Intravascular Thrombosis in Glioblastoma

Summary

Principal Investigator: Daniel Brat
Abstract: Glioblastoma (GBM) is the most common primary brain tumor and also the highest grade (WHO grade IV). Progression to a GBM represents an abrupt turning point, with rapid progression to death following the transition (mean, 50 weeks). Two pathologic features that distinguish GBM from lower grade tumors and are mechanistically instrumental are necrosis, typically with surrounding cellular pseudopalisades, and microvascular hyperplasia. Pseudopalisades are hypoxic and secrete pro-angiogenic factors that promote microvascular hyperplasia, an exuberant form of angiogenesis that supports the rapid tumor expansion. Mechanisms underlying pseudopalisades, hypoxia, and necrosis in GBM have not been defined. 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 rapidly progressive disease. This proposal follows our preliminary data, which indicates that pseudopalisades are neoplastic cells migrating away from central hypoxia created in part by microscopic thrombotic vascular occulsion. The initiating vascular insult that precedes intravascular thrombosis and pseudopalisading necrosis has not been determined. Ang-2, a Tie-2 receptor antagonsist that mediates endothelial apoptosis and vascular regression in the absence of VEGF, is expressed by endothelial cells of high grade gliomas and is a prime candidate for initiating vascular pathology. Also occurring during the transition to GBM are PTEN mutations and increased tumor cellularity, especially around blood vessels. We will examine whether neoplastic PTEN loss leads to the secretion of a protein capable of triggering endothelial apoptosis through Ang-2 mediated mechanisms. Candidate secreted or cell contact proteins will be identified by advanced protein separation methods and mass spectrometry. We also hypothesize that intravascular thrombosis is relevant to tumor necrosis and glioma biology and will examine whether PTEN loss and/or hypoxia, promote thrombosis through increased expression of the pro-thrombotic factors PAR-1 and tissue factor. The rationale and experiments in this proposal are novel and innovative, since the etiologies of hypoxia, pseudopalisades, and necrosis are unknown, vascular mechanisms have not been proposed, and intravascular thrombosis, while a frequent finding, has not been recognized as a potential driving force in tumor progression. Our emerging model represents a paradigm shift in the understanding of GBM and should lead directly to more effective therapies.
Funding Period: 2005-04-01 - 2006-03-31
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. 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

Publications4

  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. 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...