Downregulation of miR‐100‐5p in cancer‐associated fibroblast‐derived exosomes facilitates lymphangiogenesis in esophageal squamous cell carcinoma

BACKGROUND: Esophageal squamous cell carcinoma (ESCC), an aggressive gastrointestinal tumor, often has high early lymphatic metastatic potential. Cancer-associated fibroblasts (CAFs) are primary components in tumor microenvironment (TME), and the impact of CAFs and its derived exosomes on lymphangiogenesis remains elusive. MATERIALS AND METHODS: CAFs and the microlymphatic vessel density (MLVD) in ESCC was examined. Exosomes were extracted from primary normal fibroblast (NFs) and CAFs. Subsequently, tumor-associated lymphatic endothelial cells (TLECs) were treated with these exosomes, and the effect on their biological behavior was examined. miR-100-5p was selected as the target miRNA, and its effect on TLECs was examined. The target of miR-100-5p was predicted and confirmed. Subsequently, IGF1R, PI3K, AKT, and p-AKT expression in TLECs and tumors treated with exosomes and miR-100-5p were examined. RESULTS: A large number of CAFs and microlymphatic vessels were present in ESCC, leading to a poor prognosis. CAF-derived exosomes promoted proliferation, migration, invasion, and tube formation in TLECs. Further, they also enhanced lymphangiogenesis in ESCC xenografts. miR-100-5p levels were significantly lower in CAF-derived exosomes than in NF-derived exosomes. miR-100-5p inhibited proliferation, migration, invasion, and tube formation in TLECs. Further, miR-100-5p inhibited lymphangiogenesis in ESCC xenografts. Mechanistic studies revealed that this inhibition was mediated by the miR-100-5p-induced inhibition of IGF1R/PI3K/AKT axis. CONCLUSION: Taken together, our study demonstrates that CAF-derived exosomes with decreased miR-100-5p levels exhibit pro-lymphangiogenesis capacity, suggesting a possibility of targeting IGF1R/PI3K/AKT axis as a strategy to inhibit lymphatic metastasis in ESCC.