Vascularization of human glioma spheroids implanted into rat cortex is conferred by two distinct mechanisms

Goldbrunner, Roland; Bernstein, Jerald J.; Plate, Karl H.; Vince, Giles H.; Roosen, K.; Tonn, Joerg‐Christian

doi:10.1002/(sici)1097-4547(19990215)55:4<486::aid-jnr8>3.0.co;2-a

Cited by 39 publications

(5 citation statements)

References 35 publications

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“…As previously described, we found that biochemical evaluation of VEGF from tissues/tumors reveals multiple bands immunoreactive with several independent VEGF antibodies ( Fig. 6A) (39,40), representing different VEGF forms (17,41) as well as possible complexes formed with other proteins (42)(43)(44)(45). Comparison between control and ADAMTS1 expressing tumors revealed a novel VEGF immunoreactive species of ϳ130 kDa present exclusively in the ADAMTS1 tumor lysates (Fig.…”

Section: Adamts1 and Vegf Form Complexes In Vivo-supporting

confidence: 67%

ADAMTS1/METH1 Inhibits Endothelial Cell Proliferation by Direct Binding and Sequestration of VEGF165

Luque¹,

Carpizo²,

Iruela‐Arispe

2003

Journal of Biological Chemistry

235

187

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ADAMTS1 is a metalloprotease previously shown to inhibit angiogenesis in a variety of in vitro and in vivo assays. In the present study, we demonstrate that ADAMTS1 significantly blocks VEGFR2 phosphorylation with consequent suppression of endothelial cell proliferation. The effect on VEGFR2 function was due to direct binding and sequestration of VEGF 165 by ADAMTS1. Binding was confirmed by co-immunoprecipitation and cross-linking analysis. Inhibition of VEGF function was reversible, as active VEGF could be recovered from the complex. The interaction required the heparin-binding domain of the growth factor, because VEGF 121 failed to bind to ADAMTS1. Structure/ function analysis with independent ADAMTS1 domains indicated that binding to VEGF 165 was mediated by the carboxyl-terminal (CT) region. ADAMTS1 and VEGF 165 were also found in association in tumor extracts. These findings provide a mechanism for the anti-angiogenic activity of ADAMTS1 and describe a novel modulator of VEGF bioavailability.Extracellular matrix proteins can significantly modulate growth factor signaling. This occurs to a large extent, but not exclusively, from direct non-covalent interactions that mediate selective anchorage of growth factors to the extracellular milieu (1-3). Several extracellular matrix molecules have been shown to bind and sequester growth factors, as well as to enhance signaling by altering presentation to receptor binding sites (4 -10). Angiogenesis is particularly sensitive to this type of regulation due to the critical role of paracrine growth factors in endothelial cell migration and proliferation.The vascular endothelial growth factor (VEGF) 1 gene produces several splice variants critical for capillary morphogenesis and tumor angiogenesis (11-13). Haploinsufficiency of this gene is incompatible with development due to major vascular abnormalities, as demonstrated by inactivation of the gene through homologous recombination (14, 15). Isoforms of VEGF are secreted by diverse cell types including smooth muscle, fibroblasts, and epithelial cells. These proteins function by activation of two tyrosine kinase receptors, VEGFR1 and VEGFR2, as well as by binding to non-receptor tyrosine kinase coreceptors such as neuropilin 1 and 2 on endothelial cells (16,17). ADAMTS1 was the first member of a growing family of ADAMTS extracellular proteases characterized by the presence of disintegrin-like metalloprotease and a variable number of thrombospondin-like domains (18,19). Once secreted, ADAMTS1 activation requires furin cleavage and removal of the pro-domain. The active protease can undergo a secondary processing event that separates the catalytic subunit from the thrombospondin (TSP) repeats (20,21). These TSP motifs in TSP1 and TSP2 have been shown to block angiogenesis by several, and likely not independent, mechanisms (22)(23)(24).We demonstrated previously that ADAMTS1 is able to suppress capillary growth using multiple in vivo and in vitro assays (18). Interestingly, the ability of ADAMTS1 to inhibit neovascularization...

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Section: Adamts1 and Vegf Form Complexes In Vivo-supporting

confidence: 67%

ADAMTS1/METH1 Inhibits Endothelial Cell Proliferation by Direct Binding and Sequestration of VEGF165

Luque¹,

Carpizo²,

Iruela‐Arispe

2003

Journal of Biological Chemistry

235

187

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“…While many aspects of induction and regulation of vascular endothelial proliferations in glioblastomas have recently been elucidated, molecular genetic determinants and the origin of the vascular component are not fully understood [6,10]. While many aspects of induction and regulation of vascular endothelial proliferations in glioblastomas have recently been elucidated, molecular genetic determinants and the origin of the vascular component are not fully understood [6,10].…”

Section: Discussionmentioning

confidence: 99%

Analysis of the TP53 gene in laser-microdissected glioblastoma vasculature

et al. 2003

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Malignant transformation of human gliomas is accompanied by extensive proliferation of stromal blood vessels. Recent data suggest mesenchymal transdifferentiation of neoplastic cells in various human cancers, including colon and breast cancer as well as gliosarcoma. In this study, we have analyzed proliferating stromal blood vessels in glioblastoma multiforme for the presence of mutations in the tumor suppressor gene TP53. Using tissue arrays derived from glioblastoma specimens, cases with significant immunohistochemical p53 accumulation were selected for molecular genetic detection of TP53 mutations in exons 5 to 8. None of the tumors included in this series displayed properties of gliosarcoma. Proliferating glomeruloid stromal vessels were isolated by laser microdissection from paraffin sections. In six cases, single-strand conformation polymorphism analysis for mutations of the TP53 gene in stromal blood vessels compared with adjacent tumor cells and subsequent DNA sequencing of the resulting DNA fragments were carried out. Glioblastoma cells of these cases exhibited TP53 mutations in exons 5, 7 and 8. None of these tumors showed TP53 mutations in microdissected samples from glomeruloid vessels. The absence of TP53 mutations in vascular stromal components of glioblastoma multiforme supports the hypothesis that microvascular proliferations originate from the tumor stroma and are not derived from transdifferentiated glioblastoma cells.

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“…Blood vessels are signaled to sprout, or individual endothelial cells are attracted for vascular formation, but we do not know how the distinctive pattern of the newly formed blood vessels within the tumor is destined. 11,30,33 Since dierent brain areas have a distinct composition of the extracellular matrix and a distinct combination of paracrine soluble factors including growth factors, tumor speci®c vascular patterning probably is a speci®c vascular reaction in dierent areas of the brain to a growing tumor. Thus, the special histoarchitecture and extracellular environment in the cerebellum could lead to a distinct tumor vascularization pattern that is dierent from the supratentorial cerebrum.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, in high-grade astrocytomas there are free individual endothelial cells within the tumor mass. 9,11,30 Pilocytic astrocytomas (WHO grade I) have lacy clusters of small-to-medium sized vessels with intact vessel wall integrity. However, endothelial cell proliferation can be observed, as well as MRI contrast enhancement in these tumors.…”

Section: Introductionmentioning

confidence: 99%

Different vascular patterns of medulloblastoma and supratentorial primitive neuroectodermal tumors

Goldbrunner¹,

Pietsch²,

Vince³

et al. 1999

Intl J of Devlp Neuroscience

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Astrocytoma vasculature patterns differ according to histological grade of malignancy with glioblastoma multiforme (WHO grade IV) showing most extensive endothelial proliferation. Here, we determined whether the vascular patterns of medulloblastoma and supratentorial primitive neuroectodermal tumors (PNETs), which can be hardly distinguished histopathologically, differ. We evaluated the spatial organization of vessels in medulloblastomas and PNETs using antibodies to von Willebrand factor (vWF) and CD34. Medulloblastoma capillaries showed slight endothelial cell hyperplasia. Microvessels sprouted from the capillaries and formed glomeruloid clusters. There were areas with chains of unopposed endothelial cells (3-10 cells). Supratentorial PNETs had highly branched capillaries with extensive endothelial cell hyperplasia. Glomeruloid arrays of microvessels extended from the capillaries. Small fragments of endothelial tubes were scattered throughout the tumor. Therefore, medulloblastomas and supratentorial PNETs showed different spatial organization of tumor vessels which can be used for differentiation of each tumor entity. These vascular patterns may reflect different tumor derived angiogenic stimuli.

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Vascularization of human glioma spheroids implanted into rat cortex is conferred by two distinct mechanisms

Cited by 39 publications

References 35 publications

ADAMTS1/METH1 Inhibits Endothelial Cell Proliferation by Direct Binding and Sequestration of VEGF165

ADAMTS1/METH1 Inhibits Endothelial Cell Proliferation by Direct Binding and Sequestration of VEGF165

Analysis of the TP53 gene in laser-microdissected glioblastoma vasculature

Different vascular patterns of medulloblastoma and supratentorial primitive neuroectodermal tumors

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