Invited critical reviewThe role of epithelial–mesenchymal transition in oral squamous cell carcinoma and oral submucous fibrosis
Introduction
Changes in paradigms, although slow and usually difficult, are fundamental to most significant advances in science. Such a paradigm change may be underway in the current investigation into mechanisms of chronic injury and fibrosis in the oral mucosa. Oral submucous fibrosis (OSF) is a chronic, progressive, pre-cancerous condition of the oral mucosa, which is associated with betel quid (BQ) chewing habit widely prevalent in Southeast Asia and some places in China [1]. The pathogenesis of the disease is believed to be multifactorial [2]. Generally, OSF has been viewed as the result of persistent chemical irritation from BQ constituents and the mechanical irritation to the oral mucosa from the coarse fibers of areca nut. The microtrauma produced by the friction of coarse fibers of areca nut also facilitates the diffusion of BQ alkaloids and flavonoids into the subepithelial connective tissue [3]. Any external factor that causes any form of injury to tissue can elicit a protective inflammatory process. Epithelial–mesenchymal transition (EMT), a process by which epithelial cells lose cell–cell attachment, polarity and epithelial specific markers, undergo cytoskeletal remodeling, and gain a mesenchymal phenotype, has been clearly recognized for many decades in developmental biology as instrumental in effecting rapid morphogenetic changes in metazoan embryos [4]. Secondary epithelium in mature or adult tissues can also undergo EMT following epithelial stress, such as inflammation or wounding that leads to fibroblast production and fibrogenesis [5], [6]. The role of EMT in fibrosis is evidenced in many organs. Moreover, the novel evidence implies that EMT remains a very likely candidate in the processes of neoplasia and carcinoma metastasis [7], [8]. With that as background, this review focuses on a newly proposed mechanism of OSF, which will provide new strategies to prevent or treat OSF.
Section snippets
Epithelial–mesenchymal transition
EMT is characterized by a number of defined cellular changes. Initially, a transition occurs in morphology from the cobblestone-like cell sheet typical of an epithelial phenotype to the elongated, fusiform cell sheet characteristic of fibroblasts. The epithelial cells lose polarity and cell–cell adhesion, and gain mesenchymal properties including motility. Secondly, a loss of epithelial markers including E-cadherin, cytokeratin, zonula occludens-1 (ZO-1) is demonstrated [9]. A corresponding
Signaling pathways in EMT
Among the classic modulators of the EMT are members of the TGF-β superfamily, which tend to promote EMT and BMP subfamilies, which seem to counteract EMT and promote the opposite MET (Fig. 1). Each subfamily uses a distinctive set of receptors and a different complement of Smad signaling proteins.
TGF-β is a pluripotent factor that can elicit multiple cellular responses, even in the same cell type. In epithelial cells, TGF-β is able to induce both cell apoptosis and EMT [24]. TGF-β signals
EMT in oral squamous cell carcinoma
The role of EMT in the invasion and metastasis of cancer has been evidenced for some tumors and cell lines [35], [36], [37], but more recently, the effect on oral cancer has attracted significant attention. Oral carcinoma cells of epithelial origin ectopically express a mesenchyme-specific transcription factor (HMGA2) at the invasive front, which has a significant impact on tumor progression and patient survival [38]. Forced expression of the HMGA1 gene in breast carcinoma cells up-regulates a
Role of the keratinocyte in fibrogenesis
Classically, aberrant and persistent tissue inflammation is crucial to the occurrence of fibrosis and cancer. As such, the oral mucosal inflammation by BQ ingredients can be critical in the pathogenesis of OSF and oral cancer. The question is what type of cells can be the target of BQ ingredients. For a long time keratinocytes have been considered as mere victims of the oral mucosal injury, whereas fibroblasts have been classically observed as the main cells responsible for the structural and
EMT in oral submucous fibrosis
The emerging paradigm is that inflammatory mediators that are produced in response to injury cause EMT, which can lead to fibrosis. The critical importance of keratinocyte inflammation to the process of fibrosis, together with the crucial role for EMT in fibrogenesis in other tissues, naturally raise the question of whether EMT contributes to the pathogenesis of fibrosis in the oral mucous.
Although several investigations have found that exposure to ANE causes the alterations of normal
Conclusion
Little, if any, progress has been made to date on the fibrosis and cancerization characteristic of OSF. Perhaps we have been focusing on the wrong targets. The fate of the oral keratinocyte that may undergo EMT in response to injury is fascinating. Potentially, the transformed cell may proliferate to expand the fibroblast population, undergo apoptosis, or revert back to epithelial type [75]. This last possibility offers exciting potential for therapeutic development — if, on exposure to
Acknowledgements
The work related to this review is supported by the National Natural Sciences Foundation of China (Grant No. 30572044). The authors wish to thank Dr. Gregg J. Carb for reviewing the manuscript.
References (75)
- et al.
Oral submucous fibrosis: review on aetiology and pathogenesis
Oral Oncol
(2006) - et al.
Mechanisms, mechanics and function of epithelial–mesenchymal transitions in early development
Mech Dev
(2003) - et al.
Epidermal growth factor-induced epithelio-mesenchymal transition in human breast carcinoma cells
Lab Invest
(2003) - et al.
Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis
Cell
(2004) - et al.
Smad3 signaling is required for epithelial–mesenchymal transition of lens epithelium after injury
Am J Pathol
(2004) - et al.
Differential regulation of TGF-beta signal in hepatic stellate cells between acute and chronic rat liver injury
Hepatology
(2002) - et al.
Caspase-dependent apoptosis and -independent poly(ADP-ribose) polymerase cleavage induced by transforming growth factor beta1
Int J Biochem Cell Biol
(2004) - et al.
Transient adenoviral gene transfer of Smad7 prevents injury-induced epithelial–mesenchymal transition of lens epithelium in mice
Lab Invest
(2004) - et al.
Therapeutic role and potential mechanisms of active vitamin D in renal interstitial fibrosis
J Steroid Biochem Mol Biol
(2007) - et al.
Amelioration of radiation-induced fibrosis: inhibition of transforming growth factor-beta signaling by halofuginone
J Biol Chem
(2004)
Reverse correlation of E-cadherin and snail expression in oral squamous cell carcinoma cells in vitro
Oral Oncol
The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion
Mol Cell
Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression
J Biol Chem
Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions
J Biol Chem
Keratinocytes as initiators of inflammation
Lancet
Elevated vimentin expression in buccal mucosal fibroblasts by arecoline in vitro as a possible pathogenesis for oral submucous fibrosis
Oral Oncol
Immunolocalization of cytokines and growth factors in oral submucous fibrosis
Cytokine
The upregulation of insulin-like growth factor-1 in oral submucous fibrosis
Oral Oncol
Cytokeratin expression in oral submucous fibrosis—an immunohistochemical study
J Oral Pathol Med
High incidence of autoantibodies in Taiwanese patients with oral submucous fibrosis
J Oral Pathol Med
Evidence that fibroblasts derive from epithelium during tissue fibrosis
J Clin Invest
Factors influencing myofibroblast differentiation during wound healing and fibrosis
Cell Biol Int
Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis
Nat Rev Mol Cell Biol
Early role of Fsp1 in epithelial–mesenchymal transformation
Am J Physiol
Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells
J Cell Biol
An overview of epithelio-mesenchymal transformation
Acta Anat (Basel)
Detection of epithelial to mesenchymal transition in airways of a bleomycin induced pulmonary fibrosis model derived from an alpha-smooth muscle actin-Cre transgenic mouse
Respir Res
Setting a trap for tissue fibrosis
Nat Med
Epithelial–mesenchymal transition and its implications for fibrosis
J Clin Invest
Epithelial–mesenchymal transitions in tumour progression
Nat Rev Cancer
Transcriptional regulation of cadherins during development and carcinogenesis
Int J Dev Biol
The Snail genes as inducers of cell movement and survival: implications in development and cancer
Development
The transcriptional repressor Snail promotes mammary tumor recurrence
Cancer Cell
Epithelial to mesenchymal transition in human breast cancer can provide a nonmalignant stroma
Am J Pathol
NF-kappaB is essential for epithelial–mesenchymal transition and metastasis in a model of breast cancer progression
J Clin Invest
Regulation of cell proliferation by Smad proteins
J Cell Physiol
Transcriptional control by the TGF-beta/Smad signaling system
EMBO J
Cited by (50)
The role of epithelial cells in fibrosis: Mechanisms and treatment
2024, Pharmacological ResearchUnravelling the role of EMT in OSCC: A quick peek into HPV-mediated pathogenesis
2023, Oral Oncology ReportsSignaling pathways promoting epithelial mesenchymal transition in oral submucous fibrosis and oral squamous cell carcinoma
2020, Japanese Dental Science ReviewCitation Excerpt :EMT is crucial for developmental milestones such as gastrulation of the metazoans, neural crest formation, and heart morphogenesis [8]. EMT is shown to be elicited following chronic inflammation and during wound healing [9]. The role of EMT has increasingly gained significance as an essential process in fibrosis and carcinogenesis.
Loricrin expression and its implication in oral submucous fibrosis, hyperkeratosis and normal mucosa with association to habits – An immunohistochemical study
2019, Journal of Oral Biology and Craniofacial ResearchCitation Excerpt :Genetic and environmental factors can alter the normal proliferation and differentiation.7,8 For example, the continuous micro trauma provided by areca nut and other ingredients in chewing, plus friction from occluding teeth creates an environment where the keratinocytes of the epithelium tend to alter the Cornified epithelial Envelope (CE), a critical structure for barrier function at the outermost layer of the skin epidermis.9–11 Proteins of CE like Loricrin, are late differentiation markers of terminally differentiated keratinocytes.