Abstract
BACKGROUND: Cancer-associated fibroblasts (CAFs), essential components of the tumor microenvironment (TME), contribute to tumor formation. Our previous research demonstrated that exosomes containing matrix metalloproteinase 13 (MMP13) accelerate metastasis in nasopharyngeal carcinoma (NPC). This study aimed to determine whether exosomes containing MMP13 promote NPC development by stimulating the differentiation of normal fibroblasts (NFs) into CAFs. METHODS: The presence of CAFs in NPC was identified through immunohistochemistry (IHC) analysis. NPC cells activated NFs into CAFs, according to the co-culture cell model. Exosomes were characterized by Western blot and electron microscopy analysis. NFs were treated with exosomes, and Western blot, migration, and 5-ethynyl-2'-deoxyuridine (EdU) assays were conducted to assess CAFs activation. Western blot analysis was used to assess whether exosomes derived from CAFs activated the Notch signaling pathway in human low-differentiated nasopharyngeal carcinoma cell line (CNE2). The effect of MMP13 on exosomes generated from CAFs in vivo was verified using a nude mouse model, and the effect of MMP13 on the immune microenvironment of CAFs in vivo was verified using the C57BL/6 mouse model. RESULTS: We found that NPC cells, after converting NFs to CAFs, exhibited enhanced proliferative and migratory capacities. NPC cells secreted MMP13 containing exosomes, which facilitated the conversion. The secretion of exosomes by activated CAFs has been demonstrated to promote tumor progression by activating the Notch signaling system, promoting angiogenesis, and suppressing T cell immunity. The inhibition of exosome MMP13 has the potential to impede the migration and proliferation of recipient cells. Inhibition of exosomal MMP13 may suppress recipient cell migration and proliferation. CONCLUSIONS: Our research identified a critical mechanism in which MMP13-rich exosomes from NPC cells may influence the development of CAFs in the TME, while the exosomes produced by CAFs further support the malignant development of NPC.