Clinical significance of epithelial mesenchymal transition (EMT) in chronic obstructive pulmonary disease (COPD): potential target for prevention of airway fibrosis and lung cancer

Abstract

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.

Relationships between chronic obstructive pulmonary disease and lung cancer: biological insights

“…Interestingly, the blockade of TGF-beta activity attenuated EMT expression markers (113). The authors also concluded that these results may open a new avenue for research in the treatment of patients with LC and underlying COPD (113) as type II-EMT and angiogenesis (type-III EMT) favor lung tumor development (31).…”

“…For instance, oxidative and nitrosative stress as a result of reactive oxygen and nitrogen species (ROS and RNS, respectively) were shown to favor carcinogenesis through the activation of cellular processes that result in neoplastic transformation or the induction of DNA mutations (32). Other investigations have also demonstrated the contribution of oxidative damage, inflammatory events, and tumor microenvironment to lung carcinogenesis in patients and animal models (19,20,(25)(26)(27)(28)(29)(30)(31)(33)(34)(35)(36)(37).…”

“…The study of the underlying biological mechanisms that may predispose patients with chronic respiratory diseases to a higher incidence of LC has also gained much attention in the last few years by several investigators including those listed in this review (25)(26)(27)(28)(29)(30)(31). For instance, oxidative and nitrosative stress as a result of reactive oxygen and nitrogen species (ROS and RNS, respectively) were shown to favor carcinogenesis through the activation of cellular processes that result in neoplastic transformation or the induction of DNA mutations (32).…”

Roles of CEACAM1 in cell communication and signaling of lung cancer and other diseases

“…catarrhalis could induce apoptosis in human epithelial cells, which is triggered by interaction between CEACAM1 and ubiquitous surface protein A1 of M. catarrhalis [65]. M. catarrhalis-induced apoptosis as one of pathogenesis of COPD is enhanced by CEACAM1 and mitochondrial death pathways [66,67].…”

CLDN-1 promoted the epithelial to migration and mesenchymal transition (EMT) in human bronchial epithelial cells via Notch pathway

“…In functional differences, EMT can be classified into three categories: Type I EMT is related to physiological processes involved in specific organ formation during embryogenesis [5,7]; Type III EMT is associated with development of a premalignant stroma with tumor metastasis; and the occurrence of EMT activation (Type II EMT) and tissue regeneration is often associated with tissue fibrosis response to chronic inflammatory conditions [4,8]. EMT plays a vital role in airway remodeling that causes persistence of inflammatory infiltration and contributes to increasing thickness Abstract Claudin-1 (CLDN-1) is one of main tight junction components that play an important role in epithelialmesenchymal transition (EMT).…”