Oral Submucous Fibrosis: Review on Mechanisms of Pathogenesis and Malignant Transformation

Abstract

Studies focusing on epidemiology, histopathology and molecular biology/pathology on various aspects of oral submucous fibrosis (OSF), especially in the last decade have helped to understand the pathogenesis to a larger extent. In addition research in some aspects of carcinogenesis in the background of fibrosis has also advanced significantly in the recent past allowing us to understand the mechanisms involved in malignant transformation of the most prevalent oral potentially malignant disorder in South Asia. It has been shown that pathogenesis of OSF is directly related to arecoline present in arecanut and most of the alterations in various pathways and molecules leading to accumulation of collagen are mediated as a result of arecoline. Reduction of Matrix metalloproteinases (MMPs) and increased secretion of Tissue inhibitors of matrix metalloproteinases (TIMPs) play the most significant role in collagen accumulation whilst fibrogenic cytokines, mainly TGF-β over expression leads to increased production of collagen. There are various other pathways/molecules contributing to the pathogenesis in varying capacities. Malignant transformation in OSF has also been studied by various groups in the recent past. Role of arecanut as a carcinogen is proven beyond doubt with a large number of animal studies demonstrating its carcinogenicity, mutagenicity and genotoxicity. Studies involved in many molecules implicated in cell cycle regulation, hypoxia, processes leading to DNA double strand breaks, senescence and many other pathways related to carcinogenesis have shown ample evidence for the arecanut induced malignant transformation in OSF. Some of the findings in these studies may be helpful in inventing new treatment strategies for a common disease without an effective treatment up to date. Further, the understanding of mechanisms of malignant transformation may lead to early diagnosis of oral squamous cell carcinoma (OSCC) arising in the background of OSF.

Oral submucous fibrosis: An update on current theories of pathogenesis

“…1 However, there is compelling evidence from the recent studies that OSMF is essentially a result of collagen dysregulation and areca nut plays a key role in causing changes at different stages of collagen metabolism. 1,2 Studies have focused on increased synthesis or reduced collagen degradation as possible mechanisms in the development of the condition. 1,3 Nevertheless, the pathogenesis of OSMF is not well established, and the mechanism of how areca nut exactly causes OSMF is still being elucidated.…”

“…1,3 Nevertheless, the pathogenesis of OSMF is not well established, and the mechanism of how areca nut exactly causes OSMF is still being elucidated. 4 Based on available scientific literature, the pathogenesis of OSMF can be viewed under three broad theories [1][2][3][4] (summarized in Four alkaloids-arecoline (most potent), arecaidine, guvacine, and guvacine-are known to stimulate fibroblasts to produce collagen. 1,3 Moreover, the addition of slaked lime, namely calcium hydroxide, to | 407 areca nut in a paan preparation ( Figure 5) facilitates hydrolysis of arecoline to arecaidine, causing amplified fibroblastic proliferation and increased collagen formation.…”

“…6 Amplification of the production of tissue inhibitors of matrix metalloproteinases (TIMP)-1 by arecoline induces deposition of extracellular matrix (ECM). 2,7 The influence of arecoline on the extracellular matrix (ECM) is further substantiated by overexpression of transglutaminase 2 (TGM-2) in OSMF and its regulation by arecoline.…”

“…TGM-2 stabilizes ECM protein by cross-linking that has also been implicated in several fibrotic disorders. 2,8 Arecoline also has an antiproliferative and cytotoxic effect on endothelial cells, which may cause impairment of vascular function and consequently contributes to the pathogenesis of OSMF. These effects of arecoline are possibly associated with the alteration of specific cell cycle regulatory proteins such as ATM, checkpoint kinases, p53, and cdc25C for G2/M checkpoint.…”

“…These effects of arecoline are possibly associated with the alteration of specific cell cycle regulatory proteins such as ATM, checkpoint kinases, p53, and cdc25C for G2/M checkpoint. 2 The localized mucosal inflammation caused by areca nut or gutkha (a preparation of crushed areca nut, catechu, tobacco, slaked lime and either sweet or savoury flavourings) ( Figure 6) results in activated T-cell and macrophage recruitment that leads to an increase in cytokines and tumour growth factor beta (TGF-b). 1,7,9,10 An in vitro study found that arecoline augmented collagen synthesis by upregulation of proinflammatory and profibrotic cytokines, such as IL-1, IL-6, IL-8, TNF-ά, TGF-b, PDGF, FGF, KGF-1, and downregulation of IFN-c levels, causing tissue fibrosis.…”