Pre-malignant processes of smoking-induced lung adenocarcinoma development: A conceptual biological model


Chronic exposure to cigarette smoke is the leading cause of human lung cancer and its most prevalent form, adenocarcinoma. However, the mechanisms by which smoking induces adenocarcinoma are largely inferred from the analysis of fully developed tumors. The current work focuses on the early events that precede the existence of clinically detectable tumors and where the progressive mechanisms are believed to be different from the ones driving established tumor growth. Biological information was drawn from the literature and generalized into a conceptual model, or framework, which describes and integrates the main processes involved in the early stages of smoking-induced lung adenocarcinoma development. No such integrative representation currently exists. The biological framework presented here is based on the “field of injury” of the lung. It covers the smoking-induced stepwise transition of unexposed (naive) lung tissue to the first appearance of neoplastic cells through defined tissue states referred to as pre-field and field. Each tissue state exhibits its own formalized characteristics (or phenotype properties), which evolve as a result of the combined effects of smoking, the interactions between the different tissue properties, and the local environment represented in the framework as lung inflammation and immune surveillance. The resulting network of influences between the lung tissue states and properties provides a good understanding of the early events involved in lung adenocarcinoma triggered by smoking. The resulting conceptual model—an integrative mechanistic hypothesis—can explain a broad range of cigarette smoking and smoking cessation scenarios.

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Tobin, F. , Vuillaume, G. , Talikka, M. , Diserens, G. , Diserens, G. , Peitsch, M. and Hoeng, J. (2013) Pre-malignant processes of smoking-induced lung adenocarcinoma development: A conceptual biological model. Advances in Lung Cancer, 2, 32-53. doi: 10.4236/alc.2013.22006.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Herbst, R.S., Heymach, J.V. and Lippman, S.M. (2008) Lung cancer. The New England Journal of Medicine, 359, 1367-1380.
[2] CDC (2004) The health consequences of smoking: Report of the surgeon general. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.
[3] Parkin, D.M., Bray, F., Ferlay, J., et al. (2005) Global cancer statistics, 2002. CA: A Cancer Journal for Clinicians, 55, 74-108. doi:10.3322/canjclin.55.2.74
[4] Burns, D.M., Anderson, C.M. and Gray, N. (2011) Do changes in cigarette design influence the rise in adenocarcinoma of the lung? Cancer Causes & Control, 22, 13-22. doi:10.1007/s10552-010-9660-0
[5] Franceschi, S. and Bidoli, E. (1999) The epidemiology of lung cancer. Annals of Oncology, 10, S3-S6. doi:10.1093/annonc/10.suppl_5.S3
[6] Sun, S., Schiller, J.H. and Gazdar, A.F. (2007) Lung cancer in never smokers—A different disease. Nature Reviews Cancer, 7, 778-790.
[7] Lantuejoul, S., Salameire, D., Salon, C., et al. (2009) Pulmonarypreneoplasia—Sequential molecular carcinogenetic events. Histopathology, 54, 43-54. doi:10.1111/j.1365-2559.2008.03182.x
[8] Peto, R., Darby, S., Deo, H., et al. (2000) Smoking, smoking cessation, and lung cancer in the UK since 1950: Combination of national statistics with two case—Control studies. British Medical Journal, 321, 323-329. doi:10.1136/bmj.321.7257.323
[9] Beane, J., Sebastiani, P., Liu, G., et al. (2007) Reversible and permanent effects of tobacco smoke exposure on airway epithelial gene expression. Genome Biology, 8, R201. doi:10.1186/gb-2007-8-9-r201
[10] Gower, A.C., Steiling, K., Brothers, J.F., et al. (2011) Transcriptomic studies of the airway field of injury associated with smoking-related lung disease. Proceedings of the American Thoracic Society, 8, 173-179. doi:10.1513/pats.201011-066MS
[11] Izzotti, A., Bagnasco, M., Cartiglia, C., et al. (2005) Chemoprevention of genome, transcriptome, and proteome alterations induced by cigarette smoke in rat lung. European Journal of Cancer, 41, 1864-1874. doi:10.1016/j.ejca.2005.04.011
[12] Powell, C.A., Spira, A., Derti, A., et al. (2003) Gene expression in lung adenocarcinomas of smokers and nonsmokers. American Journal of Respiratory Cell and Molecular Biology, 29, 157-162. doi:10.1165/rcmb.2002-0183RC
[13] Spira, A., Beane, J., Shah, V., et al. (2004) Effects of cigarette smoke on the human airway epithelial cell transcriptome. Proceedings of the National Academy of Sciences of the United States of America, 101, 10143-10148. doi:10.1073/pnas.0401422101
[14] Spira, A., Schembri, F., Beane, J., et al. (2004) Impact of cigarette smoke on the normal airway transcriptome. Chest, 125, 115S.
[15] Spira, A., Beane, J.E., Shah, V., et al. (2007) Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer. Nature Medicine, 13, 361-366.
[16] Stav, D., Bar, I. and Sandbank, J. (2008) Gene expression subtraction of non-cancerous lung from smokers and non-smokers with adenocarcinoma, as a predictor for smokers developing lung cancer. Journal of Experimental & Clinical Cancer Research, 27, 45. doi:10.1186/1756-9966-27-45
[17] Gebel, S., Gerstmayer, B., Bosio, A., et al. (2004) Gene expression profiling in respiratory tissues from rats exposed to mainstream cigarette smoke. Carcinogenesis, 25, 169-178. doi:10.1093/car cin/bgg193
[18] Gebel, S., Gerstmayer, B., Kuhl, P., et al. (2006) The kinetics of transcriptomic changes induced by cigarette smoke in rat lungs reveals a specific program of defense, inflammation, and circadian clock gene expression. Toxicological Sciences, 93, 422-431. doi:10.1093/toxsci/kfl071
[19] Meng, Q.R., Gideon, K.M., Harbo, S.J., et al. (2006) Gene expression profiling in lung tissues from mice exposed to cigarette smoke, lipopolysaccharide, or smoke plus lipopolysaccharide by inhalation. Inhalation Toxicology, 18, 555-568.
[20] Schwartz, A.G., Prysak, G.M., Bock, C.H., et al. (2007) The molecular epidemiology of lung cancer. Carcinogenesis, 28, 507-518. doi:10.1093/carcin/bgl253
[21] Kerr, K.M. (2001) Pulmonary preinvasive neoplasia. Journal of Clinical Pathology, 54, 257-271. doi:10.1136/jcp.54.4.257
[22] Wistuba, I.I. and Gazdar, A.F. (2006) Lung cancer preneoplasia. Annual Review, 1, 331-348. doi:10.1146/annurev.pathol.1.110304.100103
[23] Borczuk, A.C. and Powell, C.A. (2007) Expression profiling and lung cancer development. Proceedings of the American Thoracic Society, 4, 127-132. doi:10.1513/pats.200607-143JG
[24] Steiling, K., Ryan, J., Brody, J.S. et al. (2008) The field of tissue injury in the lung and airway. Cancer Prevention Research, 1, 396-403. doi:10.1158/1940-6207.CAPR-08-0174
[25] Stampfli, M.R. and Anderson, G.P. (2009) How cigarette smoke skews immune responses to promote infection, lung disease and cancer. Nature Reviews Immunology, 9, 377-384.
[26] Wooten, J.B., Chouchane, S. and McGrath, T.E. (2011) Tobacco smoke constituents affecting oxidative stress. Cigarette Smoke and Oxidative Stress, 5-46.
[27] Aoshiba, K. and Nagai, A. (2003) Oxidative stress, cell death, and other damage to alveolar epithelial cells induced by cigarette smoke. Tobacco Induced Diseases, 1, 219-226.
[28] Seet, R.C., Lee, C.Y., Loke, W.M., et al. (2011) Biomarkers of oxidative damage in cigarette smokers: Which biomarkers might reflect acute versus chronic oxidative stress? Free Radical Biology and Medicine, 50, 1787-1793. doi:10.1016/j.freeradbiomed.2011.03.019
[29] Chen, G.Y. and Nunez, G. (2010) Sterile inflammation: Sensing and reacting to damage. Nature Reviews Immunology, 10, 826-837.
[30] Mian, M.F., Lauzon, N.M., Stampfli, M.R., et al. (2008) Impairment of human NK cell cytotoxic activity and cytokine release by cigarette smoke. Journal of Leukocyte Biology, 83, 774-784. doi:10.1189/jlb.0707481
[31] Lu, L.M., Zavitz, C.C., Chen, B., et al. (2007) Cigarette smoke impairs NK cell-dependent tumor immune surveillance. The Journal of Immunology, 178, 936-943.
[32] Walser, T., Cui, X., Yanagawa, J., et al. (2008) Smoking and lung cancer: The role of inflammation. Proceedings of the American Thoracic Society, 5, 811-815. doi:10.1513/pats.200809-100TH
[33] Nathan, C. and Ding, A. (2010) Nonresolving inflammation. Cell, 140, 871-882. doi:10.1016/j.cell.2010.02.029
[34] Grivennikov, S.I. and Karin, M. (2010) Inflammation and oncogenesis: A vicious connection. Current Opinion in Genetics & Development, 20, 65-71. doi:10.1016/j.gde.2009.11.004
[35] Hanahan, D. and Weinberg, R.A. (2011) Hallmarks of cancer: The next generation. Cell, 144, 646-674. doi:10.1016/j.cell.2011.02.013
[36] Takahashi, H., Ogata, H., Nishigaki, R., et al. (2010) Tobacco smoke promotes lung tumorigenesis by triggering IKKbetaand JNK1-dependent inflammation. Cancer Cell, 17, 89-97. doi:10.1016/ r.2009.12.008
[37] Botelho, F.M., Gaschler, G.J., Kianpour, S., et al. (2010) Innate immune processes are sufficient for driving cigarette smoke-induced inflammation in mice. American Journal of Respiratory Cell and Molecular Biology, 42, 394-403. doi:10.1165/rcmb.2008-0301OC
[38] Yang, I.A., Relan, V., Wright, C.M., et al. (2011) Common pathogenic mechanisms and pathways in the development of COPD and lung cancer. Expert Opinion on Therapeutic Targets, 15, 439-456.
[39] Ginsberg, R.J., Vokes, E.E and Raben, A. (1997) Cancer principles and practices of oncology. 5th Edition, Lippincott-Raven, Philadelphia.
[40] Mason, R.J., Dobbs, L.G., Greenleaf, R.D., et al. (1977) Alveolar type II cells. Federation Proceedings, 36, 2697-2702.
[41] Ochs, M. (2006) A brief update on lung stereology. Journal of Microscopy, 222, 188-200. doi:10.1111/j.1365-2818.2006.01587.x
[42] Cavarra, E., Fardin, P., Fineschi, S., et al. (2009) Early response of gene clusters is associated with mouse lung resistance or sensitivity to cigarette smoke. American Journal of Physiology—Lung Cellular and Molecular Physiology, 296, L418-L429. doi:10.1152/ajplung.90382.2008
[43] Stevenson, C.S., Docx, C., Webster, R., et al. (2007) Comprehensive gene expression profiling of rat lung reveals distinct acute and chronic responses to cigarette smoke inhalation. American Journal of Physiology— Lung Cellular and Molecular Physiology, 293, L1183-L1193. doi:10.1152/ajpl ung.00105.2007
[44] Beane, J., Spira, A. and Lenburg, M.E. (2009) Clinical impact of high-throughput gene expression studies in lung cancer. Journal of Thoracic Oncology, 4, 109-118.
[45] Nguyen, T., Sherratt, P.J. and Pickett, C.B. (2003) Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annual Reviews of Pharmacology and Toxicology, 43, 233-260. doi:10.1146/annurev.pharmtox.43.100901.140229
[46] Benjamin, R.M. (2011) Exposure to tobacco smoke causes immediate damage: A report of the surgeon general. Public Health Reports, 126, 158-159.
[47] Wickenden, J.A., Clarke, M.C., Rossi, A.G., et al. (2003) Cigarette smoke prevents apoptosis through inhibition of caspase activation and induces necrosis. American Journal of Respiratory Cell and Molecular Biology, 29, 562-570. doi:10.1165/rcmb.2002-0235OC
[48] Damico, R., Simms, T., Kim, B.S., et al. (2011) P53 mediates cigarette smoke-induced apoptosis of pulmonary endothelial cells: Inhibitory effects of macrophage migration inhibitor factor. American Journal of Respiratory Cell and Molecular Biology, 44, 323-332. doi:10.1165/rcmb.2009-0379OC
[49] Kasahara, Y., Tuder, R.M., Cool, C.D., et al. (2001) Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. American Journal of Respiratory and Critical Care, 163, 737-744. doi:10.1164/ajrccm.163.3.2002117
[50] Liu, H., Ma, L., Wu, J., et al. (2009) Apoptosis of alveolar wall cells in chronic obstructive pulmonary disease patients with pulmonary emphysema is involved in emphysematous changes. Journal of Huazhong University of Science and Technology [Medical Sciences], 29, 466-469. doi:10.1007/s11596-009-0415-7
[51] Yokohori, N., Aoshiba, K. and Nagai, A. (2004) Increased levels of cell death and proliferation in alveolar wall cells in patients with pulmonary emphysema. Chest, 125, 626-632.
[52] Hodge, S., Hodge, G., Scicchitano, R., et al. (2003) Alveolar macrophages from subjects with chronic obstructive pulmonary disease are deficient in their ability to phagocytose apoptotic airway epithelial cells. Immunology & Cell Biology, 81, 289-296. doi:10.1046/j.1440-1711.2003.t01-1-01170.x
[53] Hodge, S., Hodge, G., Ahern, J., et al. (2007) Smoking alters alveolar macrophage recognition and phagocytic ability: Implications in chronic obstructive pulmonary disease. American Journal of Respiratory Cell and Molecular Biology, 37, 748-755. doi:10.1165/rcmb.2007-0025OC
[54] Kazeros, A., Harvey, B.G., Carolan, B.J., et al. (2008) Overexpression of apoptotic cell removal receptor MERTK in alveolar macrophages of cigarette smokers. American Journal of Respiratory Cell and Molecular Biology, 39, 747-757. doi:10.1165/rcmb.2007-0306OC
[55] Crosby, L.M. and Waters, C.M. (2010) Epithelial repair mechanisms in the lung. American Journal of Physiology—Lung Cellular and Molecular Physiology, 298, L715-L731. doi:10.1152/ajpl ung.00361.2009
[56] Gardner, A., Borthwick, L.A. and Fisher, A.J. (2010) Lung epithelial wound healing in health and disease. Expert Review of Respiratory Medicine, 4, 647-660.
[57] Rennard, S.I., Togo, S. and Holz, O. (2006) Cigarette smoke inhibits alveolar repair: A mechanism for the development of emphysema. Proceedings of the American Thoracic Society, 3, 703-708. doi:10.1513/pats.200605-121SF
[58] Hodge, S., Hodge, G., Scicchitano, R., et al. (2003) Alveolar macrophages from subjects with chronic obstructive pulmonary disease are deficient in their ability to phagocytose apoptotic airway epithelial cells. Immunology & Cell Biology, 81, 289-296. doi:10.1046/j.1440-1711.2003.t01-1-01170.x
[59] Hodge, S., Hodge, G., Ahern, J., et al. (2007) Smoking alters alveolar macrophage recognition and phagocytic ability: Implications in chronic obstructive pulmonary disease. American Journal of Respiratory Cell and Molecular Biology, 37, 748-755. doi:10.1165/rcmb.2007-0025OC
[60] Vandivier, R.W., Henson, P.M. and Douglas, I.S. (2006) Burying the dead: The impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease. Chest, 129, 1673-1682. doi:10.1378/chest.129.6.1673
[61] Hang, B. (2010) Formation and repair of tobacco carcinogen-derived bulky DNA adducts. Journal of Nucleic Acids, 2010, Article ID: 709521. doi:10.4061/2010/709521
[62] Van der Toorn, M., Slebos, D.J., de Bruin, H.G., et al. (2007) Cigarette smoke-induced blockade of the mitochondrial respiratory chain switches lung epithelial cell apoptosis into necrosis. American Journal of Physiology—Lung Cellular and Molecular Physiology, 292, L1211-L1218. doi:10.1152/ajpl ung.00291.2006
[63] Medzhitov, R. (2008) Origin and physiological roles of inflammation. Nature, 454, 428-435.
[64] Cantin, A.M. (2010) Cellular response to cigarette smoke and oxidants: Adapting to survive. Proceedings of the American Thoracic Society, 7, 368-375. doi:10.1513/pats.201001-014AW
[65] Bellomi, M., Veronesi, G., Rampinelli, C., et al. (2007) Evolution of lung nodules < or =5 mm detected with low-dose CT in asymptomatic smokers. British Journal of Radiology, 80, 708-712.
[66] Diederich, S., Wormanns, D., Semik, M., et al. (2002) Screening for early lung cancer with low-dose spiral CT: Prevalence in 817 asymptomatic smokers. Radiology, 222, 773-781. doi:10.1148/radiol.2223010490
[67] Diederich, S., Thomas, M., Semik, M., et al. (2004) Screening for early lung cancer with low-dose spiral computed tomography: Results of annual follow-up examinations in asymptomatic smokers. European Radiology, 14, 691-702. doi:10.1007/s00330-003-2200-5
[68] Diederich, S., Hansen, J. and Wormanns, D. (2005) Resolving small pulmonary nodules: CT features. European Radiology, 15, 2064-2069. doi:10.1007/s00330-005-2836-4
[69] Kodama, K., Higashiyama, M., Yokouchi, H., et al. (2002) Natural history of pure ground-glass opacity after longterm follow-up of more than 2 years. The Annals of Thoracic Surgery, 73, 386-392. doi:10.1016/S0003-4975(01)03410-5
[70] Kuriyama, K., Seto, M., Kasugai, T., et al. (1999) Ground-glass opacity on thin-section CT: Value in differentiating subtypes of adenocarcinoma of the lung. American Journal of Roentgenology, 173, 465-469. doi:10.2214/ajr.173.2.10430155
[71] Novello, S., Fava, C., Borasio, P., et al. (2005) Three-year findings of an early lung cancer detection feasibility study with low-dose spiral computed tomography in heavy smokers. Annals of Oncology, 16, 1662-1666. doi:10.1093/annonc/mdi314
[72] Revel, M.P., Lefort, C., Bissery, A., et al. (2004) Pulmonary nodules: Preliminary experience with three-dimensional evaluation. Radiology, 231, 459-466. doi:10.1148/radiol.2312030241
[73] Revel, M.P., Bissery, A., Bienvenu, M., et al. (2004) Are two-dimensional CT measurements of small noncalcified pulmonary nodules reliable? Radiology, 231, 453-458. doi:10.1148/radiol.2312030167
[74] Revel, M.P., Merlin, A., Peyrard, S., et al. (2006) Software volumetric evaluation of doubling times for differrentiating benign versus malignant pulmonary nodules. American Journal of Roentgenology, 187, 135-142. doi:10.2214/AJR.05.1228
[75] Nomori, H., Horio, H., Naruke, T., et al. (2001) A case of lung cancer with extensive pleural adhesion, which could be resected by a thoracoscopic middle lobectomy. Kyobu Geka, 54, 388-390.
[76] Suzuki, K., Takahashi, K., Yoshida, J., et al. (1998) Synchronous double primary lung carcinomas associated with multiple atypical adenomatous hyperplasia. Lung Cancer, 19, 131-139. doi:10.1016/S0169-5002(97)00082-2
[77] Weng, S., Tsuchiya, E., Satoh, Y., et al. (1990) Multiple atypical adenomatous hyperplasia of type II pneumonocytes and bronchiolo-alveolar carcinoma. Histopathology, 16, 101-103.
[78] Chapman, A.D. and Kerr, K.M. (2000) The association between atypical adenomatous hyperplasia and primary lung cancer. British Journal of Cancer, 83, 632-636. doi:10.1054/bjoc.2000.1317
[79] Kerr, K.M., Carey, F.A., King, G., et al. (1994) Atypical alveolar hyperplasia: Relationship with pulmonary adenocarcinoma, p53, and c-erbB-2 expression. The Journal of Pathology, 174, 249-256. doi:10.1002/path.1711740404
[80] Mori, M., Tezuka, F., Chiba, R., et al. (1996) Atypical adenomatous hyperplasia and adenocarcinoma of the human lung: Their heterology in form and analogy in immunohistochemical characteristics. Cancer, 77, 665-674. doi:10.1002/(SICI)1097-0142(19960215)77:4<665::AID-CNCR12>3.0.CO;2-Z
[81] Mori, M., Rao, S.K., Popper, H.H., et al. (2001) Atypical adenomatous hyperplasia of the lung: A probable forerunner in the development of adenocarcinoma of the lung. Modern Pathology, 14, 72-84. doi:10.1038/modpathol.3880259
[82] Christmann, M., Verbeek, B., Roos, W.P., et al. (2011) O(6)-Methylguanine-DNA methyltransferase (MGMT) in normal tissues and tumors: Enzyme activity, promoter methylation and immunohistochemistry. Biochimica et Biophysica Acta, 1816, 179-190.
[83] Leng, S., Bernauer, A.M., Hong, C., et al. (2011) The A/G allele of rs16906252 predicts for MGMT methylation and is selectively silenced in premalignant lesions from smokers and in lung adenocarcinomas. Clinical Cancer Research, 17, 2014-2023. doi:10.1158/1078-0432.CCR-10-3026
[84] Damiani, L.A., Yingling, C.M., Leng, S., et al. (2008) Carcinogen-induced gene promoter hypermethylation is mediated by DNMT1 and causal for transformation of immortalized bronchial epithelial cells. Cancer Research, 68, 9005-9014. doi:10.1158/0008-5472.CAN-08-1276
[85] Lin, R.K., Hsieh, Y.S., Lin, P., et al. (2010) The tobaccospecific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients. Journal of Clinical Investigation, 120, 521-532. doi:10.1172/JCI40706
[86] Liu, F., Killian, J.K., Yang, M., et al. (2010) Epigenomic alterations and gene expression profiles in respiratory epithelia exposed to cigarette smoke condensate. Oncogene, 29, 3650-3664.
[87] Schetter, A.J., Heegaard, N.H. and Harris, C.C. (2010) Inflammation and cancer: Interweaving microRNA, free radical, cytokine and p53 pathways. Carcinogenesis, 31, 37-49. doi:10.1093/carcin/bgp272
[88] Kitamura, H., Kameda, Y., Nakamura, N., et al. (1995) Proliferative potential and p53 overexpression in precursor and early stage lesions of bronchioloalveolar lung carcinoma. American Journal of Pathology, 146, 876-887.
[89] Nakayama, H., Noguchi, M., Tsuchiya, R., et al. (1990) Clonal growth of atypical adenomatous hyperplasia of the lung: Cytofluorometric analysis of nuclear DNA content. Modern Pathology, 3, 314-320.
[90] Niho, S., Yokose, T., Suzuki, K., et al. (1999) Monoclonality of atypical adenomatous hyperplasia of the lung. American Journal of Pathology, 154, 249-254.
[91] Carey, F.A., Wallace, W.A., Fergusson, R.J., et al. (1992) Alveolar atypical hyperplasia in association with primary pulmonary adenocarcinoma: A clinicopathological study of 10 cases. Thorax, 47, 1041-1043. doi:10.1136/thx.47.12.1041
[92] Koga, T., Hashimoto, S., Sugio, K., et al. (2002) Lung adenocarcinoma with bronchioloalveolar carcinoma component is frequently associated with foci of high-grade atypical adenomatous hyperplasia. American Journal of ClinicalPathology, 117, 464-470. doi:10.1309/CHXA-3MH0-B7FD-JGUL
[93] Mori, M., Kaji, M., Tezuka, F., et al. (1998) Comparative ultrastructural study of atypical adenomatous hyperplasia and adenocarcinoma of the human lung. Ultrastructural Pathology, 22, 459-466. doi:10.3109/01913129809032282
[94] Hayashi, H., Miyamoto, H., Ito, T., et al. (1997) Analysis of p21Waf1/Cip1 expression in normal, premalignant, and malignant cells during the development of human lung adenocarcinoma. American Journal of Pathology, 151, 461-470.
[95] Kurasono, Y., Ito, T., Kameda, Y., et al. (1998) Expression of cyclin D1, retinoblastoma gene protein, and p16 MTS1 protein in atypical adenomatous hyperplasia and adenocarcinoma of the lung. An immunohistochemical analysis. Virchows Archiv, 432, 207-215. doi:10.1007/s004280050157
[96] Yokose, T., Ito, Y. and Ochiai, A. (2000) High prevalence of atypical adenomatous hyperplasia of the lung in autopsy specimens from elderly patients with malignant neoplasms. Lung Cancer, 29, 125-130. doi:10.1016/S0169-5002(00)00101-X
[97] Munoz-Antonia, T., Muro-Cacho, C., Sharma, S., et al. (2007) Expression of TGFbeta type-II receptor in association with markers of proliferation and apoptosis in premalignant lung lesions. Cancer, 110, 1527-1531. doi:10.1002/cncr.22937
[98] Tan, D.F., Huberman, J.A., Hyland, A., et al. (2001) MCM2—A promising marker for premalignant lesions of the lung: A cohort study. BMC Cancer, 1, 6. doi:10.1186/1471-2407-1-6
[99] Swann, J.B., Coquet, J.M., Smyth, M.J., et al. (2007) CD1-restricted T cells and tumor immunity. Current Topics in Microbiology and Immunology, 314, 293-323. doi:10.1007/978-3-540-69511-0_12
[100] Evan, G. (1994) Why we live and why we die. Chemistry & Biology, 1, 137-141. doi:10.1016/1074-5521(94)90003-5
[101] Lowe, S.W., Cepero, E. and Evan, G. (2004) Intrinsic tumour suppression. Nature, 432, 307-315. doi:10.1038/nature03098
[102] Akyurek, N., Memis, L., Ekinci, O., et al. (2006) Survivin expression in pre-invasive lesions and non-small cell lung carcinoma. Virchows Archiv, 449, 164-170. doi:10.1007/s00428-006-0239-9
[103] Nakanishi, K., Kawai, T., Kumaki, F., et al. (2003) Survivin expression in atypical adenomatous hyperplasia of the lung. American Journal of Clinical Pathology, 120, 712-719. doi:10.1309/GWTN2JTAN6K73YDE
[104] Domagala-Kulawik, J. (2008) Effects of cigarette smoke on the lung and systemic immunity. Journal of Physiology and Pharmacology, 59, 19-34.
[105] Kode, A., Yang, S.R. and Rahman, I. (2006) Differential effects of cigarette smoke on oxidative stress and proinflammatory cytokine release in primary human airway epithelial cells and in a variety of transformed alveolar epithelial cells. Respiratory Research, 7, 132. doi:10.1186/1465-9921-7-132
[106] Piccinini, A.M. and Midwood, K.S. (2010) DAMPening inflammation by modulating TLR signalling. Mediators of Inflammation, 2010, Article ID: 672395.
[107] Takashima, S., Sone, S., Li, F., et al. (2003) Indeterminate solitary pulmonary nodules revealed at population-based CT screening of the lung: Using first followup diagnostic CT to differentiate benign and malignant lesions. American Journal of Roentgenology, 180, 1255-1263. doi:10.2214/ajr.180.5.1801255
[108] Sartori, G., Cavazza, A., Bertolini, F., et al. (2008) A subset of lung adenocarcinomas and atypical adenomatous hyperplasia-associated foci are genotypically related: An EGFR, HER2, and K-ras mutational analysis. American Journal of Clinical Pathology, 129, 202-210. doi:10.1309/THU13F3JRJVWLM30
[109] Chaudhuri, R., Livingston, E., McMahon, A.D., et al. (2006) Effects of smoking cessation on lung function and airway inflammation in smokers with asthma. American Journal of Respiratory and Critical Care, 174, 127-133. doi:10.1164/rccm.200510-1589OC
[110] Karimi, R., Tornling, G., Grunewald, J., et al. (2012) Cell recovery in bronchoalveolar lavage fluid in smokers is dependent on cumulative smoking history. PLoS One, 7, e34232. doi:10.1371/journal.pone.0034232
[111] Hecht, S.S., Carmella, S.G., Chen, M., et al. (1999) Quantitation of urinary metabolites of a tobacco-specific lung carcinogen after smoking cessation. Cancer Research, 59, 590-596.
[112] Benhamou, E., Benhamou, S., Auquier, A., et al. (1989) Changes in patterns of cigarette smoking and lung cancer risk: Results of a case-control study. British Journal of Cancer, 60, 601-604. doi:10.1038/bjc.1989.322
[113] Willemse, B.W., ten Hacken, N.H., Rutgers, B., et al. (2005) Association of current smoking with airway inflammation in chronic obstructive pulmonary disease and asymptomatic smokers. Respiratory Research, 6, 38. doi:10.1186/1465-9921-6-38
[114] Lee, P. N. (2000) Epidemiology of lung cancer.
[115] Alberg, A.J. and Samet, J.M. (2003) Epidemiology of lung cancer. Chest, 123, 21S-49S.
[116] Barbone, F., Bovenzi, M., Cavallieri, F., et al. (1997) Cigarette smoking and histologic type of lung cancer in men. Chest, 112, 1474-1479. doi:10.1378/chest.112.6.1474
[117] Ebbert, J.O., Yang, P., Vachon, C.M., et al. (2003) Lung cancer risk reduction after smoking cessation: Observations from a prospective cohort of women. Journal of Clinical Oncology, 21, 921-926.
[118] Matos, E., Vilensky, M., Boffetta, P., et al. (1998) Lung cancer and smoking: A case-control study in Buenos Aires, Argentina. Lung Cancer, 21, 155-163. doi:10.1016/S0169-5002(98)00055-5
[119] Pohlabeln, H., Jockel, K.H. and Muller, K.M. (1997) The relation between various histological types of lung cancer and the number of years since cessation of smoking. Lung Cancer, 18, 223-229. doi:10.1016/S0169-5002(97)00067-6
[120] Wistuba, I.I., Lam, S., Behrens, C., et al. (1997) Molecular damage in the bronchial epithelium of current and former smokers. Journal of the National Cancer Institute, 89, 1366-1373. doi:10.1093/jnci/89.18.1366
[121] Lubin, J.H. and Caporaso, N.E. (2007) Cigarette smoking and lung cancer: Modeling total exposure and intensity. Cancer Epidemiology, Biomarkers & Prevention, 15, 517-523. doi:10.1158/1055-9965.EPI-05-0863
[122] Thurston, S.W., Liu, G., Miller, D.P., et al. (2005) Modeling lung cancer risk in case-control studies using a new dose metric of smoking. Cancer Epidemiology, Biomarkers & Prevention, 14, 2296-2302. doi:10.1158/1055-9965.EPI-04-0393
[123] Greenberg, A.K., Yee, H. and Rom, W.N. (2002) Preneoplastic lesions of the lung. Respiratory Research, 3, 20. doi:10.1186/rr170
[124] Tollerud, D.J., Clark, J.W., Brown, L.M., et al. (1989) Association of cigarette smoking with decreased numbers of circulating natural killer cells. American Review of Respiratory Disease, 139, 194-198. doi:10.1164/ajrccm/139.1.194
[125] Minematsu, N., Blumental-Perry, A. and Shapiro, S.D. (2011) Cigarette smoke inhibits engulfment of apoptotic cells by macrophages through inhibition of actin rearrangement. American Journal of Respiratory Cell and Molecular Biology, 44, 474-482. doi:10.1165/rcmb.2009-0463OC
[126] Guzik, K., Skret, J., Smagur, J., et al. (2011) Cigarette smoke-exposed neutrophils die unconventionally but are rapidly phagocytosed by macrophages. Cell Death & Disease, 2, e131.
[127] Holt, P.G. and Keast, D. (2011) Environmentally induced changes in immunological function: Acute and chronic effects of inhalation of tobacco smoke and other atmospheric contaminants in man and experimental animals. Bacteriological Reviews, 41, 205-216.
[128] Sopori, M. (2002) Effects of cigarette smoke on the immune system. Nature Reviews Immunology, 2, 372-377.
[129] Robbins, C.S., Dawe, D.E., Goncharova, S.I., et al. (2004) Cigarette smoke decreases pulmonary dendritic cells and impacts antiviral immune responsiveness. American Journal of Respiratory Cell and Molecular Biology, 30, 202-211. doi:10.1165/rcmb.2003-0259OC
[130] Chan, C.W. and Housseau, F. (2007) The “kiss of death” by dendritic cells to cancer cells. Cell Death & Differentiation, 15, 58-69. doi:10.1038/sj.cdd.4402235
[131] Wissinger, E., Goulding, J. and Hussell, T. (2009) Immune homeostasis in the respiratory tract and its impact on heterologous infection. Seminars in Immunology, 21, 147-155. doi:10.1016/j.smi m.2009.01.005
[132] Grivennikov, S.I., Greten, F.R. and Karin, M. (2010) Immunity, inflammation, and cancer. Cell, 140, 883-899. doi:10.1016/j.cell.2010.01.025
[133] Gebel, S., Diehl, S., Pype, J., et al. (2010) The transcriptome of Nrf2-/-mice provides evidence for impaired cell cycle progression in the development of cigarette smokeinduced emphysematous changes. Toxicological Sciences, 115, 238-252. doi:10.1093/toxsci/kfq039
[134] Losa, D., Chanson, M. and Crespin, S. (2011) Connexins as therapeutic targets in lung disease. Expert Opinion on Therapeutic Targets, 15, 989-1002. doi:10.1517/14728222.2011.584875
[135] Rangasamy, T., Cho, C.Y., Thimmulappa, R.K., et al. (2004) Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. Journal of Clinical Investigation, 114, 1248-1259.
[136] Ogawa, Y., Duru, E.A. and Ameredes, B.T. (2008) Role of IL-10 in the resolution of airway inflammation. Current Molecular Medicine, 8, 437-445. doi:10.2174/156652408785160907
[137] Ji, H., Houghton, A.M., Mariani, T.J., et al. (2005) K-ras activation generates an inflammatory response in lung tumors. Oncogene, 25, 2105-2112. doi:10.1038/sj.onc.1209237
[138] Iliopoulos, D., Hirsch, H.A. and Struhl, K. (2009) An epigenetic switch involving NF-kB, Lin28, Let-7 microRNA, and IL6 links inflammation to cell transformation. Cell, 139, 693-706. doi:10.1016/j.cell.2009.10.014
[139] Thorley, A.J. and Tetley, T.D. (2007) Pulmonary epithetlium, cigarette smoke, and chronic obstructive pulmonary disease. International Journal of Chronic Obstructive Pulmonary Disease, 2, 409-428.
[140] Povey, A.C., O’Donnell, P., Barber, P., et al. (2006) Smoking is associated with a decrease of O6-alkylguanine-DNA alkyltransferase activity in bronchial epithelial cells. International Journal of Cancer, 119, 463-466. doi:10.1002/ijc.21790
[141] Medzhitov, R. and Janeway Jr, C.A. (2002) Decoding the patterns of self and nonself by the innate immune system. Science, 296, 298-300. doi:10.1126/science.1068883
[142] Hanahan, D. and Weinberg, R.A. (2000) The hallmarks of cancer. Cell, 100, 57-70. doi:10.1016/S0092-8674(00)81683-9
[143] De Visser, K.E., Eichten, A. and Coussens, L.S.M. (2006) Paradoxical roles of the immune system during cancer development. Nature Reviews. Cancer, 6, 24-37.
[144] Halliwell, B. (2011) Free radicals and antioxidants—Quo vadis? Trends in Pharmacological Sciences, 32, 125-130. doi:10.1016/
[145] Iliopoulos, D., Hirsch, H.A. and Struhl, K. (2009) An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell, 139, 693-706. doi:10.1016/j.cell.2009.10.014
[146] Iliopoulos, D., Jaeger, S.A., Hirsch, H.A., et al. (2010) STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Molecular Cell, 39, 493-506. doi:10.1016/j.molcel.2010.07.023
[147] Reuter, S., Gupta, S.C., Chaturvedi, M.M., et al. (2010) Oxidative stress, inflammation, and cancer: How are they linked? Free Radical Biology and Medicine, 49, 1603-1616. doi:10.1016/j.freera dbiomed.2010.09.006
[148] Schreiber, R.D., Old, L.J. and Smyth, M.J. (2011) Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion. Science, 331, 1565-1570. doi:10.1126/science.1203486
[149] Ochs, M., Nyengaard, J.R., Jung, A., et al. (2004) The number of alveoli in the human lung. American Journal of Respiratory and Critical Care, 169, 120-124. doi:10.1164/rccm.200308-1107OC
[150] Dini, L. (2010) Phagocytosis of dying cells: Influence of smoking and static magnetic fields. Apoptosis, 15, 1147-1164. doi:10.1007/s10495-010-0490-z
[151] Rom, W.N., Hay, J.G., Lee, T.C., et al. (2000) Molecular and genetic aspects of lung cancer. American Journal of Respiratory and Critical Care, 161, 1355-1367. doi:10.1164/ajrccm.161.4.9908012
[152] Wistuba, I.I. (2007) Genetics of preneoplasia: Lessons from lung cancer. Current Molecular Medicine, 7, 3-14. doi:10.2174/156652407779940468

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