Skip to main content

Main menu

  • Home
  • Current issue
  • Past issues
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • COVID-19 submission information
    • Institutional open access agreements
    • Peer reviewer login
  • Alerts
  • Subscriptions
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

User menu

  • Log in
  • Subscribe
  • Contact Us
  • My Cart

Search

  • Advanced search
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

Login

European Respiratory Society

Advanced Search

  • Home
  • Current issue
  • Past issues
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • COVID-19 submission information
    • Institutional open access agreements
    • Peer reviewer login
  • Alerts
  • Subscriptions

Shared epithelial pathways to lung repair and disease

Magda Spella, Ioannis Lilis, Georgios T. Stathopoulos
European Respiratory Review 2017 26: 170048; DOI: 10.1183/16000617.0048-2017
Magda Spella
1Laboratory for Molecular Respiratory Carcinogenesis, Dept of Physiology, Faculty of Medicine, University of Patras, Rio, Greece
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ioannis Lilis
1Laboratory for Molecular Respiratory Carcinogenesis, Dept of Physiology, Faculty of Medicine, University of Patras, Rio, Greece
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Georgios T. Stathopoulos
1Laboratory for Molecular Respiratory Carcinogenesis, Dept of Physiology, Faculty of Medicine, University of Patras, Rio, Greece
2Comprehensive Pneumology Center and Institute for Lung Biology and Disease, University Hospital, Ludwig-Maximilians University and Helmholtz Center Munich, Member of the German Center for Lung Research (DZL), Munich, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: gstathop@upatras.gr
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Chronic lung diseases present tremendous health burdens and share a common pathobiology of dysfunctional epithelial repair. Lung adenocarcinoma, the leading cancer killer worldwide, is caused mainly by chemical carcinogens of tobacco smoke that induce mutations in pulmonary epithelial cells leading to uncontrolled epithelial proliferation. Lung epithelial cells that possess the capacity for self-renewal and regeneration of other lung cell types are believed to underlie the pathobiology of chronic obstructive, fibrotic and neoplastic lung disorders. However, the understanding of lung epithelial progenitor cell hierarchy and turnover is incomplete and a comprehensive model of the cellular and transcriptional events that underlie lung regeneration and carcinogenesis is missing. The mapping of these processes is extremely important, since their modulation would potentially allow effective cure and/or prevention of chronic lung diseases. In this review we describe current knowledge on cellular and molecular pathways at play during lung repair and carcinogenesis and summarise the critical lung cell populations with regenerative and cancerous potential.

Abstract

Cells with regenerative potential are implicated in obstructive, fibrotic and neoplastic lung diseases http://ow.ly/YH7930c00Fz

Introduction

Lung cancer, chronic obstructive pulmonary disease (COPD) and lower respiratory infections causing septic and fibrotic sequelae were among the top five leading causes of death in the 2010 Global Burden of Disease study [1], claiming altogether >7 million lives in that year. The epidemic of lung cancer appears to be on a continuous rise, despite smoking prevention and cessation programmes, as evident from its global death toll in 2012 and the comparative 2005–2015 trends in the Global Burden of Disease cancer network study [2, 3]. Human lung cancers are typed into two main histopathological groupings which, in addition, reflect treatment response and prognosis: small cell lung cancer and nonsmall cell lung cancer (NSCLC). NSCLC, including mainly adenocarcinoma and squamous cell carcinoma, accounts for ∼80–85% of lung cancer cases, and adenocarcinoma, its main subtype, increasingly affects current, ex- and even never-smokers [4–6]. Chronic lung diseases, such as COPD and idiopathic pulmonary fibrosis (IPF) are generally accepted to arise from chronic epithelial injury and incomplete or aberrant repair processes [7–11]. In contrast, lung cancer is caused by tobacco chemical-induced mutations in pulmonary epithelial cells, leading to uncontrolled cellular proliferation [12–14]. Despite significant efforts, it is still unclear whether the primary lesions of chronic obstructive, fibrotic and neoplastic disorders occur in the airways, the alveoli or both epithelial compartments, while cells with repair potential occur in large and small airways, as well as alveoli [15–20]. Although the alveoli execute the main function of the lungs, i.e. gas exchange, multiple lines of evidence indicate that the primary pathogenic abnormalities of chronic obstructive, fibrotic and neoplastic disorders can also occur in the airways, in addition to the alveoli [10, 11, 21, 22]. In addition, lineage-specific genes encoding epithelial proteins that support the physiological functions of the lungs were recently shown to suffer noncoding insertions and deletions in lung adenocarcinoma, lending further support to the longstanding notion that epithelial cells that express lung-restricted proteins are the cellular sources of lung cancer [23]. Collectively, the available evidence indicates that the same lung epithelial cells that maintain the lungs in adulthood and are responsible for their repair after injury are the culprits in chronic lung diseases and cancer.

Lung cells with regenerative potential

The identification of lung cellular populations with repair and renewal capacities has been an area of intense investigation and has yielded several candidate stem/progenitor cell lineages confined to spatially distinct compartments of the pulmonary epithelium that express discrete markers. Notably, most of our knowledge on the cellular hierarchy of the lung epithelium and the relative contributions of each epithelial cell lineage to lung homeostasis after injury stems from studies on mouse models. In the mouse, airway stem cell niches have been identified in tracheal submucosal gland ducts, neuroendocrine bodies (NEB) and the broncholalveolar duct junction (BADJ), the region where the airways transition into alveoli [24–29]. The epithelium of the large airways consists of ciliated cells effecting mucociliary clearance and expressing acetylated tubulin 1A1 and the transcription factor FOXJ1, club cells secreting thin mucus and expressing club cell secretory protein (also known as club cell 10-kDa protein, encoded by secreted uteroglobin 1a1 (Scgb1a1)), goblet cells secreting thick (viscous) mucus and expressing mucins 5A–5C, neuroendocrine cells organised in NEBs expressing neural differentiation markers and basal cells expressing transformation-related protein-63 and cytokeratins-5 and/or -14. The epithelium of smaller airways contains club, ciliated and neuroendocrine cells, while the BADJ consists mainly of club cells and cells with dual club/alveolar type II (ATII) properties called bronchoalveolar stem cells (BASCs) [19]. The alveolar epithelium is composed of alveolar type (ATI) cells adapted for optimal gas exchange and ATII cells, the main producers of surfactant proteins A–D and the stem cells of the distal lung [16, 23, 24]. Proximal airways as well as the distal bronchioles of the human lung are lined by a pseudostratified epithelium containing basal, secretory (club and goblet), ciliated and neuroendocrine cells, while human alveoli, like those in mouse lungs, are comprised of ATI and ATII cells [30–32]. For obvious reasons, not many studies investigating human lung stem cells exist. However, accumulating evidence suggests that basal cells could represent a multipotent population of stem cells, sustaining human lung homeostasis and probably contributing to disease susceptibility [31, 33]. Furthermore, an important role for ATII cells in human alveolar maintenance and repair has been proposed [15].

Cellular pathways to lung repair, disease and cancer

The lungs constitute the body's largest interface with the external environment. The ∼90 m2 of alveolar surface area of a resting adult come in contact with and filter >10 m3 of ambient air on a daily basis to sustain gas exchange. Hence, stochastic and repetitive environmental noxious stimuli including tobacco-contained and other chemicals, bacterial or viral pathogens, inhaled particles, home pneumotoxins, etc. continuously insult the lungs, even during unchallenged ageing. In addition to this background of everyday hits, the lungs sustain massive insults that ensue sporadically in cases of infection, aspiration, sepsis and other acute lung injuries. Lung stem/progenitor cells, including bronchial and alveolar epithelial cells, physiologically display sufficient repair and renewal capacity and phenotypic plasticity to maintain lung structure and function in response to chronic and acute noxious stimuli.

In the mouse lung, resting-state homeostasis is achieved mainly via self-renewal and concomitant generation of heterotypic lung cells from basal, club, BASC and ATII cells. It has been shown that basal cells can give rise to ciliated and club cells [26, 28]. Club cells maintain their own population and replenish ciliated cells, and as such maintain the bronchiolar epithelial structural and functional integrity [27, 28], while ATII cells are able to self-renew and give rise to ATI cells [15, 16].

How are cellular dynamics altered upon acute and more extensive lung injury? Airway epithelial regeneration has been widely studied after naphthalene injury in mice, which selectively depletes the vast majority of club cells. These studies demonstrated that damaged airways are regenerated by a small, variant club cell population adjacent to NEBs and in the BADJs, which is resistant to naphthalene toxicity and expands post-injury to replenish the damaged airways [17, 18]. Furthermore, BASCs were shown to possess bronchial regenerative potential post-naphthalene injury [19, 34]. An exciting notion proposed by Tata et al. [35] is that Scgb1a1+ cells can de-differentiate to give rise to basal cells. After lung injury, goblet cells are replenished by Scgb1a1+ cells, but they might also derive from ciliated Foxj1+ cells, albeit to a lesser extent [36, 37]. Conversely, ATII cells are considered to be the main cellular population regenerating the alveolar compartment, able to give rise to both ATI and ATII cells after alveolar damage induced by bleomycin [15], conditional expression of diphtheria toxin by alveolar cells [15] or hyperoxia [16, 27]. However, studies describe an emerging role for Scgb1a1+ club cells in the regeneration of both ATI and ATII cells following severe bleomycin-mediated injury [29]. In line with these observations, unpublished data of the authors support that distal alveolar epithelium is enriched in Scgb1a1+ cells after bleomycin- and hyperoxia-induced lung injury, in accordance with previous findings [38, 39], as well as during unchallenged ageing. Whether these distally located, regenerating Scgb1a1+ cells are due to the expansion of a distal basal cell population or to the activation of airway phenotypic markers in distal alveolar stem cells or to an actual migration of bronchial epithelial cells from the proximal airways remains to be investigated.

In chronic obstructive, fibrotic and neoplastic lung disorders, the normal balance of pulmonary cell death (injury) and life (repair) is tilted towards disease, manifested by the insufficiency of the lungs to perform gas exchange. The greatest evidence that chronic obstructive, fibrotic and neoplastic lung disorders are the result of abnormal epithelial homeostasis in response to chronic and acute environmental stress is their association with age [40] and smoking (figure 1). Interestingly, evidence suggests the implication of airway cells in human alveolar diseases. Indicatively, the pathogenesis of IPF has been associated with deregulated expression of MUC5B, a marker of goblet airway epithelial cells [22]. In patients with IPF, it has been suggested that regeneration of the fibrotic lung may be partly mediated by distal bronchial club or basal cells [9]. Furthermore, there is evidence that the emphysematous destruction in COPD is associated with narrowing and loss of terminal bronchioles [11].

FIGURE 1
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 1

Schematic illustration of approximate overlap of smoking with chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and lung cancer, drawn based on data from [1–3, 7, 8, 40].

The identification of lung cellular populations with stem cell characteristics has provided a valuable tool in the dissection of the underlying mechanisms of lung carcinogenesis, since stemness and oncogenic signalling in lung adenocarcinoma-initiating cells were shown to collide and to be druggable [41]. As the leading cancer killer worldwide, lung adenocarcinoma is caused mainly by chemical carcinogens in tobacco smoke that induce mutations in multiple genes of various distal pulmonary cells [12, 13], several pulmonary lineage tracing studies utilising targeted expression of oncogenes in the respiratory epithelium have been performed. However, despite considerable efforts, no definitive answer exists yet, as these studies incriminated different cells as progenitors of lung adenocarcinoma in adult mice: airway epithelial cells including basal and club cells, ATII cells and/or BASCs with dual ATII/club properties [16, 19, 20, 42–45]. In fact, new insights suggest that the molecular signature, like KRAS mutation or Sox2, Notch and Lkb1 signalling, is a crucial factor determining the cellular origin of cancer [46–48]. Similar studies on mouse models of lung squamous cell carcinoma have validated the oncogenes identified by human sequencing studies as causative of the disease, but have not yet unequivocally identified the cellular basis of the disease, even though basal cells are an attractive candidate [24, 49].

Importantly, recent studies suggest that the mutational landscape of human lung adenocarcinoma is closely mirrored by tobacco carcinogen-induced murine lung tumours, and not by lung cancers triggered by transgenic expression of oncogenic KRASG12C or KRASG12D mutations in the respiratory epithelium [14]. To this end, we have used chemical carcinogens contained in tobacco smoke in order to inflict lung adenocarcinoma in mice, in conjunction with accurate mouse models of continuous respiratory epithelial cell marking. Our unpublished results support an important role for the airway transcriptional signature in the development of lung adenocarcinoma, as we detected both airway and alveolar gene expression signatures in tobacco chemical-induced lung adenocarcinomas of mice.

Molecular signalling events in the injured and precancerous lung

Lung adenocarcinoma and squamous cell carcinoma have been associated with mutations, overexpression or loss of function of specific genes in distinct molecular pathways [13, 24, 25]. For example, indicative genes involved in squamous cell carcinoma include sex-determining region Y-box 2 (SOX2), fibroblast growth factor receptor 1 (FGFR1), phosphatase and tensin homologue (PTEN), cyclin-dependent kinase inhibitor 2A (CDKN2A), tumour protein 53 (TP53), and many more [50], while human adenocarcinomas have been associated with mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS), epidermal growth factor receptor (EGFR), and v-Raf murine sarcoma viral oncogene homologue B (BRAF) genes, etc. [13].

Interestingly, molecular signalling in lung cancer and chronic lung diseases often coincides, raising the possibility of a stepwise pathobiology. For example, Wnt pathway genes are known to be upregulated in NSCLC [51], but they are also involved in the pathogenesis of COPD [52]. Wnt signalling induces proliferation of BASCs [53] and this could represent a potential molecular link between emphysema and cancer. Along these lines, several epithelial molecular pathways with prominent roles in lung homeostasis, lung cancer and chronic lung diseases have been described. Indicatively, transforming growth factor (TGF)-β signalling underlies asthma, COPD and lung cancer [54–56], hedgehog (Hh) signalling can interfere with lung repair and tumorigenesis [57, 58], Notch 3 expression regulates basal cell numbers and is involved in COPD and possibly in lung cancer [59, 60], while FGF1 signalling can link IPF and lung cancer [50, 61]. Of course, additional pathways possibly linking chronic lung diseases and lung cancer include inflammatory signalling caused by tobacco smoke exposure, angiogenic signals and many more that are not in the scope of this mini-review. These signalling pathways, which are commonly involved in the pathogenesis of chronic lung diseases and lung cancer, such as the nuclear factor-κΒ pathway which is critically involved in both COPD and lung cancer, are lucrative potential drug targets for the simultaneous enhancement of lung regeneration and prevention of neoplasia [62, 63].

Conclusions

It is becoming increasingly evident that resident airway and alveolar cells display dynamic changes and marked plasticity of gene expression and/or localisation that are cardinal for pulmonary regeneration and neoplasia. Disruption of this homeostatic potential underlies several lung diseases. Therefore, understanding the mechanisms of lung regenerative capacity and elucidating the transcription programmes that are activated during lung repair, disease and carcinogenesis will probably identify novel therapeutic targets.

Acknowledgements

The authors thank the University of Patras Centre for Animal Models of Disease and Advanced Light Microscopy Facility (Patras, Greece) for experimental support, and their collaborators for insightful discussions on the topic of this review.

Footnotes

  • Support statement: Research funding was received from the European Research Council (Starting Independent Investigator Grant, number 260524, and Proof of Concept Grant, number 679345, to G.T. Stathopoulos) and the Hellenic State Scholarships Foundation (IKY; Research Fellowship 2014 to M. Spella). Funding information for this article has been deposited with the Crossref Funder Registry.

  • Conflict of interest: None declared.

  • Provenance: Commissioned article, peer reviewed.

  • Received April 12, 2017.
  • Accepted May 19, 2017.
  • Copyright ©ERS 2017.

ERR articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

References

  1. ↵
    1. Lozano R,
    2. Naghavi M,
    3. Foreman K, et al.
    Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2095–2128.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Torre LA,
    2. Bray F,
    3. Siegel RL, et al.
    Global cancer statistics, 2012. CA Cancer J Clin 2015; 65: 87–108.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Fitzmaurice C,
    2. Allen C,
    3. Barber RM, et al.
    Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the Global Burden of Disease Study. JAMA Oncol 2017; 3: 524–548.
    OpenUrl
  4. ↵
    1. Ujiie H,
    2. Kadota K,
    3. Chaft JE, et al.
    Solid predominant histologic subtype in resected stage I lung adenocarcinoma is an independent predictor of early, extrathoracic, multisite recurrence and of poor postrecurrence survival. J Clin Oncol 2015; 33: 2877–2884.
    OpenUrlAbstract/FREE Full Text
    1. Tsao MS,
    2. Marguet S,
    3. Le Teuff G, et al.
    Subtype classification of lung adenocarcinoma predicts benefit from adjuvant chemotherapy in patients undergoing complete resection. J Clin Oncol 2015; 33: 3439–3446.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Ma J,
    2. Ward EM,
    3. Smith R, et al.
    Annual number of lung cancer deaths potentially avertable by screening in the United States. Cancer 2013; 119: 1381–1385.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Barnes PJ
    . Chronic obstructive pulmonary disease. N Engl J Med 2000; 343: 269–280.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Gross TJ,
    2. Hunninghake GW
    . Idiopathic pulmonary fibrosis. N Engl J Med 2001; 345: 517–525.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Chilosi M,
    2. Poletti V,
    3. Murer B, et al.
    Abnormal re-epithelialization and lung remodeling in idiopathic pulmonary fibrosis: the role of ΔN-p63. Lab Invest 2002; 82: 1335–1345.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Hogg JC,
    2. Paré PD,
    3. Hackett TL
    . The contribution of small airway obstruction to the pathogenesis of chronic obstructive pulmonary disease. Physiol Rev 2017; 97: 529–552.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. McDonough JE,
    2. Yuan R,
    3. Suzuki M, et al.
    Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N Engl J Med 2011; 365: 1567–1575.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Hecht SS
    . Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 1999; 91: 1194–1210.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014; 511: 543–550.
    OpenUrlCrossRefPubMed
  13. ↵
    1. Westcott PM,
    2. Halliwill KD,
    3. To MD, et al.
    The mutational landscapes of genetic and chemical models of Kras-driven lung cancer. Nature 2015; 517: 489–492.
    OpenUrlCrossRefPubMed
  14. ↵
    1. Barkauskas CE,
    2. Cronce MJ,
    3. Rackley CR, et al.
    Type 2 alveolar cells are stem cells in adult lung. J Clin Invest 2013; 123: 3025–3036.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Desai TJ,
    2. Brownfield DG,
    3. Krasnow MA
    . Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature 2014; 507: 190–194.
    OpenUrlCrossRefPubMed
  16. ↵
    1. Giangreco A,
    2. Arwert EN,
    3. Rosewell IR, et al.
    Stem cells are dispensable for lung homeostasis but restore airways after injury. Proc Natl Acad Sci USA 2009; 106: 9286–9291.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Giangreco A,
    2. Reynolds SD,
    3. Stripp BR
    . Terminal bronchioles harbor a unique airway stem cell population that localizes to the bronchoalveolar duct junction. Am J Pathol 2002; 161: 173–182.
    OpenUrlCrossRefPubMed
  18. ↵
    1. Kim CF,
    2. Jackson EL,
    3. Woolfenden AE, et al.
    Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 2005; 121: 823–835.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Zuo W,
    2. Zhang T,
    3. Wu DZ, et al.
    p63+Krt5+ distal airway stem cells are essential for lung regeneration. Nature 2015; 517: 616–620.
    OpenUrlPubMed
  20. ↵
    1. Seibold MA,
    2. Smith RW,
    3. Urbanek C, et al.
    The idiopathic pulmonary fibrosis honeycomb cyst contains a mucocilary pseudostratified epithelium. PLoS One 2013; 8: e58658.
    OpenUrlCrossRefPubMed
  21. ↵
    1. Seibold MA,
    2. Wise AL,
    3. Speer MC, et al.
    A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med 2011; 364: 1503–1512.
    OpenUrlCrossRefPubMed
  22. ↵
    1. Imielinski M,
    2. Guo G,
    3. Meyerson M
    . Insertions and deletions target lineage-defining genes in human cancers. Cell 2017; 168: 460–472.
    OpenUrl
  23. ↵
    1. Sutherland KD,
    2. Berns A
    . Cell of origin of lung cancer. Mol Oncol 2010; 4: 397–403.
    OpenUrlCrossRefPubMed
  24. ↵
    1. Giangreco A,
    2. Groot KR,
    3. Janes SM
    . Lung cancer and lung stem cells: strange bedfellows? Am J Respir Crit Care Med 2007; 175: 547–553.
    OpenUrlCrossRefPubMed
  25. ↵
    1. Hong KU,
    2. Reynolds SD,
    3. Watkins S, et al.
    In vivo differentiation potential of tracheal basal cells: evidence for multipotent and unipotent subpopulations. Am J Physiol Lung Cell Mol Physiol 2004; 286: L643–L649.
    OpenUrlAbstract/FREE Full Text
  26. ↵
    1. Rawlins EL,
    2. Okubo T,
    3. Xue Y, et al.
    The role of Scgb1a1+ Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium. Cell Stem Cell 2009; 4: 525–534.
    OpenUrlCrossRefPubMed
  27. ↵
    1. Rock JR,
    2. Onaitis MW,
    3. Rawlins EL, et al.
    Basal cells as stem cells of the mouse trachea and human airway epithelium. Proc Natl Acad Sci USA 2009; 106: 12771–12775.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Zheng D,
    2. Limmon GV,
    3. Yin L, et al.
    Regeneration of alveolar type I and II cells from Scgb1a1-expressing cells following severe pulmonary damage induced by bleomycin and influenza. PLoS One 2012; 7: e48451.
    OpenUrlCrossRefPubMed
  29. ↵
    1. Boers JE,
    2. Ambergen AW,
    3. Thunnissen FB
    . Number and proliferation of basal and parabasal cells in normal human airway epithelium. Am J Respir Crit Care Med 1998; 157: 2000–2006.
    OpenUrlCrossRefPubMed
  30. ↵
    1. Rock JR,
    2. Randell SH,
    3. Hogan BL
    . Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodeling. Dis Model Mech 2010; 3: 545–556.
    OpenUrlAbstract/FREE Full Text
  31. ↵
    1. Volckaert T,
    2. De Langhe S
    . Lung epithelial stem cells and their niches: Fgf10 takes center stage. Fibrogenesis Tissue Repair 2014; 7: 8.
    OpenUrlCrossRefPubMed
  32. ↵
    1. Teixeira VH,
    2. Nadarajan P,
    3. Graham TA, et al.
    Stochastic homeostasis in human airway epithelium is achieved by neutral competition of basal cell progenitors. Elife 2013; 2: e00966.
    OpenUrlAbstract/FREE Full Text
  33. ↵
    1. Lee JH,
    2. Bhang DH,
    3. Beede A, et al.
    Lung stem cell differentiation in mice directed by endothelial cells via a BMP4-NFATc1-thrombospondin-1 axis. Cell 2014; 156: 440–455.
    OpenUrlCrossRefPubMed
  34. ↵
    1. Tata PR,
    2. Mou H,
    3. Pardo-Saganta A, et al.
    Dedifferentiation of committed epithelial cells into stem cells in vivo. Nature 2013; 503: 218–223.
    OpenUrlCrossRefPubMed
  35. ↵
    1. Turner J,
    2. Roger J,
    3. Fitau J, et al.
    Goblet cells are derived from a FOXJ1-expressing progenitor in a human airway epithelium. Am J Respir Cell Mol Biol 2011; 44: 276–284.
    OpenUrlCrossRefPubMed
  36. ↵
    1. Pardo-Saganta A,
    2. Law BM,
    3. Gonzalez-Celeiro M, et al.
    Ciliated cells of pseudostratified airway epithelium do not become mucous cells after ovalbumin challenge. Am J Respir Cell Mol Biol 2013; 48: 364–373.
    OpenUrlCrossRefPubMed
  37. ↵
    1. Daly HE,
    2. Baecher-Allan CM,
    3. Paxhia AT, et al.
    Cell-specific gene expression reveals changes in epithelial cell populations after bleomycin treatment. Lab Invest 1998; 78: 393–400.
    OpenUrlPubMed
  38. ↵
    1. Pinkerton KE,
    2. Dodge DE,
    3. Cederdahl-Demmler J, et al.
    Differentiated bronchiolar epithelium in alveolar ducts of rats exposed to ozone for 20 months. Am J Pathol 1993; 142: 947–956.
    OpenUrlPubMed
  39. ↵
    1. Meiners S,
    2. Eickelberg O,
    3. Königshoff M
    . Hallmarks of the ageing lung. Eur Respir J 2015; 45: 807–827.
    OpenUrlAbstract/FREE Full Text
  40. ↵
    1. Seguin L,
    2. Kato S,
    3. Franovic A, et al.
    An integrin β3-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition. Nat Cell Biol 2014; 16: 457–468.
    OpenUrlCrossRefPubMed
  41. ↵
    1. Cho HC,
    2. Lai CY,
    3. Shao LE, et al.
    Identification of tumorigenic cells in Kras(G12D)-induced lung adenocarcinoma. Cancer Res 2011; 71: 7250–7258.
    OpenUrlAbstract/FREE Full Text
    1. Mainardi S,
    2. Mijimolle N,
    3. Francoz S, et al.
    Identification of cancer initiating cells in K-Ras driven lung adenocarcinoma. Proc Natl Acad Sci USA 2014; 111: 255–260.
    OpenUrlAbstract/FREE Full Text
    1. Sutherland KD,
    2. Song JY,
    3. Kwon MC, et al.
    Multiple cells-of-origin of mutant K-Ras-induced mouse lung adenocarcinoma. Proc Natl Acad Sci USA 2014; 111: 4952–4957.
    OpenUrlAbstract/FREE Full Text
  42. ↵
    1. Xu X,
    2. Rock JR,
    3. Lu Y, et al.
    Evidence for type II cells as cells of origin of K-Ras-induced distal lung adenocarcinoma. Proc Natl Acad Sci USA 2012; 109: 4910–4915.
    OpenUrlAbstract/FREE Full Text
  43. ↵
    1. Zhang H,
    2. Fillmore Brainson C,
    3. Koyama S, et al.
    Lkb1 inactivation drives lung cancer lineage switching governed by polycomb repressive complex 2. Nat Commun 2017; 8: 14922.
    OpenUrl
    1. Xu X,
    2. Huang L,
    3. Futtner C, et al.
    The cell of origin and subtype of K-Ras-induced lung tumors are modified by Notch and Sox2. Genes Dev 2014; 28: 1929–1939.
    OpenUrlAbstract/FREE Full Text
  44. ↵
    1. Ischenko I,
    2. Zhi J,
    3. Moll UM, et al.
    Direct reprogramming by oncogenic Ras and Myc. Proc Natl Acad Sci USA 2013; 110: 3937–3942.
    OpenUrlAbstract/FREE Full Text
  45. ↵
    1. Ferone G,
    2. Song JY,
    3. Sutherland KD, et al.
    SOX2 is the determining oncogenic switch in promoting lung squamous cell carcinoma from different cells of origin. Cancer Cell 2016; 30: 519–532.
    OpenUrlCrossRef
  46. ↵
    Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012; 489: 519–525.
    OpenUrlCrossRefPubMed
  47. ↵
    1. Stewart DJ
    . Wnt signaling pathway in non-small cell lung cancer. J Natl Cancer Inst 2014; 106: djt356.
    OpenUrlAbstract/FREE Full Text
  48. ↵
    1. Baarsma HA,
    2. Skronska-Wasek W,
    3. Mutze K, et al.
    Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD. J Exp Med 2017; 214: 143–163.
    OpenUrlAbstract/FREE Full Text
  49. ↵
    1. Zhang Y,
    2. Goss AM,
    3. Cohen ED, et al.
    A Gata6-Wnt pathway required for epithelial stem cell development and airway regeneration. Nat Genet 2008; 40: 862–870.
    OpenUrlCrossRefPubMed
  50. ↵
    1. Verhamme FM,
    2. Bracke KR,
    3. Joos GF, et al.
    Transforming growth factor-β superfamily in obstructive lung diseases. More suspects than TGF-β alone. Am J Respir Cell Mol Biol 2015; 52: 653–662.
    OpenUrlCrossRefPubMed
    1. Königshoff M,
    2. Kneidinger N,
    3. Eickelberg O
    . TGF-β signaling in COPD: deciphering genetic and cellular susceptibilities for future therapeutic regimen. Swiss Med Wkly 2009; 139: 554–563.
    OpenUrlPubMed
  51. ↵
    1. Jeon HS,
    2. Jen J
    . TGF-β signaling and the role of inhibitory Smads in non-small cell lung cancer. J Thorac Oncol 2010; 5: 417–419.
    OpenUrlCrossRefPubMed
  52. ↵
    1. Kugler MC,
    2. Joyner AL,
    3. Loomis CA, et al.
    Sonic hedgehog signaling in the lung. From development to disease. Am J Respir Cell Mol Biol 2015; 52: 1–13.
    OpenUrl
  53. ↵
    1. Peng T,
    2. Frank DB,
    3. Kadzik RS, et al.
    Hedgehog actively maintains adult lung quiescence and regulates repair and regeneration. Nature 2015; 526: 578–582.
    OpenUrlCrossRefPubMed
  54. ↵
    1. Tilley AE,
    2. Harvey BG,
    3. Heguy A, et al.
    Down-regulation of the notch pathway in human airway epithelium in association with smoking and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009; 179: 457–466.
    OpenUrlCrossRefPubMed
  55. ↵
    1. Mori M,
    2. Mahoney JE,
    3. Stupnikov MR, et al.
    Notch3-Jagged signaling controls the pool of undifferentiated airway progenitors. Development 2015; 142: 258–267.
    OpenUrlAbstract/FREE Full Text
  56. ↵
    1. El Agha E,
    2. Kosanovic D,
    3. Schermuly RT, et al.
    Role of fibroblast growth factors in organ regeneration and repair. Semin Cell Dev Biol 2016; 53: 76–84.
    OpenUrl
  57. ↵
    1. Houghton AM
    . Mechanistic links between COPD and lung cancer. Nat Rev Cancer 2013; 13: 233–245.
    OpenUrlCrossRefPubMed
  58. ↵
    1. Stathopoulos GT,
    2. Sherrill TP,
    3. Cheng DS, et al.
    Epithelial NF-κB activation promotes urethane-induced lung carcinogenesis. Proc Natl Acad Sci USA 2007; 104: 18514–18519.
    OpenUrlAbstract/FREE Full Text
PreviousNext
Back to top
View this article with LENS
Vol 26 Issue 144 Table of Contents
European Respiratory Review: 26 (144)
  • Table of Contents
  • Table of Contents (PDF)
  • Index by author
Email

Thank you for your interest in spreading the word on European Respiratory Society .

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Shared epithelial pathways to lung repair and disease
(Your Name) has sent you a message from European Respiratory Society
(Your Name) thought you would like to see the European Respiratory Society web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
Citation Tools
Shared epithelial pathways to lung repair and disease
Magda Spella, Ioannis Lilis, Georgios T. Stathopoulos
European Respiratory Review Jun 2017, 26 (144) 170048; DOI: 10.1183/16000617.0048-2017

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Shared epithelial pathways to lung repair and disease
Magda Spella, Ioannis Lilis, Georgios T. Stathopoulos
European Respiratory Review Jun 2017, 26 (144) 170048; DOI: 10.1183/16000617.0048-2017
Reddit logo Technorati logo Twitter logo Connotea logo Facebook logo Mendeley logo
Full Text (PDF)

Jump To

  • Article
    • Abstract
    • Abstract
    • Introduction
    • Lung cells with regenerative potential
    • Cellular pathways to lung repair, disease and cancer
    • Molecular signalling events in the injured and precancerous lung
    • Conclusions
    • Acknowledgements
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF

Subjects

  • Lung biology and experimental studies
  • Mechanisms of lung disease
  • Tweet Widget
  • Facebook Like
  • Google Plus One

More in this TOC Section

  • Mitochondrial dysfunction in lung ageing and disease
  • Metabolism in tumour-associated macrophages
  • Respiratory muscle senescence in ageing and chronic lung diseases
Show more Lung Science Conference

Related Articles

Navigate

  • Home
  • Current issue
  • Archive

About the ERR

  • Journal information
  • Editorial board
  • Press
  • Permissions and reprints
  • Advertising
  • Sponsorship

The European Respiratory Society

  • Society home
  • myERS
  • Privacy policy
  • Accessibility

ERS publications

  • European Respiratory Journal
  • ERJ Open Research
  • European Respiratory Review
  • Breathe
  • ERS books online
  • ERS Bookshop

Help

  • Feedback

For authors

  • Instructions for authors
  • Publication ethics and malpractice
  • Submit a manuscript

For readers

  • Alerts
  • Subjects
  • RSS

Subscriptions

  • Accessing the ERS publications

Contact us

European Respiratory Society
442 Glossop Road
Sheffield S10 2PX
United Kingdom
Tel: +44 114 2672860
Email: journals@ersnet.org

ISSN

Print ISSN: 0905-9180
Online ISSN: 1600-0617

Copyright © 2023 by the European Respiratory Society