Glioblastoma (GBM) is the most common primary brain tumor and also the highest grade (WHO gradeIV). Progression to GBM represents an abrupt turning point, with death quickly following the transition. One of the most specific pathologic features that emerges during the transition and distinguishes GBM from lower grade tumors is necrosis with surrounding cellular """"""""pseudopalisades"""""""". Pseudopalisades are composed of hypoxic tumor cells that secrete pro-angiogenic factors critical for promoting angiogenesis and tumor expansion. Mechanisms underlying the development of pseudopalisades, hypoxia, and necrosis in GBM are undefined, but we believe that understanding their origins will be critical for attempts to stabilize this disease. We hypothesize that vaso-occlusion and intravascular thrombosis give rise to pseudopalisades and the ensuing hypoxia-induced angiogenic cascade, accounting for the abrupt onset of rapid disease progression. Our preliminary data has demonstrated that thrombotic vascular occlusion within the neoplasm is associated with hypoxia-induced outward migration of glioma cells to form pseudopalisades. Mechanisms by which neoplastic cells induce endothelial damage, vaso-occlusion, and thrombosis have not been established. Ang- 2 is a Tie-2 receptor antagonist that mediates endothelial apoptosis in experimental gliomas and is a prime candidate for initiating these events. Since PTEN mutations occur during the transition to GBM, we will examine whether PTEN loss leads to the secretion of proteins that trigger endothelial apoptosis through Ang- 2. We also hypothesize that increased expression of the pro-thrombotic proteins tissue factor (TF) and protease activated receptor-1 (PAR1) promote intravascular thrombosis. We will examine whether PTEN loss or hypoxia promotes TF-mediated intravascular clotting and whether PAR1 activation leads to increased cellular migration associated with pseudopalisade formation. An animal model of astrocytoma will be used to validate the significance of PTEN loss, TF expression and intravascular thrombosis in the progression to GBM and to determine if anti-thrombotic therapies are capable of delaying the development of hypoxia and prolonging survival. Vaso-occlusion and intravascular thrombosis have not been previously recognized as driving forces in the development of hypoxia, angiogenesis and glioma progression. This proposal introduces entirely novel concepts that may explain the highly aggressive properties of GBM and suggests therapeutic approaches that could potentially stabilize its progression.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Fountain, Jane W
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Emory University
Schools of Medicine
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Rong, Yuan; Belozerov, Vladimir E; Tucker-Burden, Carol et al. (2009) Epidermal growth factor receptor and PTEN modulate tissue factor expression in glioblastoma through JunD/activator protein-1 transcriptional activity. Cancer Res 69:2540-9
Tehrani, Mahtab; Friedman, Theodore M; Olson, Jeffrey J et al. (2008) Intravascular thrombosis in central nervous system malignancies: a potential role in astrocytoma progression to glioblastoma. Brain Pathol 18:164-71
Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061-8
Brat, Daniel J; Shehata, Bahig M; Castellano-Sanchez, Amilcar A et al. (2007) Congenital glioblastoma: a clinicopathologic and genetic analysis. Brain Pathol 17:276-81
Rong, Yuan; Hu, Fang; Huang, Ruopan et al. (2006) Early growth response gene-1 regulates hypoxia-induced expression of tissue factor in glioblastoma multiforme through hypoxia-inducible factor-1-independent mechanisms. Cancer Res 66:7067-74
Khwaja, Fatima W; Nolen, John David Larkin; Mendrinos, Savaas E et al. (2006) Proteomic analysis of cerebrospinal fluid discriminates malignant and nonmalignant disease of the central nervous system and identifies specific protein markers. Proteomics 6:6277-87
Rong, Yuan; Durden, Donald L; Van Meir, Erwin G et al. (2006) 'Pseudopalisading' necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis. J Neuropathol Exp Neurol 65:529-39
Rong, Yuan; Post, Dawn E; Pieper, Russell O et al. (2005) PTEN and hypoxia regulate tissue factor expression and plasma coagulation by glioblastoma. Cancer Res 65:1406-13