Multifaceted Mechanisms of Areca Nuts in Oral Carcinogenesis: the Molecular Pathology from Precancerous Condition to Malignant Transformation

Abstract

Oral cancer is one of the most frequent malignant diseases worldwide, and areca nut is a primary carcinogen causing this cancer in Southeast Asia. It has been widely reported that areca nut induced several cytotoxic effects in oral cells, including ROS generation, inflammation, tissue hypoxia, DNA damage, and cell invasion. Recently, through chronic exposure model, more extensive pathological effects due to areca nut have been found. These include the induction of autophagy, promotion of epithelial-mesenchymal transition, and facilitation of cancer stemness conversion. Clinical findings support these adverse effects. Oral submucosal fibrosis, a premalignant condition, is prevalent in the area with habitual chewing of areca nuts. Consistently, oral cancer patients with habitual chewing areca nut exhibit more aggressive phenotypes, including resistance to chemo-radiotherapy. In this review, we comprehensively discuss and concisely summarize the up-to-date molecular and cellular mechanisms by which areca nuts contribute to malignant transformation. This review may provide critical information regarding clinical applications in risk assessment, disease prevention, diagnosis, and personalized therapeutics for areca nut-induced oral malignancy.

Oral cancer: Clinicopathological features and associated risk factors in a high risk population presenting to a major tertiary care center in Pakistan

“…Results from this study imply the association of low SES with chewing habits and late stage presentation supported by different studies. Areca nut is the fourth most common psychoactive substance used in the world [45] and habitual areca nut chewers present with more aggressive cancer phenotypes, high rates of metastasized cancer, recurrence, and poor patient survival [46]. Though the association of areca nut chewing with late stage tumor remains largely unexplored, this is just an observation with no definite answers.…”

The Porphyromonas gingivalis inhibitory effects, antioxidant effects and the safety of a Sri Lankan traditional betel quid - an in vitro study

“…However, it contains a relatively low content of arecanut (12.5% of the mixture) when compared to the CBQ. Both epidemiological and animal studies have shown an association between arecanut and development of oral potentially malignant disorders (OPMDs) and the risk of oral cancer [ 68 , 71 , 72 ]. However, it has been demonstrated that such association depends on the frequency and the dose of arecanut consumption [ 71 , 73 ].…”

Loss of oral mucosal stem cell markers in oral submucous fibrosis and their reactivation in malignant transformation

“…49,50 Furthermore, areca nut-induced chemoradioresistance results from the upregulation of ATP-binding cassette subfamily G member-2 (ABCG-2), a drug-efflux pump and a stem cell marker. 22,49,50 Oral cancers among habitual areca nut chewers demonstrate an aggressive phenotype, chemoradioresistance and a much lower 5-year survival rate than those without areca habits. 18 Studies on oral premalignant lesions have shown that CSC markers, such as ABCG-2 and Bmi-1, predict the transformation of oral leukoplakia to cancer.…”

“…Other stemness markers, such as CD44, CD133, glucose-regulated protein 78 (Grp-78), Grp-96, Oct-4, Nanog and SOX2, are upregulated upon exposure to areca nut and correlate with worse prognosis in areca nut-induced cancers. 49 , 50 Furthermore, areca nut-induced chemoradioresistance results from the upregulation of ATP-binding cassette subfamily G member-2 (ABCG-2), a drug- efflux pump and a stem cell marker. 22 , 49 , 50 Oral cancers among habitual areca nut chewers demonstrate an aggressive phenotype, chemoradioresistance and a much lower 5-year survival rate than those without areca habits.…”