A tale of two tumors: differential, but detrimental, effects of glioblastoma extracellular vesicles (EVs) on normal human brain cells

Abstract

Glioblastomas (GBMs) are dreadful brain tumors with abysmal survival outcomes. GBM EVs dramatically affect normal brain cells (largely astrocytes) constituting the tumor microenvironment (TME). EVs from different patient-derived GBM spheroids induced differential transcriptomic, secretomic, and proteomic effects on cultured astrocytes/brain tissue slices as GBM EV recipients. The net outcome of brain cell differential changes nonetheless converges on increased tumorigenicity. GBM spheroids and brain slices were derived from neurosurgical patient tissues following informed consent. Astrocytes were commercially obtained. EVs were isolated from conditioned culture media by ultrafiltration, ultraconcentration, and ultracentrifugation. EVs were characterized by nanoparticle tracking analysis, electron microscopy, biochemical markers, and proteomics. Astrocytes/brain tissues were treated with GBM EVs before downstream analyses. EVs from different GBMs induced brain cells to alter secretomes with pro-inflammatory or TME-modifying (proteolytic) effects. Astrocyte responses ranged from anti-viral gene/protein expression and cytokine release to altered extracellular signal-regulated protein kinase (ERK1/2) signaling pathways, and conditioned media from EV-treated cells increased GBM cell proliferation. Thus, astrocytes/brain slices treated with different GBM EVs underwent non-identical changes in various omics readouts and other assays, indicating personalized tumor-specific GBM EV effects on the TME. This raises concern regarding reliance on model systems as a sole basis for translational direction. Nonetheless, net downstream impacts from differential cellular and TME effects still led to increased tumorigenic capacities for the different GBMs.

Pushing Forward the DNA Walkers in Connection with Tumor-Derived Extracellular Vesicles

“…EVs from different GBM induce brain cells to alter secretomes with proinflammatory or tumor microenvironment-modifying effects. 28 It is also important to note that cancer cells have the ability to release EVs into the tumor microenvironment, which impacts many cells such as cancer-associated fibroblasts (CAF), cancer stem cells and other stromal cells. This interaction influences inter-and intracellular signaling, promoting cancer cell survival, proliferation, invasion, metabolic reorganization and tumor angiogenesis.…”

“…EVs from different GBM induce brain cells to alter secretomes with pro-inflammatory or tumor microenvironment-modifying effects. 28 …”