Vaso-occlusive and prothrombotic mechanisms associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma

Abstract

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 vasoocclusion 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. Vasoocclusive 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.

What drives intense apoptosis resistance and propensity for necrosis in glioblastoma? A role for Bcl2L12 as a multifunctional cell death regulator

“…To date, such investigations have identified key apoptosis modulators, such as XIAP, decoy receptors, p53 and RTKs 2 and have provided a detailed histopathological description of events driving necrogenesis. 3 We have recently identified and characterized Bcl2L12, a novel multi-functional protein possessing potent oncogenic and cell death modulatory activities. In this perspective, we highlight Bcl2L12's modus operandi in glial cells in vitro and in vivo, discuss how knowledge of Bcl2L12 function complements current views of cell death models in glioma, and we propose future avenues of investigation that may enable the development of targeted anti-Bcl2L12 therapies in GBM.…”

Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2–mediated heparin-binding EGF signaling in endothelial cells

“…Hypoxic activation is a hallmark of growing tumors as a result of inadequate oxygen supply, and increased angiogenesis serves to restore the supply of nutrients and oxygen to the tumor environment (3). GBM is further characterized by the activation of the coagulation system, and intravascular thrombosis exacerbates intratumoral hypoxia, abnormal endothelial cell (EC) proliferation, and tumor necrosis (4).…”

Derived vascular endothelial cells induced by mucoepidermoid carcinoma cells: 3-dimensional collagen matrix model

“…Among the MCCs, some fibroblasts were bundle-shaped or whirlpool-shaped; (d) Most purified MCCs were different-sized polygonal epithelial cells with a giant cell nucleus and a high karyoplasmic ratio. Very few were oval epithelial cells; (e) HE staining for purified MCCs showed no spindle-shaped or fibroblast-like cells, but polygonal epithelial cells appeared in various colonies; (f) With immunohistochemical staining for cytokeratin, cytoplasm and membrane of nearly all MCCs showed buffy granules; (g) With immunohistochemical staining for vimentin, almost all cells were negatively stained; (h) Alcian blue staining showed obvious blue staining in mucus-secreting cells as indicated with the arrow 100 μm 100 μm 100 μm 100 μm 100 μm 100 μm 100 μm 100 μm invasion (Konerding et al, 1998;Bian, 2001;Shirakawa et al, 2002a;2002b;Brat and van Meir, 2004). Some studies have indicated that activated ECs have an essential role in initiating the onset of tumor angiogenesis that is regulated by positive/negative regulation factors secreted by tumor Hess et al, 2001;Zeng et al, 2005).…”