Metabolic Reprogramming and GM-CSF Secretion in Areca Nut-Activated Fibroblasts Drive Oral Precancer Progression.

Area of Science:

• Oral pathology
• Cancer research
• Fibroblast biology

Background:

• Oral cancer incidence is rising globally, particularly in South/Southeast Asia, linked to areca nut use.
• Areca nut extract (ANE) is a suspected carcinogen, but its mechanism on oral tissue requires elucidation.
• Fibroblast behavior modulation is a potential factor in oral carcinogenesis.

Purpose of the Study:

• To investigate the effects of areca nut extract (ANE) on oral carcinogenesis.
• To determine how ANE modulates fibroblast behavior in oral tissue.
• To explore the role of fibroblast activation in oral precancerous lesion progression.

Main Methods:

• Assessed fibroblast viability, migration, and invasion using cell-based assays.
• Utilized cytokine arrays, ELISA, phospho-kinase arrays, and Western blotting to analyze cell functions.
• Employed immunohistochemistry and immunofluorescence in human and hamster oral tissues for validation.

Main Results:

• ANE increased fibroblast mitochondrial metabolism and induced myofibroblast transition, evidenced by increased alpha smooth muscle actin (α-SMA) and fibroblast activation protein (FAP).
• ANE enhanced epithelial-to-mesenchymal transition and granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion in fibroblasts.
• ANE-treated fibroblasts and GM-CSF promoted epidermal growth factor receptor (EGFR) phosphorylation and malignant transformation in dysplastic oral keratinocytes.

Conclusions:

• Areca nut extract (ANE) drives oral carcinogenesis by promoting fibroblast activation and epithelial-to-mesenchymal transition.
• ANE-induced GM-CSF secretion from fibroblasts activates EGFR signaling in adjacent epithelial cells.
• This fibroblast-epithelial cell crosstalk mediated by ANE contributes to the malignant transformation of oral precancerous cells.