Vaso-occlusive Mechanisms that Induce Hypoxia and Cause Glioma Progression.

Summary

Principal Investigator: Daniel Brat
Abstract: 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.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi 'Pseudopalisading' necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis
    Yuan Rong
    Department of Pathology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA
    J Neuropathol Exp Neurol 65:529-39. 2006
  2. pmc Early growth response gene-1 regulates hypoxia-induced expression of tissue factor in glioblastoma multiforme through hypoxia-inducible factor-1-independent mechanisms
    Yuan Rong
    Department of Pathology and Laboratory Medicine, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    Cancer Res 66:7067-74. 2006
  3. ncbi Proteomic analysis of cerebrospinal fluid discriminates malignant and nonmalignant disease of the central nervous system and identifies specific protein markers
    Fatima W Khwaja
    Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA 30322, USA
    Proteomics 6:6277-87. 2006
  4. ncbi Congenital glioblastoma: a clinicopathologic and genetic analysis
    Daniel J Brat
    Departments of Pathology and Laboratory Medicine and Winship Cancer Institute, Emory University School of Medicine, 1364 Clifton Road NE, Atlanta, GA 30322, USA
    Brain Pathol 17:276-81. 2007
  5. pmc Intravascular thrombosis in central nervous system malignancies: a potential role in astrocytoma progression to glioblastoma
    Mahtab Tehrani
    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
    Brain Pathol 18:164-71. 2008
  6. pmc Epidermal growth factor receptor and PTEN modulate tissue factor expression in glioblastoma through JunD/activator protein-1 transcriptional activity
    Yuan Rong
    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
    Cancer Res 69:2540-9. 2009

Detail Information

Publications6

  1. ncbi 'Pseudopalisading' necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis
    Yuan Rong
    Department of Pathology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA
    J Neuropathol Exp Neurol 65:529-39. 2006
    ....
  2. pmc Early growth response gene-1 regulates hypoxia-induced expression of tissue factor in glioblastoma multiforme through hypoxia-inducible factor-1-independent mechanisms
    Yuan Rong
    Department of Pathology and Laboratory Medicine, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    Cancer Res 66:7067-74. 2006
    ..We conclude that hypoxic up-regulation of tissue factor in glioblastoma multiforme cells depends largely on Egr-1 and is independent of HIF-1...
  3. ncbi Proteomic analysis of cerebrospinal fluid discriminates malignant and nonmalignant disease of the central nervous system and identifies specific protein markers
    Fatima W Khwaja
    Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA 30322, USA
    Proteomics 6:6277-87. 2006
    ..3-13.7 kDa peak range in non-neoplastic CSF and was most prominent in inflammatory conditions. Our approach provides a rational basis for identifying biomarkers that could be used for detection, diagnosis, and monitoring of CNS diseases...
  4. ncbi Congenital glioblastoma: a clinicopathologic and genetic analysis
    Daniel J Brat
    Departments of Pathology and Laboratory Medicine and Winship Cancer Institute, Emory University School of Medicine, 1364 Clifton Road NE, Atlanta, GA 30322, USA
    Brain Pathol 17:276-81. 2007
    ..Nonetheless, the strong nuclear expression of p53 in these and other pediatric GBMs could indicate that p53 dysregulation is important to tumorigenesis...
  5. pmc Intravascular thrombosis in central nervous system malignancies: a potential role in astrocytoma progression to glioblastoma
    Mahtab Tehrani
    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
    Brain Pathol 18:164-71. 2008
    ..Thus, intravascular thrombosis is more frequent in GBM than other CNS malignancies. When present in AAs, it appears to indicate aggressive clinical behavior...
  6. pmc Epidermal growth factor receptor and PTEN modulate tissue factor expression in glioblastoma through JunD/activator protein-1 transcriptional activity
    Yuan Rong
    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
    Cancer Res 69:2540-9. 2009
    ..These mechanisms are likely at work in vivo, as EGFR expression was highly correlated with TF expression in human high-grade astrocytoma specimens...