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"Effects of Platelet Derived Growth Factor on Neural Progenitor Proliferation, Differentiation and Transformation"

by
Lisamarie Moore
Interdisciplinary Biomedical Sciences Program
M.S. 2008, New Jersey Institute of Technology, Newark, NJ
B.S. 2001, Old Dominion University, Norfolk, VA


Thesis Advisor: Steven W. Levison, Ph.D.
Professor
Department of Neurology and Neurosciences

Friday, February 27, 2015
1:00 P.M., Cancer Center, G Level Conference Room ,1196


Abstract

Platelet derived growth factor receptor alpha (PDGFRŠ) is over-expressed by the Proneural subclass of GBMs and it has been shown to drive tumor growth. Proneural GBMs frequently have mutations in p53 and PTEN. As oligodendrocyte progenitors (OPCs) are PDGF responsive precursors, we tested the hypothesis that OPCs lacking both p53 and PTEN would form Proneural type brain tumors. We infected cultured mouse OPCs isolated from double floxed p53/PTEN/stop floxed YFP mice with a PDGFbb-IRES-Cre retrovirus and then transplanted transformed OPCs into the subcortical white matter of young adult syngeneic mice. Approximately thirty days later, massive YFP+ tumors formed in the ipsilateral hemisphere. Histologically the tumors possessed the classical hallmarks of GBM and the YFP+ cells within the tumor expressed markers of the oligodendrocytic lineage such as NG2, PDGFRŠ and Olig2 as well as the proliferation marker, Ki67. Some of the cells within the tumor also expressed the stem/progenitor cell marker Sox2, but none of the YFP+ tumor cells expressed the astrocytic marker GFAP. Using a 7-antigen flow cytometry panel we characterized the transformed OPCs prior to and after transplantation. The cells prior to transplantation were largely NG2+PDGFRŠ+A2B5+O4+Glast+CD133-LeX+ as were the vast majority of the YFP+ cells within the end stage tumor. Cells with the phenotype of the NSC, i.e. CD133+/LeX+/NG2-/CD140a- were not detected in the cultured OPCs either prior to or immediately after retroviral transfection. However, a small percentage of cells expressing neural stem cell markers, CD133 and LeX, were detected within the tumor. Whereas the transformed OPCs rapidly formed tumors, a mixture of astrocytes and fibroblasts that were isolated from the same genetically engineered mouse and infected with PDGFbb-IRES-Cre failed to form tumors upon transplantation. Altogether, these data strongly support the hypothesis that OPCs are the cell of origin for Proneural GBMs. Importantly, they show that after transformation, a small subset of cells within the tumor express markers associated with stem cells. Our studies also show that the astrocytes within Proneural GBMs are not derived from the cell of origin.


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