Tumor-associated macrophage-derived exosomes transmitting miR-193a-5p promote the progression of renal cell carcinoma via TIMP2-dependent vasculogenic mimicry

Previous studies have investigated whether tumor-associated macrophages (TAMs) play tumorigenic and immunosuppressive roles to encourage cancer development, but the role of TAMs in regulating vasculogenic mimicry (VM) in clear-cell renal cell carcinoma (ccRCC) cells has not been completely clarified. We conducted immunostaining of the tumor-associated macrophage biomarkers CD68/CD163 and double staining for PAS/CD31 in ccRCC human specimens to find that higher TAM infiltration was positively correlated with VM formation. Then we demonstrated that TAM-derived exosomes downregulate TIMP2 expression in RCC cells to promote VM and invasion by shuttling miR-193a-5p. Mechanistic analysis indicated that HIF-1α upregulation in macrophages could transcriptionally increase miR-193a-5p expression. Exosome-shuttled miR-193a-5p then targeted the 3′ untranslated region (UTR) of TIMP2 mRNA to suppress its translation. A preclinical study using an in vivo orthotopic xenograft model of ccRCC in mice substantiated that TAM-derived exosomes enhance VM and enable tumor progression, which confirmed our in vitro data. Suppressing TAM-derived exosomal miR-193a-5p successfully inhibited tumor progression and metastasis. Overall, miR-193a-5p from TAM-derived exosomes downregulates the TIMP2 gene to facilitate the development of RCC, which provides a novel perspective for developing therapeutic strategies for RCC.