Date of Graduation
5-2014
Document Type
Dissertation (PhD)
Program Affiliation
Biomedical Sciences
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Frederick Lang, M.D.
Committee Member
Andrew Bean, PhD.
Committee Member
George Calin, M.D., PhD.
Committee Member
Juan Fueyo-Margareto, PhD.
Committee Member
E. Terry Walters, PhD.
Abstract
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, I hypothesized that GA-MSC-derived exosomes increase the growth and evolution of gliomas. Here I 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 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. I 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.
Keywords
Exosome, Glioma, Microenvironment, Glioma Stem Cell, Mesenchymal Stem Cell