Figure 7. Proposed model for TNFα-mediated OSCC invasion.

Schematic diagram of TNFα signaling in OSCC invasion. TNFα released by neutrophils during oral inflammation signals via TNFR1 to induce gene expressional changes, invadopodia formation, and inflammatory cytokine and chemokine release. TNFR1 mediated PI3K and Src activation, heightened by EGFR signaling, leads to invadopodia formation, MMP9 secretion, ECM degradation, and invasion. Additionally, TNFR1 signaling leads to down-regulation of cell cycle-related genes. TNFR1 induced up-regulation of genes associated with inflammation and chemotaxis leads to cytokine and chemokine release by OSCC cells and acts through paracrine signaling and activation of nearby neutrophils. Active neutrophils promote increased inflammatory signaling and TNFα release, completing a positive feedback loop with OSCC cells.