Glioma-derived extracellular vesicles promote tumor progression by conveying WT1

Abstract Glioma persists as one of the most aggressive primary tumors of the central nervous system. Glioma cells are known to communicate with tumor-associated macrophages/microglia via various cytokines to establish the tumor microenvironment. However, how extracellular vesicles (EVs), emerging regulators of cell–cell communication networks, function in this process is still elusive. We report here that glioma-derived EVs promote tumor progression by affecting microglial gene expression in an intracranial implantation glioma model mouse. The gene expression of thrombospondin-1 (Thbs1), a negative regulator of angiogenesis, was commonly downregulated in microglia after the addition of EVs isolated from different glioma cell lines, which endogenously expressed Wilms tumor-1 (WT1). Conversely, WT1-deficiency in the glioma-derived EVs significantly attenuated the Thbs1 downregulation and suppressed the tumor progression. WT1 was highly expressed in EVs obtained from the cerebrospinal fluid of human patients with malignant glioma. Our findings establish a novel model of tumor progression via EV-mediated WT1–Thbs1 intercellular regulatory pathway, which may be a future diagnostic or therapeutic target. We found that Wilms tumor-1 in glioma-derived extracellular vesicles serves as a potent promoter of tumor progression by inhibiting thrombospondin-1 gene expression in microglia, providing a new concept that it serves as an intercellular messenger that regulates tumor microenvironment.