Can Glioblastoma Extracellular Vesicles Drive Normal Astrocytes Toward a Tumor-Enhancing Phenotype?
Michael Graner,
Professor,
University of Colorado Anschutz School of Medicine
Glioblastomas (GBMs, WHO grade IV astrocytomas) are the worst of the central nervous system tumors; despite maximum (and damaging) therapeutic intervention, median survival time for patients is > 15 months, and overall quality of life becomes quite poor. These abysmal outcomes have changed little in the past 20 years. Clearly, our current therapies are inadequate, and we need innovative strides in understanding GBM biology to rectify this situation. One “hot” research area is that of the impact of tumor extracellular vesicles (EVs) on normal recipient cells. Tumor cell EVs have extraordinary abilities to manipulate their microenvironments and recipient cells both proximally and distally (eg, fibroblast differentiation, endothelial cell tubule formation, stromal cell interactions, immune cell influence). Tumor EVs prepare the “metastatic niche” for circulating tumor cells prior to colonization of a target organ. Thus, tumor EVs can impact recipient cells to support tumor growth and progression, which undoubtedly holds true for GBMs as well. However, it appears no one has asked what effects GBM EVs have on normal astrocytes—do GBM EVs drive astrocyte phenotypic changes, potentially making the astrocytes into tumor promotors? The answers could re-shape our paradigms on gliomagenesis, particularly in the recurrent setting. Here we show that GBM EVs activate cancer-type signaling pathways in recipient astrocytes, promoting astrocyte migration towards the EVs, as well as astrocyte anchorage-independent growth in soft agar. The extracellular release of various factors by astrocytes generates a tumor-promoting milieu, which results in increased tumor cell growth. We will discuss the consequences of these phenomena in the context of our current therapies with a view towards therapeutic improvement.
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