Exploration Into the Effects of Hypoxia in an In Vitro Canine Glioblastoma Model
Type of Degreedissertation
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Glioblastomas are aggressive, lethal primary brain tumors that affect human and canine patients. A subpopulation representing a variably large percentage of the bulk of tumor cells has been identified to have stem cell-like properties based on expression of certain molecular markers and growth properties in specialized culture conditions. This cancer stem-like cell (CSLC) population has been demonstrated to have increased resistance to radiation and chemotherapy, and is postulated to drive the bulk of tumor growth, invasion, regrowth, and treatment failure. Expression of several of these markers in human tumors, including CD133, nestin, and HIF2α, are associated with increasing tumor grade and/or a negative prognostic outcome, and because of their known roles in developmental biology have been utilized as markers for identifying CSLC. The role of the microenvironment in acquisition and maintenance of the stem-like state has not been fully elucidated; however, there is mounting evidence to indicate that hypoxia plays a crucial role. Although rodent and in vitro models exist to study the biology of glioblastoma and potential therapeutics, canine patients with naturally-occurring tumors offer a unique opportunity to serve as a bridge between these models and human clinical trials. Their usefulness in this regard necessitates a detailed and systematic investigation of the comparative biology of the disease beyond the histomorphologic level. In this body of work, we utilize an in vitro canine glioblastoma model system to demonstrate that hypoxia produces transcriptional upregulation of multiple putative CSLC and angiogenesis markers, and that siRNA-mediated gene silencing of HIF2α abrogates some of these effects and increases susceptibility to the chemotherapeutic agent doxorubicin.