Invited critical review
The role of epithelial–mesenchymal transition in oral squamous cell carcinoma and oral submucous fibrosis

https://doi.org/10.1016/j.cca.2007.04.014Get rights and content

Abstract

Epithelial–mesenchymal transition (EMT) is an indispensable mechanism during morphogenesis. Interest and research in EMT are currently at a high level due to its important role in cancer and fibrosis. Emerging evidence suggests that EMT is also a crucial event in oral squamous cell carcinoma (OSCC). Oral submucous fibrosis (OSF) is a chronic debilitating disease and a premalignant condition of the oral cavity. It is characterized by a generalized submucosal fibrosis. The pathogenesis of the disease is not well established. Epidemiological evidence strongly indicates an association between the betel quid (BQ) chewing habit and OSF. In a simplistic view, OSF represents a failed wound-healing process of the oral mucosa after chronic, sustained injury. This review highlights the signaling pathways involved in EMT, recent advances in the study of EMT in OSCC, and summarizes the evidence supporting a role for EMT in the pathogenesis of OSF.

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.

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