Extracellular vesicle-transported Semaphorin3A promotes vascular permeability in glioblastoma

Abstract

Glioblastoma are malignant highly vascularized brain tumours, which feature large oedema resulting from tumour-promoted vascular leakage. The pro-permeability factor Semaphorin3A (Sema3A) produced within glioblastoma has been linked to the loss of endothelial barrier integrity. Here, we report that extracellular vesicles (EVs) released by patient-derived glioblastoma cells disrupt the endothelial barrier. EVs expressed Sema3A at their surface, which accounted for in vitro elevation of brain endothelial permeability and in vivo vascular permeability, in both skin and brain vasculature. Blocking Sema3A or its receptor Neuropilin1 (NRP1) hampered EV-mediated permeability. In vivo models using ectopically and orthotopically xenografted mice revealed that Sema3A-containing EVs were efficiently detected in the blood stream. In keeping with this idea, sera from glioblastoma multiforme (GBM) patients also contain high levels of Sema3A carried in the EV fraction that enhanced vascular permeability, in a Sema3A/NRP1-dependent manner. Our results suggest that EV-delivered Sema3A orchestrates loss of barrier integrity in glioblastoma and may be of interest for prognostic purposes.

Newt cells secrete extracellular vesicles with therapeutic bioactivity in mammalian cardiomyocytes

“…Additionally, we used highly-sensitive, single particle flow nanocytometry to quantify the relative proportions of A1-EVs expressing a particular protein surface marker within the entire EV population [29,47]. Sizable fractions of A1-EVs expressed TSP1 (79%), POSTN (60%), FN (52%) and low levels of CD81 (22%) (right panels, Figure 6(a,b)); positive particles highlighted in green).…”

Spitting out the demons: Extracellular vesicles in glioblastoma

“…25,35 Likewise, EVs collected from GBM cell lines can tRNA to normal brain endothelial cells. 10 Moreover, our team has demonstrated that GSC-liberated EVs convey the pro-permeability guidance molecule semaphorin 3A toward neighboring brain endothelial cells and ultimately contribute to enhance vascular permeability in orthotopic GBM xenograft models, 21 reinforcing the concept that tumor-derived EVs can pervert the vasculature. In line with the hypothesis that EVs play a role in the sabotage of their environment, GBM-produced EVs can be taken up by innate immune cells, microglia and monocytes/macrophages within the brain, and shift their cytokine expression profile and mRNA content toward a pro-tumoral phenotype (Fig.…”

“…10,21 Indeed, mRNA materials identified in GBM-derived EVs could be transferred to surrounding recipient cells. 10,14,15 Moreover, specific mRNA mutations (i.e.…”

“…EVs emanating from the tumor mass have been detected outside the tumor microenvironment, in particular circulating freely in the plasma. 21,26,27 While this feature could be employed as a diagnostic tool (please see our next section), the functional and biological consequences remain unclear in GBM (Fig. 1).…”

“…Mass spectrometry analysis of GBM-derived EVs identified more than 100 proteins that are also usually found in exosomes, based on the ExoCarta database. 15,20 Interestingly, cytokines are enriched in GBM-produced EVs, such as pro-angiogenic agents, among which VEGF-A, 10 the pro-permeability guidance molecule Semaphorin 3A, 21 and the immunosuppressive cytokine TGF-b. 22 Additionally, one of the best-characterized GBM-based EV-harbored proteins is the tumor-specific EGF mutated receptor EGFRvIII.…”