Semaphorin-7A on Exosomes: A Promigratory Signal in the Glioma Microenvironment

Abstract

Exosomes are one of the most important mediators of the cross talk occurring between glioma stem cells (GSCs) and the surrounding microenvironment. We have previously shown that exosomes released by patient-derived glioma-associated stem cells (GASC) are able to increase, in vitro, the aggressiveness of both GSC and glioblastoma cell lines. To understand which molecules are responsible for this tumour-supporting function, we performed a descriptive proteomic analysis of GASC-exosomes and identified, among the others, Semaphorin7A (SEMA7A). SEMA7A was described as a promigratory cue in physiological and pathological conditions, and we hypothesised that it could modulate GSC migratory properties. Here, we described that SEMA7A is exposed on GASC-exosomes’ surface and signals to GSC through Integrin β1. This interaction activates focal adhesion kinase into GSC and increases their motility, in our patient-based in vitro model. Our findings suggest SEMA7A-β1-integrin as a new target to disrupt the communication between GSCs and the supporting microenvironment.

Heterogeneity Matters: Different Regions of Glioblastoma Are Characterized by Distinctive Tumor-Supporting Pathways

“…Regarding the mechanisms responsible for these changes we have previously shown that GASC are able to increase proliferation, motility and anchorage independent growth of both commercially available glioblastoma cell lines and GSC isolated from the same tumors through the release of exosomes [ 30 ]. We identified a protein, carried on the surface of GASC-exosomes (SEMAPHORIN-7A), that signals to GSC through integrin-β1, activating focal adhesion kinase and increasing GSC motility, in vitro [ 86 ]. On the other side, we also observed that exosomes released in the glioma microenvironment by GSC regulate the immunomodulatory properties of peripheral immune cell populations and promote the tumor immune escape [ 87 ].…”

mTOR Modulates Intercellular Signals for Enlargement and Infiltration in Glioblastoma Multiforme

“…GSC-derived exosomes support GBM infiltration by inducing a pro-migratory activation of GBM cells [42]. For instance, exosome-dependent release of Sema7A enhances GSC motility via activation of β1-integrin/FAK signaling [152]. Again, GBM-secreted Sema3A act as an autocrine migration-promoting stimulus on GSCs [153][154][155] through the binding to NRP1/PlxA1.…”

Human Adipose-Derived Stem Cells in Madelung’s Disease: Morphological and Functional Characterization

“…We have previously shown that MASC isolated from diseased tissues, either neoplastic [18,19] or nonneoplastic [20,21], are able to modify the phenotype of target cells through their secretome. Therefore, we wondered if MD-ASC cells were able to change the phenotype of normal cells through their secretome.…”

“…We thought that developing an in vitro model of the disease could help in getting further insights into the biological and molecular pathophysiology of MD, possibly contributing to novel strategies for disease diagnosis and therapy. In this regard, our group demonstrated in several neoplastic and nonneoplastic diseases the usefulness of isolating stem cells from diseased tissues to obtain an in vitro model recapitulating the pathological condition of the tissue of origin [17][18][19][20][21][22]. Specifically, we demonstrated that it was possible to isolate from human adipose tissue a population of adipose-derived stem cells (ASC) that not only could be a valuable source for regenerative medicine [23][24][25] but also, when isolated from patients affected by human Nieman Pick C disease, could represent an in vitro model resembling the features of diseased cells [17].…”