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The Culture of Glioblastoma-Derived Stem Cells and the Studies on the Mechanism of TRAIL Resistance

Author: DingLiJuan
Tutor: YuanChangJi;HaoChunMei
School: Jilin University
Course: Internal Medicine
Keywords: Apoptosis Cancer stem cells Cisplatin Glioblastoma TRAIL
CLC: R739.4
Type: PhD thesis
Year: 2011
Downloads: 85
Quote: 0
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Abstract


Glioma is the most common primary brain tumor, glioblastoma is the most common and most harmful type. Characteristics of glioblastoma has the incidence of relapse rate, high mortality and low cure rate \Tumor necrosis factor-related apoptosis-inducing ligand (tumor necrosis factor related apoptosis-inducing ligand, TRAIL) is a tumor necrosis factor superfamily, normally expressed in the immune system play a role of immune surveillance of tumor cells TRAIL apoptotic signaling pathways in vivo, a natural anti-tumor pathways, can induce apoptosis in tumor cells, in clinical trials, did not achieve the expected results of targeted therapy for TRAIL apoptotic pathway. Our research TRAIL in the process of the molecular basis of glioblastoma resistant glioblastoma-derived stem cells (GSCs) TRAIL-resistant. In this study, our fresh tumor tissue from two cases of glioblastoma patients surgical resection the train out neurosphere cell lines GSC091106 the GSC001112 well and they match serum cultured cell lines SC091106 and SC091112. A combination of in vivo experiments and in vitro experiments, using flow cytometry, Western blot, siRNA technology, research GSC cells and serum sensitivity of cultured cell lines to TRAIL-induced apoptosis GSC cells resistant to TRAIL-induced apoptosis drugs reasons, and combined with the chemotherapy drug cisplatin detection GSC cells to TRAIL-induced apoptosis changes. GSC cell molecular mechanism of resistance to TRAIL-induced apoptosis, and apoptosis mechanism of cisplatin combined with TRAIL induced glioblastoma stem cells to investigate the purpose to provide experimental evidence for the combination therapy of brain tumors. The neurospheres cell lines with characteristics of cancer stem cells, including the ability to self-renew, express stem cell surface markers CD133 and CD15, and transplanted tumor formation in nude mice brain. Serum cultured cell lines by cell drug test and caspase-8, caspase-3 and of caspase-7 activity detection proved to TRAIL-induced apoptosis in sensitive, the neurospheres cell lines but not these manifestations. Neurosphere cell lines by flow cytometry to cell surface death receptors DR4 and DR5 low expression, Western blot assay to cell type within the neurosphere cell lines Fas-associated death domain protein-like self-converting enzyme interleukin -1-13 inhibit the high expression of the protein (c-FLIP), the two are the root cause of glioblastoma stem cells resistance to TRAIL. Further experiments confirmed that cisplatin-rich glioblastoma tumor stem cell neurospheres can cause DR5 upregulation and c-FLIP down, thereby restoring TRAIL apoptosis pathway. Draw the the major following conclusions: (1) brain glioma stem cells resistance to TRAIL-induced apoptosis, the mechanism because of the decrease in the expression of cell surface DR5 intracellular c-FLIP protein expression. (2) The the Cisplatin role in the brain glioma stem cells can upregulate DR5, and down-regulates c-FLIP, thereby lifting the tumor stem cell resistance to TRAIL. (3) cisplatin combined with TRAIL in vitro can be more effective in the treatment of glioma. The main innovations: (1) the GBM primary cultured cells and glioblastoma stem cells to TRAIL-induced apoptosis sensitivity compared glioblastoma stem cells resistant to TRAIL-induced apoptosis. (2) Research TRAIL resistance in glioblastoma stem cells the mechanism proved DR5, c-FLIP and TRAIL-induced apoptosis sensitivity is directly related. (3) cisplatin in glioblastoma stem cells to TRAIL-induced apoptosis, and can upregulate DR5, lowered c-FLIP.

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