Targeting Hypoxia-Inducible Factor 1α in a New Orthotopic Model of Glioblastoma Recapitulating the Hypoxic Tumor Microenvironment.

摘要: Tissue hypoxia and necrosis represent pathophysiologic histologic hallmarks of glioblastoma (GBM). Although inducible factor 1α (HIF-1α) plays crucial roles in the malignant phenotypes GBM, developing HIF-1α-targeted agents has been hampered by lack a suitable preclinical model that recapitulates complex biology clinical GBM. We present new GBM model, MGG123, which was established from recurrent human Orthotopic xenografting stem-like MGG123 cells reproducibly generated lethal tumors were characterized foci palisading necrosis, hypervascularity, robust stem cell marker expression. Perinecrotic neoplastic distinctively express HIF-1α are proliferative both xenografts patient tissue. The contain scattered hypoxic consistently greater than 50 μm distant blood vessels, indicating intratumoral heterogeneity oxygenation. Hypoxia enhanced expression cultured cells, abrogated inhibitors digoxin or ouabain. In vivo, treatment orthotopic with decreased expression, vascular endothelial growth mRNA levels, CD34-positive vasculature within tumors, extended survival mice bearing aggressive This tumor faithfully GBM-relevant microenvironment stemness is platform for studying disease hypoxia-targeted agents.