Introduction: Glioblastoma Multiforme (GBM) is a devastating tumor with poor prognoses. Current treatment strategies marginally altered the natural history of the disease over the past 20 years. Novel approaches to understand GBM disease processes and therapeutic targets are needed. Extracellular vesicles (EVs) are membrane-enclosed nanospheres released locally and systemically by all cells. Tumor EVs are capable of manipulating their local environment and distal targets. This phenomenon could be a mechanism for tumorigenesis in the recurrent GBM setting. We hypothesize that GBM EVs are able to drive molecular changes in normal astrocytes, converting those cells into phenotypically tumorigenic entities.
Methods: Commercially available normal human astrocytes (NHAs) were incubated with different quantities of GBM and astrocytoma EVs (50 and 500 ug/ml). NHAs were examined following incubation for changes in intracellular signaling pathways, extracellular “secretome” release, cell migration, and transformation capacity using membrane-based antibody arrays, wound healing assays, and soft-agar assays, respectively. Untreated or “normal” EV-treated NHAs were used for controls.
Results: EV-treated NHAs displayed enhanced tumor-like signaling patterns that developed over 24-hours of incubation when compared to controls. Treated NHAs increased cytokine and chemokine production at 24-hours compared to controls, which promotes tumor cell proliferation. NHA treated with 500 ug/ml of GBM exosomes for 5 days demonstrated 20% more growth in soft ager compared to controls. Additionally, treated NHAs were noted to migrate in the presence of GBM EVs.
Conclusions: GBM EVs are capable of modifying their local environment by enhancing NHA cytokine production and promoting NHA migration. GBM EVs may drive molecular changes in NHAs by enhancing growth in a semi-solid matrix and altering intracellular signaling pathways in a pattern reminiscent of the tumor itself.
Patient Care: Our research focuses on the biology of glioblastoma multiforme (GBM), providing a novel avenue for improving our understanding of GBM. Current treatment modalities of GBM marginally altered the natural history of the disease. By improving our understanding of GBM tumorgenesis, we hope to expand and improve the current treatments available for GBM patients.
Learning Objectives: By the conclusion of this session, participants should be able to:
1) Understand the need for an alternative approach to glioblastoma therapy
2) Understand the potential role of exosomes in furthering our understanding of glioblastoma biology
3) Identify future application of exosomes in the field of GBM research and therapy