Molecular Mechanisms of Malignant Transformation of Oral Submucous Fibrosis by Different Betel Quid Constituents-Does Fibroblast Senescence Play a Role?

Abstract

Betel quid (BQ) is a package of mixed constituents that is chewed by more than 600 million people worldwide, particularly in Asia. The formulation of BQ depends on a variety of factors but typically includes areca nut, betel leaf, and slaked lime and may or may not contain tobacco. BQ chewing is strongly associated with the development of potentially malignant and malignant diseases of the mouth such as oral submucous fibrosis (OSMF) and oral squamous cell carcinoma (OSCC), respectively. We have shown recently that the constituents of BQ vary geographically and that the capacity to induce disease reflects the distinct chemical composition of the BQ. In this review, we examined the diverse chemical constituents of BQ and their putative role in oral carcinogenesis. Four major areca alkaloids-arecoline, arecaidine, guvacoline and guvacine-together with the polyphenols, were identified as being potentially involved in oral carcinogenesis. Further, we propose that fibroblast senescence, which is induced by certain BQ components, may be a key driver of tumour progression in OSMF and OSCC. Our study emphasizes that the characterization of the detrimental or protective effects of specific BQ ingredients may facilitate the development of targeted BQ formulations to prevent and/or treat potentially malignant oral disorders and oral cancer in BQ users.

Keywords: areca nut; arecoline; betel quid; carcinogenic potential; fibroblast senescence; oral carcinogenesis; oral submucous fibrosis.

Figure 1

Proposed pathogenic model for oral submucous fibrosis. Briefly, BQ constituents induce direct damage to both keratinocytes and fibroblasts resulting in DNA damage and production of reactive oxygen species (1). There is cross-talk between epithelial and mesenchymal compartments that amplifies the pathogenic loop and leads to fibrosis and hypoxia (2). Senescent fibroblasts promote the development of a microenvironment permissive for cancer progression (3).