Glioblastoma multiforme-derived extracellular vesicles drive normal astrocytes towards a tumour-enhancing phenotype

Abstract

Glioblastoma multiforme (GBM) is a devastating tumour with abysmal prognoses. We desperately need novel approaches to understand GBM biology and therapeutic vulnerabilities. Extracellular vesicles (EVs) are membrane-enclosed nanospheres released locally and systemically by all cells, including tumours, with tremendous potential for intercellular communication. Tumour EVs manipulate their local environments as well as distal targets; EVs may be a mechanism for tumourigenesis in the recurrent GBM setting. We hypothesized that GBM EVs drive molecular changes in normal human astrocytes (NHAs), yielding phenotypically tumour-promoting, or even tumourigenic, entities. We incubated NHAs with GBM EVs and examined the astrocytes for changes in cell migration, cytokine release and tumour cell growth promotion via the conditioned media. We measured alterations in intracellular signalling and transformation capacity (astrocyte growth in soft agar). GBM EV-treated NHAs displayed increased migratory capacity, along with enhanced cytokine production which promoted tumour cell growth. GBM EV-treated NHAs developed tumour-like signalling patterns and exhibited colony formation in soft agar, reminiscent of tumour cells themselves. GBM EVs modify the local environment to benefit the tumour itself, co-opting neighbouring astrocytes to promote tumour growth, and perhaps even driving astrocytes to a tumourigenic phenotype. Such biological activities could have profound impacts in the recurrent GBM setting.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'.

Astrocytes, the rising stars of the glioblastoma microenvironment

“…Regarding astrocytes, despite being the most abundant glial cells in the CNS and therefore highly abundant within the GBM microenvironment, their impact on the tumor development is yet to be fully understood (Jakel & Dimou, ; O'Brien et al, ). Nevertheless, a few recent reports have acknowledged that question so that the interest about the role of astrocytes on the GBM microenvironment is constantly increasing (Oushy et al, ; Quail & Joyce, ).…”

“…In the same picture, ion channels and ion transporters, expressed at the membrane of both astrocytes and GBM cells might then form a bridge between the two cellular types, thus enhancing tumor progression and therapeutic resistance, as suggested by a recent review (Guan, Hasan, Maniar, Jia, & Sun, ). Also, the GBM‐derived extracellular vesicles (EVs) might significantly alter the intracellular signaling and cytokine profile of normal human astrocytes to push them towards a tumor supporting behavior (Oushy et al, ). EVs are membrane‐enclosed nanospheres secreted by all cell types (Kim & Kim, ) that are essential players in intercellular communication as they carry proteins, lipids, and nucleic acids between cells (Yanez‐Mo et al, ).…”

“…It appears that the exposure of normal astrocytes to GBM EVs generates a growth‐stimulant medium loaded with growth factors (VEGF, fibroblast growth factor (FGF), human growth factor (HGF), and EGF), chemokines, and interleukins. Consequently, proliferation of GBM cells has been detected as enhanced when exposed to conditioned medium derived from astrocytes under the influence of tumor EVs (Oushy et al, ).…”

“…GBM cell‐derived EVs have also been found to modulate surrounding astrocytes signaling, thereby promoting evasion of apoptosis in GBM cells (Oushy et al, ). Indeed, Oushy et al showed that the phosphorylation of BAD—a pro‐apoptotic member of the Bcl‐2 family that becomes inactive when phosphorylated—is observed in astrocytes grown in the presence of GBM cells‐derived EVs.…”

“…Similarly, other key oncogenic mediators such as ERK, AKT, and STATs (Steelman et al, ; Steelman et al, ) are also found increasingly phosphorylated in GBM EV‐stimulated astrocytes. Overall, these studies suggest that a tight GBM/astrocytes cross‐talk in the tumor microenvironment is important to limit tumor cells apoptosis, thus promoting aggressiveness (Oushy et al, ). Having an in‐depth understanding of the related underlying mechanisms may be important for the development of new innovative GBM treatments.…”