Introduction: Evidence indicates that human cancers are maintained by a population of cells with stem-like properties called cancer stem cells (CSCs). However, 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, the most aggressive human brain tumors, contains both glioma stem cells (GSCs) and cells that resemble human bone marrow-derived mesenchymal stem cells (BM-MSCs), called Glioma Associated-MSCs (GA-MSCs). We have also shown that GA-MSCs generate a cytokine-mediated increase in the growth and self-renewal (clonogenicity) of GSCs. However, other paracrine interactions between GA-MSCs and GSCs have not been fully explored. Recent studies have suggested that nano-sized vesicles, termed exosomes, may contribute to intercellular communication within the tumor niche. Therefore, we hypothesized that GA-MSC-derived exosomes increase the tumorigenicity GSCs.
Methods: GA-MSC-derived exosomes were isolated by differential ultra-centrifugation of GA-MSC-derived conditioned medium. MicroRNA profiling of GA-MSC-derived exosomes was performed utilizing micro-array hybridization. Specified target miRNA were over-expressed in GSCs by lentiviral transduction. In vivo experiments were conducted by co-culture of GSCs with GA-MSC-derived exosomes, and subsequent implantation into the brains of nude mice.
Results: We show for the first time that exosomes can be isolated from patient-derived GA-MSCs and that these exosomes contain oncogenic microRNAs. Importantly, in vitro delivery of exosomes isolated from GA-MSCs significantly increased both the proliferation and clonogenicity of GSCs. Furthermore, GSC xenografts, treated with GA-MSC-derived exosomes, in the brains of nude mice resulted in a greater tumor burden and significantly decreased animal survival. Lastly, delivery of specific microRNA identified as both highly expressed and highly enriched in GA-MSC-derived exosomes, altered gene expression in recipient GSCs resulting in the glioma-enhancing effects described.
Conclusions: We conclude that GA-MSC-derived exosomes represent an alternative intercellular communication mechanism for the transfer of specific microRNAs which enhance the aggressive nature of gliomas.
Patient Care: Significant findings will establish a novel mechanism for communication within the tumor micro-environment, as well as a potential target for adjunct therapy. Given the complexity of cancer, the success of future curative therapies relies on a full understanding of tumor biology that includes evaluation of the intercellular exosomal communication system within the tumor microenvironment. Future therapies must account for the tumor-promoting properties present in the tumor niche in order to effectively improve outcomes in patients with gliomas.
Learning Objectives: By the conclusion of this session, participants should be able to:
1) Describe the importance of exosome communication in the glioma microenvironment.
2) Discuss other properties of stroma-derived exosomes in glioma progression.
3) Identify possible adjunct therapeutic strategies that target exosome-mediated tumor promotion.