Clinical significance of epithelial mesenchymal transition (EMT) in chronic obstructive pulmonary disease (COPD): potential target for prevention of airway fibrosis and lung cancer
Tóm tắt
Unfortunately, the research effort directed into chronic obstructive pulmonary disease (COPD) has been disproportionately weak compared to its social importance, and indeed it is the least researched of all common chronic conditions. Tobacco smoking is the major etiological factor. Only 25% of smokers will develop “classic” COPD; in these vulnerable individuals the progression of airways disease to symptomatic COPD occurs over two or more decades. We know surprisingly little about the pathobiology of COPD airway disease, though small airway fibrosis and obliteration are likely to be the main contributors to physiological airway dysfunction and these features occur earlier than any subsequent development of emphysema. One potential mechanism contributing to small airway fibrosis/obliteration and change in extracellular matrix (ECM) is epithelial mesenchymal transition (EMT), so called Type-II EMT. When associated with angiogenesis (Type-III EMT) it may well also be a link with the development of lung (airway) cancer which is closely associated with COPD. Active EMT in COPD may help to explain why lung cancer is so common in smokers and also the core pathophysiology of small airway fibrosis. Better understanding may lead to new markers for incipient neoplasia, and better preventive management of patients. There is serious need to understand key components of airway EMT in smokers and COPD, and to demarcate novel drug targets for the prevention of lung cancer and airway fibrosis, as well as better secondary management of COPD. Since over 90% of human cancer arises in epithelia and the involvement of EMT in all of these may be a central paradigm, insights gained in COPD may have important generalizable value.
Tài liệu tham khảo
Kalluri R, Weinberg RA: The basics of epithelial-mesenchymal transition. J Clin Invest 2009, 119(6):1420–1428. 10.1172/JCI39104
Willis BC, Borok Z: TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease. Am J Physiol Lung Cell Mol Physiol 2007, 293(3):L525–534. 10.1152/ajplung.00163.2007
Hay ED: Interaction of embryonic surface and cytoskeleton with extracellular matrix. Am J Anat 1982, 165(1):1–12. 10.1002/aja.1001650102
Hay ED: An overview of epithelio-mesenchymal transformation. Acta Anat (Basel) 1995, 154(1):8–20. 10.1159/000147748
Guarino M, Tosoni A, Nebuloni M: Direct contribution of epithelium to organ fibrosis: epithelial-mesenchymal transition. Hum Pathol 2009, 40(10):1365–1376. 10.1016/j.humpath.2009.02.020
Kalluri R, Neilson EG: Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 2003, 112(12):1776–1784. 10.1172/JCI200320530
Sohal SS, Soltani A, Weston S, Wood-Baker R, Walters H: Intermediate filament vimentin and potential role in epithelial mesenchymal transition (EMT). Vimentin concepts and molecular mechanisms 2013, 37–61.
Sohal SS, Walters EH: Epithelial mesenchymal transition (EMT) in small airways of COPD patients. Thorax 2013, 68(8):783–784. 10.1136/thoraxjnl-2013-203373
Sohal SS, Walters EH: Role of epithelial mesenchymal transition (EMT) in chronic obstructive pulmonary disease (COPD). Respir Res 2013, 14(1):120. 10.1186/1465-9921-14-120
Sohal SS, Ward C, Danial W, Wood-Baker R, Walters EH: Recent advances in understanding inflammation and remodeling in the airways in chronic obstructive pulmonary disease. Expert Rev Respir Med 2013, 7(3):275–288. 10.1586/ers.13.26
Sohal SS, Ward C, Walters EH: Importance of epithelial mesenchymal transition (EMT) in COPD and asthma. Thorax 2014. Sohal SS, Ward C, Walters EH: Importance of epithelial mesenchymal transition (EMT) in COPD and asthma.Thorax 2014.
Kalluri R: EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Invest 2009, 119(6):1417–1419. 10.1172/JCI39675
Zeisberg M, Neilson EG: Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 2009, 119(6):1429–1437. 10.1172/JCI36183
Soltani A, Muller HK, Sohal SS, Reid DW, Weston S, Wood-Baker R, Walters EH: Distinctive characteristics of bronchial reticular basement membrane and vessel remodelling in chronic obstructive pulmonary disease (COPD) and in asthma: they are not the same disease. Histopathology 2012, 60(6):964–970. 10.1111/j.1365-2559.2011.04147.x
Soltani A, Reid DW, Sohal SS, Wood-Baker R, Weston S, Muller HK, Walters EH: Basement membrane and vascular remodelling in smokers and chronic obstructive pulmonary disease: a cross-sectional study. Respir Res 2010, 11(1):105. 10.1186/1465-9921-11-105
Soltani A, Sohal SS, Reid D, Weston S, Wood-Baker R, Walters EH: Vessel-associated transforming growth factor-Beta1 (TGF-beta1) is increased in the bronchial reticular basement membrane in COPD and normal smokers. PLoS One 2012, 7(6):e39736. 10.1371/journal.pone.0039736
Sohal SS, Reid D, Soltani A, Ward C, Weston S, Muller HK, Wood-Baker R, Walters EH: Reticular basement membrane fragmentation and potential epithelial mesenchymal transition is exaggerated in the airways of smokers with chronic obstructive pulmonary disease. Respirology 2010, 15(6):930–938. 10.1111/j.1440-1843.2010.01808.x
Sohal SS, Reid D, Soltani A, Ward C, Weston S, Muller HK, Wood-Baker R, Walters EH: Evaluation of epithelial mesenchymal transition in patients with chronic obstructive pulmonary disease. Respir Res 2011, 12(1):130. 10.1186/1465-9921-12-130
Nowrin K, Sohal SS, Peterson G, Patel R, Walters EH: Epithelial-mesenchymal transition as a fundamental underlying pathogenic process in COPD airways: fibrosis, remodeling and cancer. Expert Rev Respir Med 2014, 1–13. Nowrin K, Sohal SS, Peterson G, Patel R, Walters EH: Epithelial-mesenchymal transition as a fundamental underlying pathogenic process in COPD airways: fibrosis, remodeling and cancer.Expert Rev Respir Med 2014, 1–13.
Milara J, Peiro T, Serrano A, Cortijo J: Epithelial to mesenchymal transition is increased in patients with COPD and induced by cigarette smoke. Thorax 2013. Milara J, Peiro T, Serrano A, Cortijo J: Epithelial to mesenchymal transition is increased in patients with COPD and induced by cigarette smoke.Thorax 2013.
Milara J, Peiro T, Serrano A, Guijarro R, Zaragoza C, Tenor H, Cortijo J: Roflumilast N-oxide inhibits bronchial epithelial to mesenchymal transition induced by cigarette smoke in smokers with COPD. Pulm Pharmacol Ther 2014, 28(2):138–148. 10.1016/j.pupt.2014.02.001
Wang Q, Wang Y, Zhang Y, Xiao W: The role of uPAR in epithelial-mesenchymal transition in small airway epithelium of patients with chronic obstructive pulmonary disease. Respir Res 2013, 14: 67. 10.1186/1465-9921-14-67
Sohal SS, Soltani A, Reid D, Ward C, Wills KE, Muller HK, Walters EH: A randomized controlled trial of inhaled corticosteroids (ICS) on markers of epithelial-mesenchymal transition (EMT) in large airway samples in COPD: an exploratory proof of concept study. Int J Chron Obstruct Pulmon Dis 2014, 9: 533–542. 10.2147/COPD.S63911
Reid DW, Wen Y, Johns DP, Williams TJ, Ward C, Walters EH: Bronchodilator reversibility, airway eosinophilia and anti-inflammatory effects of inhaled fluticasone in COPD are not related. Respirology 2008, 13(6):799–809. 10.1111/j.1440-1843.2008.01380.x
Parimon T, Chien JW, Bryson CL, McDonell MB, Udris EM, Au DH: Inhaled corticosteroids and risk of lung cancer among patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007, 175(7):712–719. 10.1164/rccm.200608-1125OC
Kiri VA: Inhaled corticosteroids and lung cancer chemoprevention in chronic obstructive pulmonary disease patients: what should we make of what we observe? Annals of respiratory medicine 2010, 1(2):23–30.
Kiri VA, Fabbri LM, Davis KJ, Soriano JB: Inhaled corticosteroids and risk of lung cancer among COPD patients who quit smoking. Respir Med 2009, 103(1):85–90. 10.1016/j.rmed.2008.07.024
Young RP, Hopkins R, Eaton TE: Pharmacological actions of statins: potential utility in COPD. Eur Respir Rev 2009, 18(114):222–232. 10.1183/09059180.00005309
Palena C, Fernando RI, Hamilton DH: An immunotherapeutic intervention against tumor progression: targeting a driver of the epithelial-to-mesenchymal transition. Oncoimmunology 2014, 3(1):e27220. 10.4161/onci.27220
Roselli M, Fernando RI, Guadagni F, Spila A, Alessandroni J, Palmirotta R, Costarelli L, Litzinger M, Hamilton D, Huang B, Tucker J, Tsang KY, Schlom J, Palena C: Brachyury, a driver of the epithelial-mesenchymal transition, is overexpressed in human lung tumors: an opportunity for novel interventions against lung cancer. Clin Cancer Res 2012, 18(14):3868–3879. 10.1158/1078-0432.CCR-11-3211
Hamilton DH, Litzinger MT, Fernando RI, Huang B, Palena C: Cancer vaccines targeting the epithelial-mesenchymal transition: tissue distribution of brachyury and other drivers of the mesenchymal-like phenotype of carcinomas. Semin Oncol 2012, 39(3):358–366. 10.1053/j.seminoncol.2012.02.005
Garber K: Epithelial-to-mesenchymal transition is important to metastasis, but questions remain. J Natl Cancer Inst 2008, 100(4):232–233. 239 239 10.1093/jnci/djn032
Barnes PJ, Adcock IM: Chronic obstructive pulmonary disease and lung cancer: a lethal association. Am J Respir Crit Care Med 2011, 184(8):866–867. 10.1164/rccm.201108-1436ED
de Torres JP, Marin JM, Casanova C, Cote C, Carrizo S, Cordoba-Lanus E, Baz-Davila R, Zulueta JJ, Aguirre-Jaime A, Saetta M, Cosio MG, Celli BR: Lung cancer in patients with chronic obstructive pulmonary disease- incidence and predicting factors. Am J Respir Crit Care Med 2011, 184(8):913–919. 10.1164/rccm.201103-0430OC
Zhang J, Chen YL, Ji G, Fang W, Gao Z, Liu Y, Wang J, Ding X, Gao F: Sorafenib inhibits epithelial-mesenchymal transition through an epigenetic-based mechanism in human lung epithelial cells. PLoS One 2013, 8(5):e64954. 10.1371/journal.pone.0064954
Camara J, Jarai G: Epithelial-mesenchymal transition in primary human bronchial epithelial cells is Smad-dependent and enhanced by fibronectin and TNF-alpha. Fibrogenesis Tissue Repair 2010, 3(1):2. 10.1186/1755-1536-3-2
Yang K, Song Y, Tang YB, Xu ZP, Zhou W, Hou LN, Zhu L, Yu ZH, Chen HZ, Cui YY: mAChRs activation induces epithelial-mesenchymal transition on lung epithelial cells. BMC Pulm Med 2014, 14: 53. 10.1186/1471-2466-14-53
Byers LA, Diao L, Wang J, Saintigny P, Girard L, Peyton M, Shen L, Fan Y, Giri U, Tumula PK, Nilsson MB, Gudikote J, Tran H, Cardnell RJ, Bearss DJ, Warner SL, Foulks JM, Kanner SB, Gandhi V, Krett N, Rosen ST, Kim ES, Herbst RS, Blumenschein GR, Lee JJ, Lippman SM, Ang KK, Mills GB, Hong WK, Weinstein JN, et al.: An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin Cancer Res 2013, 19(1):279–290. 10.1158/1078-0432.CCR-12-1558
Chen YL, Lv J, Ye XL, Sun MY, Xu Q, Liu CH, Min LH, Li HP, Liu P, Ding X: Sorafenib inhibits transforming growth factor beta1-mediated epithelial-mesenchymal transition and apoptosis in mouse hepatocytes. Hepatology 2011, 53(5):1708–1718. 10.1002/hep.24254
Steinestel J, Cronauer MV, Muller J, Al Ghazal A, Skowronek P, Arndt A, Kraft K, Schrader M, Schrader AJ, Steinestel K: Overexpression of p16(INK4a) in urothelial carcinoma in situ is a marker for MAPK-mediated epithelial-mesenchymal transition but is not related to human papillomavirus infection. PLoS One 2013, 8(5):e65189. 10.1371/journal.pone.0065189
King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigris JJ, Noble PW: A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014, 370(22):2083–2092. 10.1056/NEJMoa1402582
Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y, Kim DS, Kolb M, Nicholson AG, Noble PW, Selman M, Taniguchi H, Brun M, Le Maulf F, Girard M, Stowasser S, Schlenker-Herceg R, Disse B, Collard HR: Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014, 370(22):2071–2082. 10.1056/NEJMoa1402584
Borchers AT, Chang C, Keen CL, Gershwin ME: Idiopathic pulmonary fibrosis-an epidemiological and pathological review. Clin Rev Allergy Immunol 2011, 40(2):117–134. 10.1007/s12016-010-8211-5