The angiopoietin 1/angiopoietin 2 balance as a prognostic marker in primary glioblastoma multiforme

2009 ◽  
Vol 110 (1) ◽  
pp. 147-155 ◽  
Author(s):  
Mariska Sie ◽  
Michiel Wagemakers ◽  
Grietje Molema ◽  
Jan Jakob A. Mooij ◽  
Eveline S. J. M. de Bont ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Antiangiogenic Therapy ◽  
Special Focus ◽  
Vascular Endothelial ◽  
Ki 67 ◽  
Primary Glioblastoma ◽  
Polymerase Chain ◽  
Angiopoietin 2 ◽  
Endothelial Growth Factor ◽  
Tumor Area

Object In the present study, the authors analyzed the ANGPT1/ANGPT2 balance in the context of therapeutic outcome in 62 patients with primary glioblastomas multiforme (GBMs). Methods The tumor tissue used was obtained in adult patients who underwent neurosurgical debulking. Microvessel density was assessed by morphometric analysis. Double immunostaining for Ki 67/CD34 and cleaved caspase-3/CD34 was used to investigate the proliferation and apoptotic fraction of both endothelial and tumor cells. The expression of VEGFs (A–D) was evaluated on immunohistochemistry. To measure tumor vascular stabilization, the ANGPT1/ANGPT2 mRNA balance was determined using real-time reverse transcriptase polymerase chain reaction. Results Within the hypoxic perinecrotic tumor area, the apoptotic fraction of endothelial cells was positively correlated with VEGFA expression (p < 0.001). Higher levels of VEGFA correlated with greater proliferation of endothelial cells in the intermediate tumor area (p = 0.031). Vascular endothelial growth factor D was significantly more highly expressed within the perinecrotic tumor area compared with the intermediate tumor area (p < 0.001). Multivariate analysis showed a significant association between the ANGPT1/ANGPT2 balance and the survival time of patients with GBMs (p = 0.035). Conclusions The results of the present study suggest that the ANGPT1/ANGPT2 balance has prognostic value in patients with primary GBMs. The authors' findings support the need for further studies of the feasibility of antiangiogenic therapy in primary GBMs, with a special focus on the normalization of tumor vasculature.

scholarly journals Localization of mRNA for vascular endothelial growth factor (VEGF), angiopoietins and their receptors during the peri-implantation period and early pregnancy in marmosets (Callithrix jacchus)

Reproduction ◽  
2003 ◽  
pp. 227-238 ◽  
Author(s):  
AJ Rowe ◽  
C Wulff ◽  
HM Fraser
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Early Pregnancy ◽  
Glandular Epithelium ◽  
Vascular Endothelial ◽  
Angiopoietin 2 ◽  
Endothelial Growth Factor ◽  
Implantation Period ◽  
Angiopoietin 1

Implantation of a blastocyst into a receptive endometrium is a prerequisite for successful pregnancy. Angiogenesis is a key event in this process but the mechanisms by which localized changes in vascular permeability and angiogenesis occur have yet to be elucidated. Vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2 have been implicated as key players in vascular remodelling and placentation. Angiopoietins also appear to have a significant role in regulation of blood vessel growth, maturation and regression. The aim of this study was to describe the molecular regulation of angiogenesis in the first month of pregnancy in marmosets and to address the putative physiological roles for these factors. Uteri were studied at weeks 2, 3 and 4 of pregnancy and compared with late secretory non-pregnant endometrium. Implantation in marmosets occurs at day 11 of pregnancy; hence, these time points were chosen so that the peri-implantation period and very early pregnancy could be studied. mRNAs for VEGF, VEGFR-1 and VEGFR-2, angiopoietin 1, angiopoietin 2 and their receptor Tie-2 were localized and quantified by in situ hybridization. Endothelial cells were identified by CD31 immunocytochemistry. VEGF mRNA was present in all compartments except endothelial cells, and its expression generally increased throughout pregnancy except in upper zone glandular epithelium and luminal epithelium, where a decrease in expression was observed. VEGF receptor mRNAs were found in endothelial cells of the upper zones immediately surrounding glandular epithelium. Angiopoietin 1 mRNA was localized to glandular epithelium of the upper and lower zones throughout pregnancy, and increased in stroma at week 4. Expression of angiopoietin 2 mRNA was localized exclusively to endothelial cells of large luminal vessels and was higher in endometrium from marmosets at week 4 of pregnancy than in endometrium from all other stages. These data provide comprehensive evidence that VEGFR-1 and -2, and angiopoietin 1, angiopoietin 2 and Tie-2 interactions may be involved in the preparation of endometrium for implantation, remodelling of the maternal vasculature and trophoblast invasion during the peri-implantation period in this primate species.

scholarly journals VEGF-dependent and PDGF-dependent dynamic neurovascular reconstruction in the neurohypophysis of adult mice

2014 ◽  
Vol 222 (1) ◽  
pp. 161-179 ◽  
Author(s):  
Eriko Furube ◽  
Tetsuya Mannari ◽  
Shoko Morita ◽  
Kazunori Nishikawa ◽  
Ayaka Yoshida ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Kinase Inhibitor ◽  
Vascular Density ◽  
Oligodendrocyte Progenitor Cells ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Ki 67 ◽  
Adult Mice ◽  
Endothelial Growth Factor

Hypothalamo-neurohypophysial system (HNS) releases arginine vasopressin (AVP) and oxytocin (OXT) from axonal terminals of the neurohypophysis (NH) into blood circulation for controlling body fluid homeostasis and lactation. Chronic osmotic and suckling stimulations have been shown to cause neurovascular and neuroglial reconstruction in the NH of adult mammals and no study has been reported for vascular dynamics. The aim of this study was to elucidate the occurrence of continuous angiogenesis and growth factor-dependent neurovascular reconstruction in the NH of adult mice. Active proliferation of endothelial cells and oligodendrocyte progenitor cells (OPCs) was observed using the immunohistochemistry of bromodeoxyuridine and Ki-67. Vascular endothelial growth factor A (VEGFA) and VEGF receptor 2 (VEGFR2 (KDR)) were highly expressed at pituicytes and endothelial cells respectively. Moreover, prominent expression of platelet-derived growth factor B (PDGFB) and PDGF receptor beta was observed at OXT-containing axonal terminals and pericytes respectively. Administration of the selective tyrosine kinase inhibitor AZD2171 for VEGFRs and STI571 for PDGFRs significantly decreased proliferation of endothelial cells and OPCs. Moreover, AZD2171 treatment decreased vascular density by facilitating apoptosis of endothelial cells and the withdrawal of its treatment led to remarkable rebound proliferation of endothelial cells, so that vascular density rapidly returned to normal levels. AZD2171 decreased the density of both AVP- and OXT-containing axonal terminals, whereas STI571 selectively decreased the density of AVP-containing ones. Thus, this study demonstrates that the signaling pathways of VEGF and PDGF are crucial mediators for determining proliferation of endothelial cells and OPCs and the density of AVP- and OXT-containing axonal terminals in the HNS.

scholarly journals Characteristics of tumor-associated endothelial cells derived from glioblastoma multiforme

2006 ◽  
Vol 20 (4) ◽  
pp. E22 ◽  
Author(s):  
Christiana Charalambous ◽  
Thomas C. Chen ◽  
Florence M. Hofman
Keyword(s):  
Endothelial Cells ◽  
Antiangiogenic Therapy ◽  
Cell Types ◽  
Antiangiogenic Agents ◽  
Normal Brain ◽  
Vascular Endothelial ◽  
Phenotypic Characteristics ◽  
Normal Human ◽  
Endothelial Growth Factor

✓ Glioblastomas multiforme (GBMs) are highly vascular brain tumors characterized by abnormal vessel structures in vivo. This finding supports the theory that glioma-associated endothelial cells (ECs) have intrinsically different properties from ECs in normal human brain. Therefore, identification of the functional and phenotypic characteristics of tumor-associated ECs is essential for designing a rational antiangiogenic therapy. The GBM-associated ECs have a large, flat, and veil-like appearance, in contrast to normal ones, which are small and plump. Although the tumor ECs have the typical markers, they proliferate more slowly than these cell types in normal brain. The GBM-associated ECs are resistant to cytotoxic drugs, and they undergo less apoptosis than control cells. Also, GBM-associated ECs migrate faster than controls and constitutively produce high levels of growth factors such as endothelin-1, interleukin-8, and vascular endothelial growth factor. An understanding of these unique characteristics of glioma-associated ECs is important for the development of novel antiangiogenic agents that specifically target tumor-associated ECs in gliomas.

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