COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

Abstract

The expansion of myeloid-derived suppressor cells (MDSCs) is a common feature of cancer, but its biological roles and molecular mechanism remain unclear. Here, we investigated a molecular link between MDSC expansion and tumor cell metastasis in nasopharyngeal carcinoma (NPC). We demonstrated that MDSCs expanded and were positively correlated with the elevated tumor <i>COX-2</i> expression and serum IL-6 levels in NPC patients. Importantly, <i>COX-2</i> and MDSCs were poor predictors of patient disease-free survival (DFS). Knocking down tumor <i>COX-2</i> expression hampered functional TW03-mediated-MDSC cell (T-MDSC) induction with IL-6 blocking. We identified that T-MDSCs promoted NPC cell migration and invasion by triggering the epithelial-mesenchymal transition (EMT) on cell-to-cell contact, and T-MDSCs enhanced tumor experimental lung metastasis <i>in vivo</i>. Interestingly, the contact between T-MDSCs and NPC cells enhanced tumor <i>COX-2</i> expression, which subsequently activated the <i>β-catenin</i>/<i>TCF4</i> pathway, resulting in EMT of the cancer cells. Blocking transforming growth factor β (TGFβ) or inducible nitric oxide synthase (iNOS) significantly abolished the T-MDSC-induced upregulation of <i>COX-2</i> and EMT scores in NPC cells, whereas the administration of TGFβ or L-arginine supplements upregulated <i>COX-2</i> expression and EMT scores in NPC cells. These findings reveal that <i>COX-2</i> is a key factor mediating the interaction between MDSCs and tumor cells, suggesting that the inhibition of <i>COX-2</i> or MDSCs has the potential to suppress NPC metastasis.