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Identification of Potential Molecular Targets in Tumor-Associated Endothelial Cell in Glioblastoma Multiforme

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Glioblastoma multiforme (GBM) is an aggressive, primary brain tumor characterized by extensive vascularization and a high degree of invasion. The median survival time of the patient is only 12-15 months with the high recurring rate despite the earlier diagnosis and conventional therapy. In this thesis, we mainly considered the endothelial cell as the key role in tumor microenvironment with the clinical significance by applying the cell model from isolated human specimen. Brain endothelial cells originally play as the critical role to tightly attach as the inner layer of blood vessel and closely connect with the nearby cells. During the tumor development, the difference of cell morphology and genetics variances were observed between healthy brain endothelial cells (BEC) and tumor-associated endothelial cells (TuBEC). Isolated TuBEC presented relatively larger, veil-like, irregular cell shape compared to the BEC which had smaller and rod shape with tight junctions. We then hypothesized that the cellular process endothelial-to-mesenchymal transition (EndMT) occurs in the brain endothelial barrier in GBM with the properties to support the angiogenesis and invasion. Our in silico gene enrichment results from microarray indicated that EndMT was one of the top significant variances with the significant enrichment score. Several candidate targets/ pathways were summarized and investigated to trigger the EndMT from gene expression data. The main blockades of Nicotinamide (NAM) metabolism-- salvage pathway and clearance pathway, were linked with EndMT in GBM. By using the inhibitor FK228 to block the clearance pathway, we further successfully confirmed that one of NAM blockade impaired the EndMT. Other two novel candidates, inducing the periostin (POSTN) and metallotheionin (MT), were investigated in our model with EndMT. To sum, the significance of this thesis is to clarify the potential molecular mechanism of the specialized BEC transition in GBM and further identify an approach for terminating the mechanism in primary brain tumors.

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