Vaso-occlusive and prothrombotic mechanisms associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma.
Glioblastoma (GBM) has explosive biologic properties with rapid clinical progression leading to death. Its distinguishing pathologic features, necrosis with surrounding pseudopalisades and microvascular hyperplasia, are believed to be instrumental to its accelerated growth. Microvascular hyperplasia arises in response to the secretion of proangiogenic factors by hypoxic pseudopalisades and allows for peripheral neoplastic expansion. Mechanisms underlying necrosis and hypoxia remain obscure, but vaso-occlusive and prothrombotic contributions could be substantial. Recent investigations on the origin of pseudopalisades suggest that this morphologic phenomenon is created by a tumor cell population actively migrating away from a central hypoxic region and that, in at least a significant subset, hypoxia-induced migration appears due to vaso-occlusion caused by intravascular thrombosis. Both vascular endothelial growth factor induced vascular permeability to plasma coagulation factors and the increased neoplastic expression of tissue factor likely contribute to a prothrombotic state favoring intravascular thrombosis. In addition to prothrombotic mechanisms, vaso-occlusion could also result from angiopoietin-2-mediated endothelial cell apoptosis and vascular regression, which follows neoplastic co-option of native vessels in animal models of gliomas. Vaso-occlusive and prothrombotic mechanisms in GBM could readily explain the presence of pseudopalisades and coagulative necrosis in tissue sections, the emergence of central contrast enhancement and its rapid peripheral expansion on neuroimaging, and the dramatic shift to an accelerated rate of clinical progression. Since the hypoxic induction of angiogenesis appears to support further neoplastic growth, therapeutic targeting of the underlying vascular pathology and thrombosis could provide a new means to prolong time to progression.
Brat
Daniel J
DJ
Department of Pathology and Laboratory Medicine, Emory University School of Medicine H-176, 1364 Clifton Road NE, Atlanta, GA 30322, USA. dbrat@emory.edu
Van Meir
Erwin G
EG
D001808:Blood Vessels / Q000473:pathology; D001932:Brain Neoplasms / Q000473:pathology*; D002455:Cell Division; D015687:Cell Hypoxia; D005909:Glioblastoma / Q000098:blood supply / Q000473:pathology*; D006801:Humans; D009336:Necrosis; D009389:Neovascularization, Pathologic / Q000473:pathology; D013925:Thromboplastin / Q000502:physiology; D013927:Thrombosis / Q000209:etiology*
D013925:Thromboplastin