Abstract Date: 4/7/2014
Javier Figueroa (Richmond, TX)
Tal Shahar, MD
Anwar Hossain, PhD
Lang Frederick, MD (Houston, TX)
Although recent evidence indicates that human cancers are maintained by a population of cells with stem-like properties called cancer stem cells (CSCs), the influence of the surrounding stromal cells on the behavior of the CSCs remains poorly understood. We have recently shown that the micro-environment of human gliomas contains both glioma stem cells (GSCs) and cells that resemble human bone marrow mesenchymal stem cells (BM-hMSCs), called Glioma Associated-MSCs (GA-MSCs). We have also shown that these GA-MSCs enhance the growth of Glioma Stem Cells (GSCs). However, the mechanism underlying the communication between GA-MSCs and GSCs has not been established. Recent studies have suggested that nano-vesicles, called exosomes, may contribute to cellular communication within the tumor niche. Therefore, we hypothesized that exosomes released by GA-MSCs may promote the growth of GSCs.
GA-MSC exosomes were harvested by ultracentrifugation and sucrose cushion, and analyzed by both CD63 western blot and immuno-gold electron microscopy. Both GA-MSCs and GSCs were isolated from patient tumor samples.
Here we show for the first time that in vitro delivery of exosomes isolated from GA-MSCs significantly increased both the viability and clonogenicity of GSCs. Furthermore, in vivo xenograft implantation of GSCs, pre-treated with GA-MSC exosomes, into the brains of nude mice resulted in a greater tumor burden and a significant decrease in animal survival compared with untreated controls. These exosomes were also found to contain a wide variety of miRNA, including many which are associated with glioma. Treatment of GSCs with GA-MSC exosomes, was enough to alter the miRNA profile of GSCs, increasing the amount of these oncogenic miRNAs intracellularly.
We conclude that exosomes released by GA-MSCs represent a novel and alternative intra-tumoral communication mechanism for the exchange of miRNA, which significantly impacts the tumor microenvironment and enhances the aggressive nature of gliomas.
Article ID: AA-28840