FLT1-enriched extracellular vesicles induce a positive feedback loop between nasopharyngeal carcinoma cells and endothelial cells to promote angiogenesis and tumour metastasis.

Distant metastasis is one of the main reasons for treatment failure in nasopharyngeal carcinoma (NPC) patients. Tumour angiogenesis is a key basis for the distant metastasis of NPC. However, the molecular mechanisms underlying the mutual interaction between endothelial and NPC cells in tumour angiogenesis and NPC metastasis are still unclear. Here, we found that extracellular vesicles (EVs) mediate intercellular communication between endothelial cells and NPC cells, thereby promoting NPC cell migration, invasion, colony formation, and angiogenesis. Further experiments indicated that EV-mediated information exchange between endothelial cells and NPC cells upregulated the expression of the vascular endothelial growth factor receptor FLT1 in both types of cells. Mechanistically, FLT1-enriched EVs promoted NPC metastasis through the PI3K/AKT pathway and increased tumour angiogenesis, tumour growth, and distant lung and liver metastasis of NPC in xenografted mice. This effect was achieved through the delivery and upregulation of FLT1 in both endothelial and NPC cells. Thus, our findings reveal that FLT1-enriched EVs induce a positive feedback loop between NPC cells and endothelial cells to promote tumour angiogenesis and tumour metastasis. These results increase our understanding of the intricate interplay between tumour angiogenesis and distant metastasis and have major implications for the diagnosis and management of NPC patients with increased levels of FLT1-enriched EVs.