies of lung cancer and COPD. An agreement on the common phenotyping is needed to relate findings from the clinical expressions of disease to discovery from basic science.
3. We need to better understand what regulates host defense against oxidative stress. We should develop tools that can be used clinically to determine the status of oxidative stress and the antioxidant reserve. Such tools could be used to monitor response to therapy.
4. There is a need to collect biological samples and tissue banking (including tumor tissue) in patients enrolled in observational and clinical trials. Molecular profiling should provide information about pathways that can become possible therapy targets.
5. The field of epigenetics offers great hope. How does genetic signature change over time? Can we modify it in ways that modify the risk of clinical disease development?
6. The time is right to conduct observational population studies of subjects who are exposed to environmental agents to establish the responses that lead to the different clinical expressions of disease. Just think how much benefit has been gained from such studies of cardiovascular disease risk factors.
7. Continue expansion of the knowledge gained in the use of personalized medicine for cancer and apply it to COPD. It is likely that different phenotypes of COPD will require different therapies.
As the conference drew to an end, it became clear that the most important conclusion of the conference is the need to join efforts to study COPD and lung cancer as different clinical expressions of diseases with many common roots. This could be extended to diseases such as idiopathic pulmonary fibrosis, where there is evidence that exposure to tobacco smoke may cause early changes of idiopathic pulmonary fibrosis in subjects with airflow obstruction (93). The efforts to elucidate the pathways that lead to different clinical expressions in the presence of common environmental exposure should lead to exciting new discoveries and revolutionize how we approach these diseases. In 1892, Sir William Osler published his book Principles and Practice of Medicine. In that book, he devoted only one sentence to lung cancer, stating that it was a rare disease. In just over one century, lung cancer kills more persons than all of the other cancers combined. Whereas the medical community has been unable to decipher the mechanism behind the pathobiology of lung cancer, the advent of technological progress and teamwork is changing the way we approach the study of this disease. This is also occurring in COPD (36). In both areas, the application of new approaches is widening the horizons and providing promises of a better future for our patients.
Author disclosures are available with the text of this article at www.atsjournals.org.
1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74–108.
2. Pirozynski M. 100 years of lung cancer. Respir Med 2006;100:2073–2084.
3. Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J 2009;33:1165–1185.
4. Celli B, Decramer M, Kesten S, Liu D, Mehra S, Tashkin DP. Mortality in the 4-year trial of tiotropium (UPLIFT) in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009;180: 948–955.
5. Lange JH, Mastrangelo G, Fadda E, Priolo G, Montemurro D, Buja A, Grange JM. Elevated lung cancer risk shortly after smoking cessation: is it due to a reduction of endotoxin exposure? Med Hypotheses 2005; 65:534–541.
6. Lange P, Nyboe J, Appleyard M, Jensen G, Schnohr P. Ventilatory function and chronic mucus hypersecretion as predictors of death from lung cancer. Am Rev Respir Dis 1990;141:613–617.
7. Loganathan RS, Stover DE, Shi W, Venkatraman E. Prevalence of COPD in women compared to men around the time of diagnosis of primary lung cancer. Chest 2006;129:1305–1312.
8. Lopez-Encuentra A, Astudillo J, Cerezal J, Gonzalez-Aragoneses F, Novoa N, Sanchez-Palencia A. Prognostic value of chronic obstructive pulmonary disease in 2994 cases of lung cancer. Eur J Cardiothorac Surg 2005;27:8–13.
9. Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet 1997;349:1269–1276.
10. Sin DD, Anthonisen NR, Soriano JB, Agusti AG. Mortality in COPD: role of comorbidities. Eur Respir J 2006;28:1245–1257.
11. Smith BD, Smith GL, Hurria A, Hortobagyi GN, Buchholz TA. Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol 2009;27:2758–2765.
12. McGarvey LP, John M, Anderson JA, Zvarich M, Wise RA. Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee. Thorax 2007;62:411–415.
13. Celli B, Vestbo J, Jenkins CR, Jones PW, Ferguson GT, Calverley PM, Yates JC, Anderson JA, Willits LR, Wise RA. Sex differences in mortality and clinical expressions of patients with chronic obstructive pulmonary disease: the TORCH Experience. Am J Respir Crit Care Med 2010;183:317–322.
14. Menezes AM, Perez-Padilla R, Jardim JR, Muino A, Lopez MV, Valdivia G, Montes de Oca M, Talamo C, Hallal PC, Victora CG. Chronic obstructive pulmonary disease in five Latin American cities (the PLATINO study): a prevalence study. Lancet 2005;366:1875–1881.
15. Buist AS, McBurnie MA, Vollmer WM, Gillespie S, Burney P, Mannino DM, Menezes AM, Sullivan SD, Lee TA, Weiss KB, et al. International variation in the prevalence of COPD (the BOLD Study): a population-based prevalence study. Lancet 2007;370:741–750.
16. Pillai SG, Ge D, Zhu G, Kong X, Shianna KV, Need AC, Feng S, Hersh CP, Bakke P, Gulsvik A, et al. A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genet 2009;5:e1000421.
17. Pillai SG, Kong X, Edwards LD, Cho MH, Anderson WH, Coxson HO, Lomas DA, Silverman EK. Loci identified by genome-wide association studies influence different disease-related phenotypes in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010;182:1498–1505.
18. Silverman EK, Mosley JD, Rao DC, Palmer LJ, Province MA, Elston RC, Weiss ST, Campbell EJ. Linkage analysis of alpha 1-antitrypsin deficiency: lessons for complex diseases. Hum Hered 2001;52:223–232.
19. Silverman EK, Palmer LJ, Mosley JD, Barth M, Senter JM, Brown A, Drazen JM, Kwiatkowski DJ, Chapman HA, Campbell EJ, et al. Genomewide linkage analysis of quantitative spirometric phenotypes in severe early-onset chronic obstructive pulmonary disease. Am J Hum Genet 2002;70:1229–1239.
20. Silverman EK, Spira A, Pare PD. Genetics and genomics of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2009;6:539–542.
21. Punturieri A, Szabo E, Croxton TL, Shapiro SD, Dubinett SM. Lung cancer and chronic obstructive pulmonary disease: needs and opportunities for integrated research. J Natl Cancer Inst 2009;101:554–559.
22. Sundar IK, Mullapudi N, Yao H, Spivack SD, Rahman I. Lung cancer and its association with chronic obstructive pulmonary disease: update on nexus of epigenetics. Curr Opin Pulm Med 2011;17:279–285.
23. Kurishima K, Satoh H, Ishikawa H, Yamashita YT, Homma T, Ohtsuka M, Sekizawa K. Lung cancer patients with chronic obstructive pulmonary disease. Oncol Rep 2001;8:63–65.
24. Schwartz AG, Wenzlaff AS, Bock CH, Ruterbusch JJ, Chen W, Cote ML, Artis AS, Van Dyke AL, Land SJ, Harris CC, et al. Admixture mapping of lung cancer in 1812 African-Americans. Carcinogenesis 2010;32:312–317.
25. Young RP, Hopkins RJ, Whittington CF, Hay BA, Epton MJ, Gamble GD. Individual and cumulative effects of GWAS susceptibility loci in lung cancer: associations after sub-phenotyping for COPD. PLoS One 2011;6:e16476.
26. Yoon KA, Park JH, Han J, Park S, Lee GK, Han JY, Zo JI, Kim J, Lee JE, Takahashi A, et al. A genome-wide association study reveals susceptibility variants for non-small cell lung cancer in the Korean population. Hum Mol Genet 2010;19:4948–4954.
27. Anto JM, Vermeire P, Vestbo J, Sunyer J. Epidemiology of chronic obstructive pulmonary disease. Eur Respir J 2001;17:982–994.
28. Yang IV, Schwartz DA. Epigenetic control of gene expression in the lung. Am J Respir Crit Care Med 2011;183:1295–1301.
29. Adcock IM, Tsaprouni L, Bhavsar P, Ito K. Epigenetic regulation of airway inflammation. Curr Opin Immunol 2007;19:694–700.
30. Issa JP, Baylin SB. Epigenetics and human disease. Nat Med 1996;2:281– 282.
31. Bowman RV, Wright CM, Davidson MR, Francis SM, Yang IA, Fong KM. Epigenomic targets for the treatment of respiratory disease. Expert Opin Ther Targets 2009;13:625–640.
32. Jones PA, Baylin SB. The epigenomics of cancer. Cell 2007;128:683–692.
33. Baylin S, Bestor TH. Altered methylation patterns in cancer cell genomes: cause or consequence? Cancer Cell 2002;1:299–305.
34. Baylin SB. Stem cells, cancer, and epigenetics. Cambridge, MA: Harvard Stem Cell Institute; 2008.
35. Loscalzo J. Systems biology and personalized medicine: a network approach to human disease. Proc Am Thorac Soc 2011;8:196–198.
36. Agusti A, Sobradillo P, Celli B. Addressing the complexity of chronic obstructive pulmonary disease: from phenotypes and biomarkers to scale-free networks, systems biology, and P4 medicine. Am J Respir Crit Care Med 2100;183:1129–1137.
37. Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23:932–946.
38. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007;176:532–555.
39. Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca M, Mendez RA, Pinto Plata V, Cabral HJ. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 2004;350:1005–1012.
40. Agusti A, Calverley PM, Celli B, Coxson HO, Edwards LD, Lomas DA, MacNee W, Miller BE, Rennard S, Silverman EK, et al. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res 2010;11:122.
41. Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J 2008;32:962–969.
42. Houghton AM, Mouded M, Shapiro SD. Common origins of lung cancer and COPD. Nat Med 2008;14:1023–1024.
43. Houghton AM. The paradox of tumor-associated neutrophils: fueling tumor growth with cytotoxic substances. Cell Cycle 2010;9:1732– 1737.
44. Malhotra D, Thimmulappa R, Navas-Acien A, Sandford A, Elliott M, Singh A, Chen L, Zhuang X, Hogg J, Pare P, et al. Decline in NRF2- regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator, DJ-1. Am J Respir Crit Care Med 2008;178:592–604.
45. Singh A,Wu H, Zhang P, Happel C, Ma J, Biswal S. Expression of ABCG2 (BCRP) is regulated by Nrf2 in cancer cells that confers side population and chemoresistance phenotype. Mol Cancer Ther 2010;9:2365–2376.
46. Purdue MP, Gold L, Jarvholm B, Alavanja MC, Ward MH, Vermeulen R. Impaired lung function and lung cancer incidence in a cohort of Swedish construction workers. Thorax 2007;62:51–56.
47. Reynolds SD, Hong KU, Giangreco A, Mango GW, Guron C, Morimoto Y, Stripp BR. Conditional clara cell ablation reveals a self-renewing progenitor function of pulmonary neuroendocrine cells. Am J Physiol Lung Cell Mol Physiol 2000;278:L1256–L1263.
48. Kajstura J, Rota M, Hall SR, Hosoda T, D’Amario D, Sanada F, Zheng H, Ogorek B, Rondon-Clavo C, Ferreira-Martins J, et al. Evidence for human lung stem cells. N Engl J Med 2011;364:1795–1806.
49. Campisi J. Cellular senescence: putting the paradoxes in perspective. Curr Opin Genet Dev 2011;21:107–112.
50. Campisi J. Aging and cancer cell biology, 2007. Aging Cell 2007;6:261– 263.
51. Campisi J, Kim SH, Lim CS, Rubio M. Cellular senescence, cancer and aging: the telomere connection. Exp Gerontol 2001;36:1619–1637.
52. de Keizer PL, Laberge RM, Campisi J. p53: pro-aging or pro-longevity? Aging (Albany NY) 2010;2:377–379.
53. Yaswen P, Campisi J. Oncogene-induced senescence pathways weave an intricate tapestry. Cell 2007;128:233–234.
54. Bartels CL, Tsongalis GJ. MicroRNAs: novel biomarkers for human cancer. Clin Chem 2009;55:623–631.
55. Ko JL, Chiao MC, Chang SL, Lin P, Lin JC, Sheu GT, Lee H. A novel p53 mutant retained functional activity in lung carcinomas. DNA Repair (Amst) 2002;1:755–762.
56. Mui TS,Man JM,McElhaney JE, Sandford AJ, Coxson HO, Birmingham CL, Li Y, Man SF, Sin DD. Telomere length and chronic obstructive pulmonary disease: evidence of accelerated aging. J Am Geriatr Soc 2009;57:2372–2374.
57. Jang JS, Choi YY, Lee WK, Choi JE, Cha SI, Kim YJ, Kim CH, Kam S, Jung TH, Park JY. Telomere length and the risk of lung cancer. Cancer Sci 2008;99:1385–1389.
58. Morla M, Busquets X, Pons J, Sauleda J, MacNee W, Agusti AG. Telomere shortening in smokers with and without COPD. Eur Respir J 2006;27:525–528.
59. Bisoffi M, Heaphy CM, Griffith JK. Telomeres: prognostic markers for solid tumors. Int J Cancer 2006;119:2255–2260.
60. Coppe JP, Patil CK, Rodier F, Krtolica A, Beausejour CM, Parrinello S, Hodgson JG, Chin K, Desprez PY, Campisi J. A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen. PLoS ONE 2010;5:e9188.
61. Coppe JP, Patil CK, Rodier F, Sun Y,Munoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 2008;6:2853–2868.
62. Feng Z, Hu W, Rajagopal G, Levine AJ. The tumor suppressor p53: cancer and aging. Cell Cycle 2008;7:842–847.
63. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009;460:392–395.
64. Yoshida T, Mett I, Bhunia AK, Bowman J, Perez M, Zhang L, Gandjeva A, Zhen L, Chukwueke U, Mao T, et al. Rtp801, a suppressor of mTOR signaling, is an essential mediator of cigarette smoke-induced pulmonary injury and emphysema. Nat Med 2010;16:767–773.
65. Chupp GL, Lee CG, Jarjour N, Shim YM, Holm CT, He S, Dziura JD, Reed J, Coyle AJ, Kiener P, et al. A chitinase-like protein in the lung and circulation of patients with severe asthma. N Engl J Med 2007; 357:2016–2027.
66. Lee CG, Hartl D, Lee GR, Koller B, Matsuura H, Da Silva CA, Sohn MH, Cohn L, Homer RJ, Kozhich AA, et al. Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13-induced tissue responses and apoptosis. J Exp Med 2009;206:1149–1166.
67. Ober C, Chupp GL. The chitinase and chitinase-like proteins: a review of genetic and functional studies in asthma and immune-mediated diseases. Curr Opin Allergy Clin Immunol 2009;9:401–408.
68. Johansen JS, Schultz NA, Jensen BV. Plasma YKL-40: a potential new cancer biomarker? Future Oncol 2009;5:1065–1082.
69. Kazakova MH, Sarafian VS. YKL-40: a novel biomarker in clinical practice? Folia Med (Plovdiv) 2009;51:5–14.
70. Rathcke CN, Vestergaard H. YKL-40: an emerging biomarker in cardiovascular disease and diabetes. Cardiovasc Diabetol 2009;8:61.
71. Roslind A, Johansen JS. YKL-40: a novel marker shared by chronic inflammation and oncogenic transformation. Methods Mol Biol 2009; 511:159–184.
72. Keith RL. Chemoprevention of lung cancer. Proc Am Thorac Soc 2009; 6:187–193.
73. Keith RL, Miller YE, Hudish TM, Girod CE, Sotto-Santiago S, Franklin WA, Nemenoff RA, March TH, Nana-Sinkam SP, Geraci MW. Pulmonary prostacyclin synthase overexpression chemoprevents tobacco smoke lung carcinogenesis in mice. Cancer Res 2004;64:5897–5904.
74. Wistuba II. Genetics of preneoplasia: lessons from lung cancer. Curr Mol Med 2007;7:3–14.
75. Wistuba II, Meyerson M. Chromosomal deletions and progression of premalignant lesions: less is more. Cancer Prev Res (Phila) 2008;1: 404–408.
76. Carbone DP. Profiles in variation: lung carcinogenesis. Cancer Prev Res (Phila) 2009;2:695–697.
77. Kadara H, Lacroix L, Behrens C, Solis L, Gu X, Lee JJ, Tahara E, Lotan D, Hong WK, Wistuba II, et al. Identification of gene signatures and molecular markers for human lung cancer prognosis using an in vitro lung carcinogenesis system. Cancer Prev Res (Phila) 2009;2:702–711.
78. Boelens MC, van den Berg A, Fehrmann RS, Geerlings M, de Jong WK, te Meerman GJ, Sietsma H, Timens W, Postma DS, Groen HJ. Current smoking-specific gene expression signature in normal bronchial epithelium is enhanced in squamous cell lung cancer. J Pathol 2009;218:182–191.
79. Spira A, Beane JE, Shah V, Steiling K, Liu G, Schembri F, Gilman S, Dumas YM, Calner P, Sebastiani P, et al. Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer. Nat Med 2007;13:361–366.
80. Tang X, Shigematsu H, Bekele BN, Roth JA, Minna JD, Hong WK, Gazdar AF, Wistuba II. EGFR tyrosine kinase domain mutations are detected in histologically normal respiratory epithelium in lung cancer patients. Cancer Res 2005;65:7568–7572.
81. Pao W, Iafrate AJ, Su Z. Genetically informed lung cancer medicine. J Pathol 2011;223:230–240.
82. Pao W, Kris MG, Iafrate AJ, Ladanyi M, Janne PA, Wistuba II, Miake- Lye R, Herbst RS, Carbone DP, Johnson BE, et al. Integration of molecular profiling into the lung cancer clinic. Clin Cancer Res 2009; 15:5317–5322.
83. Mok T, Wu YL, Zhang L. A small step towards personalized medicine for non-small cell lung cancer. Discov Med 2009;8:227–231.
84. Reck M. A major step towards individualized therapy of lung cancer with gefitinib: the IPASS trial and beyond. Expert Rev Anticancer Ther 2010;10:955–965.
85. Atherton JC, Blaser MJ. Coadaptation of Helicobacter pylori and humans: ancient history, modern implications. J Clin Invest 2009;119: 2475–2487.
86. Blaser MJ. Theodore E. Woodward Award: global warming and the human stomach: microecology follows macroecology. Trans Am Clin Climatol Assoc 2005;116:65–75, discussion 75–76.]
87. Blaser MJ, Berg DE. Helicobacter pylori genetic diversity and risk of human disease. J Clin Invest 2001;107:767–773.
88. D’Elios MM, Codolo G, Amedei A, Mazzi P, Berton G, Zanotti G, Del Prete G, de Bernard M. Helicobacter pylori, asthma and allergy. FEMS Immunol Med Microbiol 2009;56:1–8.
89. Raj SM, Choo KE, Noorizan AM, Lee YY, Graham DY. Evidence against Helicobacter pylori being related to childhood asthma. J Infect Dis 2009;199:914–915.
90. Reibman J, Marmor M, Filner J, Fernandez-Beros ME, Rogers L, Perez- Perez GI, Blaser MJ. Asthma is inversely associated with Helicobacter pylori status in an urban population. PLoS ONE 2008;3: e4060.
91. Erb-Downward JR, Thompson DL, Han MK, Freeman CM, McCloskey L, Schmidt LA, Young VB, Toews GB, Curtis JL, Sundaram B, et al. Analysis of the lung microbiome in the „healthy“ smoker and in COPD. PLoS ONE 2011;6:e16384.
92. Sapkota AR, Berger S, Vogel TM. Human pathogens abundant in the bacterial metagenome of cigarettes. Environ Health Perspect 2010; 118:351–356.
93. Washko GR, Hunninghake GM, Fernandez IE, Nishino M, Okajima Y, Yamashiro T, Ross JC, Este´par RS, Lynch DA, Brehm JM, et al. The COPDGene Investigators. Lung volumes and emphysema in smokers with interstitial lung abnormalities. N Engl J Med 2011;364:897–906.
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