The Effect of Cellular Microenvironment on Vessels in the Brain. Part 1: Vessel Structure in Tumour, Peritumour and Brain from Humans with Malignant Glioma

Stewart, Patricia A.; Farrell, Catherine L.; Maestro, Rolando F. Del

doi:10.1080/09553009114551701

Cited by 26 publications

(7 citation statements)

References 18 publications

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“…In a recent study, Helmlinger et al (1997) measured PO 2 using a phosphorescence quenching microscopy technique in human tumour xenografts, and reported that hypoxic (≤ 5 mmHg) and near anoxic values (0-0.5 mmHg) were reached 70-80 and ≥ 150 µm away from tumour vessels respectively. However, a few histological studies on malignant gliomas have failed to obtain a certain tendency of tumour vascular density (Yoshii and Sugiyama, 1988;Stewart et al, 1991;Wesseling et al, 1994), although blood flow is lower in malignant gliomas than in normal white matter (Ito et al, 1982;Tyler et al, 1987;Mineura et al, 1994). These conflicting observations support the hypothesis that tumour tissue perfusion is incomplete due to transient (acute hypoxia) or partial occlusion of vessels (Chaplin et al, 1986).…”

Section: Tumour Hypoxiamentioning

confidence: 45%

Effects of radiotherapy after hyperbaric oxygenation on malignant gliomas

et al. 1999

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The purpose of this non-randomized trial was to evaluate the efficacy of radiotherapy combined with hyperbaric oxygen (HBO) in patients with malignant glioma. Between 1987 and 1997, 29 patients in whom computerized tomography (CT) or magnetic resonance imaging (MRI) scans showed post-operative residual tumours were locally irradiated with nitrosourea-based chemotherapy. Treatments were consecutively combined with HBO at two institutions since 1991 and 1993. Fifteen patients were irradiated daily after HBO, and the periods of time from decompression to irradiation were within 15 and 30 min in 11 and four patients respectively. Fourteen other patients were treated without HBO. Tumour responses were assessed by CT or MRI scans and survival times were compared between the treated groups. In the HBO group, 11 of 15 patients (73%) showed ≥ 50% tumour regression. All responders were irradiated within 15 min after decompression. In the non-HBO group, four of 14 patients (29%) showed tumour regression. The median survivals in patients with and without HBO were 24 and 12 months, respectively, and were significantly different ( P < 0.05). No serious side-effects were observed in the HBO patients. In conclusion, irradiation after HBO seems to be a useful form of treatment for malignant gliomas, but irradiation should be administered immediately after decompression. © 1999 Cancer Research Campaign

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Section: Tumour Hypoxiamentioning

confidence: 45%

Effects of radiotherapy after hyperbaric oxygenation on malignant gliomas

et al. 1999

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“…This notion is in line with our experience that staining for α-SMA and NG2, in contrast to the desmin and PDGFR-β staining, has proven insufficient for a reliable detection of pericytes in our C6 xenograft model when compared with the gold standard technique electron microscopy (unpublished data). Due to this heterogeneity in marker expression, the amount of pericyte coverage on tumor blood vessels (both under experimental and clinical conditions) has been reported to range from extensive (10)(11)(12) to little or none (8). Only recently, this controversy was convincingly addressed when pericyte-tumor blood vessel association was investigated by electron microscopy in combination with various immunohistochemical techniques, clearly demonstrating that the maturation index in experimental and human tumors may be as high as >95% (14).…”

Section: Discussionmentioning

confidence: 99%

“…This is supported by the observation that contact between endothelial cells and periendothelial support cells, such as pericytes or smooth muscle cells, stabilizes new blood vessels, promotes endothelial survival, and inhibits endothelial cell proliferation (9). The fact that only immature vessels may be forced into regression by interference with VEGF/VEGFR-2 signaling is of therapeutic relevance since the literature on the pericyte coverage on tumor vessels suggests that the pericyte-free fraction of tumor blood vessels may be little or none for a significant number of both experimental and human tumor types (10)(11)(12)(13)(14). As a consequence, additional targeting of pericyte recruitment and pericyte/endothelial cell interaction may enhance tumor vessel destruction after interference with VEGF/VEGFR-2 signaling.…”

mentioning

confidence: 99%

Combined inhibition of VEGF‐ and PDGF‐signaling enforces tumor vessel regression by interfering with pericyte‐mediated endothelial cell survival mechanisms

et al. 2003

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Destruction of existing tumor blood vessels may be achieved by targeting vascular endothelial growth factor (VEGF) signaling, which mediates not only endothelial cell proliferation but also endothelial cell survival. In this study, however, intravital microscopy failed to demonstrate that targeting of VEGFR-2 (by the tyrosine kinase inhibitor SU5416) induces significant regression of experimental tumor blood vessels. Immunohistochemistry, electron microscopy, expression analyses, and in situ hybridization provide evidence that this resistance of tumor blood vessels to VEGFR-2 targeting is conferred by pericytes that stabilize blood vessels and provide endothelial cell survival signals via the Ang-1/Tie2 pathway. In contrast, targeting VEGFR-2 plus the platelet-derived growth factor receptor (PDGFR)-beta system (PDGFR-beta) signaling (by SU6668) rapidly forced 40% of tumor blood vessels into regression, rendering these tumors hypoxic as shown by phosphorescence quenching. TUNEL staining, electron microscopy, and apoptosis blocking experiments suggest that VEGFR-2 plus PDGFR-beta targeting enforced tumor blood vessel regression by inducing endothelial cell apoptosis. We further show that this is achieved by an interference with pericyte-endothelial cell interaction. This study provides novel insights into the mechanisms of how 1) pericytes may provide escape strategies to anti-angiogenic therapies and 2) novel concepts that target not only endothelial cells but also pericyte-associated pathways involved in vascular stabilization and maturation exert potent anti-vascular effects.

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“…Although the calculations of the effects of receptors on the diffusion of [ 3 H]SCH 23390 were made using data from the slice experiment, these calculations are also applicable, in principle at least, to the in vivo situation. However, in the in vivo situation the diffusion distances for [ 3 H]SCH 23390 will be shorter since the average distance between capilliaries is 50-100 µm (Stewart et al, 1991), whereas the brain slices had a thickness of 300 µm.…”

Section: Factors Influencing the Time Course Of [ 3 H]sch 23390 Bindimentioning

confidence: 99%

Evaluation of the importance of rebinding to receptors in slowing the approach to equilibrium of high-affinity PET and SPECT radiotracers

Gifford

Gatley

Volkow

1998

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The importance of rebinding to receptors in influencing the kinetics of in vivo binding of PET and SPECT radiotracers was evaluated by examining the binding of a high-affinity D1 receptor radiotracer, [3H]SCH 23390, in tissue homogenates, living brain slices, and in vivo. In rat striatal homogenates, [3H]SCH 23390 binding reached equilibrium with a half-time of 6 min. By contrast, in striatal brain slices incubated in [3H] SCH 23390, the radioactivity levels in the slice increased in a linear fashion over the 4-h incubation, with no indication of an approach to equilibrium at the termination of the experiment. In in vivo experiments, [3H]SCH 23390 was given as a slow intravenous infusion to mice, using a paradigm that kept the plasma concentration at a constant level. Under these conditions, striatal [3H] SCH 23390 levels increased in a linear fashion over the 4-h infusion period, similar to what was observed in the brain slices, and as in the slices there was no indication of approach to a steady state. However, when given instead as a single-bolus intravenous dose, the striatal [3H]SCH 23390 levels reached a peak only 15 min after injection. Calculations based on the slice experiments, in which the blood-brain barrier is absent, suggested that the rate-limiting step accounting for the failure of [3H]SCH 23390 levels to reach equilibrium was its hindered diffusion as a result of repeated rebinding to receptors. This phenomenon may also be important in vivo and should be considered as a factor in determining the time-course of binding of radiotracers in PET and SPECT experiments where either the receptor density or radiotracer affinity is high.

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The Effect of Cellular Microenvironment on Vessels in the Brain. Part 1: Vessel Structure in Tumour, Peritumour and Brain from Humans with Malignant Glioma

Cited by 26 publications

References 18 publications

Effects of radiotherapy after hyperbaric oxygenation on malignant gliomas

Effects of radiotherapy after hyperbaric oxygenation on malignant gliomas

Combined inhibition of VEGF‐ and PDGF‐signaling enforces tumor vessel regression by interfering with pericyte‐mediated endothelial cell survival mechanisms

Evaluation of the importance of rebinding to receptors in slowing the approach to equilibrium of high-affinity PET and SPECT radiotracers

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