Glioblastoma multiforme (GBM) is an aggressive and rapidly fatal brain tumor. Despite a treatment regimen of surgical resection, radiotherapy, and temozolomide (TMZ) chemotherapy, over 90% of patients experience tumor recurrence and death. The mechanisms by which GBM tumors recur following treatment are currently unknown, however, they may provide novel therapeutic targets. Galectins are carbohydrate-binding proteins that are overexpressed in the stroma of GBM tumors, and are potent modulators of GBM cell migration and angiogenesis. The overall purpose of this work was to characterize the role of galectins in mediating glioma resistance to combination chemoradiation. The initial goal of this project was to characterize the response of tumor and endothelial cells to radiation, TMZ, and TMZ-based chemoradiation (Chapter 2). We assessed clonogenic survival, as well as galectin protein expression and secretion. Glioma cells secreted significant levels of galectin-1 and galectin-3 into the microenvironment following ionizing radiation, with potential to mediate endothelial cell activation and subsequent angiogenesis. Additionally, endothelial cells were highly resistant to TMZ-based chemotherapy, suggesting that following chemoradiation, the surviving vasculature could be highly angiogenic due to endothelial chemoresistance and galectin-induced activation. We hypothesized that hypoxia-inducible factor 1 (HIF-1) potentiates galectin-1 and galectin-3 expression following chemoradiation exposure in glioma cells (Chapter 3). Chemoradiation induced significant upregulation of galectin-1 and galectin-3, and this effect was significantly inhibited by HIF-1α siRNA.
To further investigate the effect of tumor-derived galectin-1 and galectin-3 on endothelial cells following chemoradiation, we developed a co-culture system between human glioma cells and endothelial cells (Chapter 4). We confirmed that glioma cells co-cultured with endothelial cells expressed higher galectin-1 and galectin-3 in response to combination chemoradiation. Our final studies investigated galectin-1 expression and inhibition in vivo (Chapter 5). We found that combination chemoradiation increased tumor galectin-1 expression compared to sham-treated animals. Using the galectin-1 small peptide antagonist, Anginex, we were able to inhibit cell migration and decrease angiogenesis following radiation exposure. In conclusion, the results of our studies suggest that crosstalk between tumor and endothelial cells in response to standard chemoradiation may be an important factor in mediating glioma recurrence, potentially via galectin upregulation.
|Advisor:||Griffin, Robert J.|
|Commitee:||Cifarelli, Christopher P., Diekman, Alan B., McGehee, Robert E., Suva, Larry|
|School:||University of Arkansas for Medical Sciences|
|Department:||Interdisciplinary Biomedical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 77/11(E), Dissertation Abstracts International|
|Keywords:||Chemotherapy, Galectin, Glioblastoma multiforme, Radiation, Tumor recurrence|
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