The Multistep Carcinogenic Journey from Oral Mucosa to Fibrosis to Carcinoma: Integrating Genomic Evolution, Microenvironment Remodeling, and Stem Cell Dynamics

Abstract

Oral submucous fibrosis (OSF) is a chronic, progressive, and potentially malignant disorder of the oral mucosa strongly associated with areca nut chewing. Despite decades of research, OSF remains a major public health challenge in South and Southeast Asia, where its prevalence continues to rise. Malignant transformation to oral squamous cell carcinoma (OSCC) is the most serious consequence, with reported rates ranging from 3% to 19%. This review synthesizes current evidence on the cellular, molecular, and epidemiological factors that drive this transition. Chronic exposure to arecoline and other alkaloids induces oxidative stress, activates the TGF-β/SMAD signaling pathway, and promotes excessive collagen deposition, creating a hypoxic and fibrotic microenvironment. Over time, persistent epithelial atrophy and inflammation foster genetic and epigenetic alterations including TP53 mutation, loss of p16, and dysregulation of microRNAs that destabilize cell-cycle control and DNA repair. Histopathologically, this is reflected by progressive epithelial dysplasia and eventual invasion of malignant keratinocytes. Epidemiological studies consistently highlight duration and frequency of areca nut use, concurrent tobacco exposure, and high-grade fibrosis as key predictors of transformation. Understanding these pathways is critical for developing reliable biomarkers, refining risk stratification, and guiding early detection strategies. A clearer grasp of the molecular crosstalk between fibrogenesis and carcinogenesis will inform targeted prevention and therapeutic interventions aimed at interrupting the OSF–OSCC continuum.

Keywords: Oral submucous fibrosis, Oral squamous cell carcinoma, Malignant transformation, Areca nut, Arecoline, TGF-β signaling, Hypoxia, Fibrosis, Epithelial dysplasia, Molecular pathogenesis, Biomarkers, Carcinogenesis