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

Ivana Manini,Anna Bartolini,Guidalberto Manfioletti,Tamara Ius,Riccardo Sgarra,Antonio Paolo Beltrami,Daniela Cesselli,Carla Di Loreto,Federica Caponnetto,Maria Elisabetta Ruaro,Miran Skrap

doi:10.3390/cancers11060758

Ivana Manini, Anna Bartolini + Show 9 more

Open Access

https://doi.org/10.3390/cancers11060758

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Journal: Cancers	Publication Date: May 30, 2019
Citations: 22	License type: CC BY 4.0

Affiliation: University of Udine, University of Trieste

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.

Highlights

Despite a state-of-the art treatment, the median overall survival of glioblastoma multiforme (GBM)’s patients is 14 months [1]
Our results strongly suggest that SEMA-7A-Fc ng/mL (SEMA7A) exposed on glioma-associated stem cells (GASC)-released exosomes, upon binding to β1-integrin on the surface of glioma stem cells (GSCs), accelerates their migration, which is correlated with tumour aggressiveness
In our previously established in vitro model of GBM microenvironment, we found that exosomes, released by GASC, have a tumour-supporting role towards GSC [19]

Summary

Introduction

Despite a state-of-the art treatment, the median overall survival of glioblastoma multiforme (GBM)’s patients is 14 months [1]. The lack of therapeutic efficacy is due to the great intertumour and intratumour cellular and molecular heterogeneity, biological aggressiveness, the ability to develop drug resistance, as well as the infiltrative nature of tumour cells into the surrounding brain parenchyma [2]. Infiltration makes impossible a radical surgery favouring recurrences within 1 to 2 cm from the original tumour mass, appearing few months after the first diagnosis and treatment or being already present at the time of the initial presentation [3]. Single infiltrating cells are often spread throughout the entire brain parenchyma, escaping from surgery and treatment [4]. Cancers 2019, 11, 758 invasion, stimulation of angiogenesis, ability to suppress immune responses and to develop resistance to therapy [8,9]. As normal neural stem cells, GSCs reside in specialised niches, where they receive maintenance stimuli and protection by interacting with the components of the surrounding milieu [5]

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