Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1658953 (tumor vasculature)
 2,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial growth factor (VEGF) is a hypoxia-inducible angiogenic factor, which is known to be upregulated in most cases of glioblastoma multiforme (GBM). The expression of VEGF and its receptors in ependymomas, oligodendrogliomas, and particularly the expression during anaplastic progression of these three types of gliomas has not been studied extensively. Fifty-six gliomas, consisting of 10 ependymomas, 12 oligodendrogliomas, 3 anaplastic oligodendrogliomas, 6 astrocytomas grade II, 5 anaplastic astrocytomas, and 20 glioblastoma multiformes, were investigated for VEGF and receptor expression using in situ hybridization (ISH) and reverse transcription polymerase chain reaction (RT-PCR). Results showed that VEGF was moderately to strongly expressed in 8 of 10 ependymomas and in all anaplastic oligodendrogliomas and glioblastoma multiforme cases. These tumors displayed similar degrees of extensive necrosis and vascular proliferation, with VEGF expression consistently seen in tumor cells around necrotic areas. The VEGF expression, although present at a lower level, also was shown in 4 of 12 oligodendrogliomas, in 3 of 6 astrocytomas grade II, and in 2 of 5 anaplastic astrocytomas, with a regional rather than diffuse pattern of positive result. The findings from the in situ hybridization study correlated with the expression index, as determined by reverse transcription polymerase chain reaction. Expression of VEGF was correlated significantly with vascular proliferation (p < 10(-5)) and necrosis (p < 10(-5)), as well as with microvessel density (p = 0.002, rs = 0.41). The VEGF receptors, kinase domain region (KDR) and Fms-like-tyrosine kinase (Flt-1), also were upregulated in the tumor vasculature of glioblastoma multiforme, anaplastic oligodendrogliomas, and ependymomas with necrosis, whereas the astrocytomas grade II, anaplastic astrocytomas, and oligodendroglioma tumors tended to express a weak to nondetectable signal. Anaplastic progression in all three types of gliomas is heralded by the occurrence of small zones of VEGF-expressing cells and early vascular proliferation, followed by an accelerated phase of angiogenesis closely associated with VEGF induction around areas of necrosis and with the expression of VEGF receptors in the tumor vasculature.
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PMID:Expression of vascular endothelial growth factor and its receptors in the anaplastic progression of astrocytoma, oligodendroglioma, and ependymoma. 966 44

Stanniocalcin 1 (STC1) is a secreted glycoprotein originally described as a hormone involved in calcium and phosphate homeostasis in bony fishes. We recently identified the mammalian homolog of this molecule to be highly up-regulated in an in vitro model of angiogenesis, as well as focally and intensely expressed at sites of pathological angiogenesis (e.g. tumor vasculature). In the present study, we report that STC1 is a selective modulator of hepatocyte growth factor (HGF)-induced endothelial migration and morphogenesis, but not proliferation. STC1 did not inhibit proliferative or migratory responses to vascular endothelial growth factor or basic fibroblast growth factor. The mechanism of STC1 inhibitory effects on HGF-induced endothelial migration seem to occur secondary to receptor activation because STC1 did not inhibit HGF-induced c-met receptor phosphorylation, but did block HGF-induced focal adhesion kinase activation. In the mouse femoral artery ligation model of angiogenesis, STC1 expression closely paralleled that of the endothelial marker CD31, and the peak level of STC1 expression occurred after an increase in HGF expression. We propose that STC1 may play a selective modulatory role in angiogenesis, possibly serving as a "stop signal" or stabilizing factor contributing to the maturation of newly formed blood vessels. HGF is a mesenchyme-derived pleiotropic factor with mitogenic, motogenic, and morphogenic activities on a number of different cell types. HGF effects are mediated through a specific tyrosine kinase, c-met, and aberrant HGF and c-met expression are frequently observed in a variety of tumors. Recent studies have shown HGF to be a potent growth factor implicated in wound healing, tissue regeneration, and angiogenesis.
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PMID:Stanniocalcin 1 is an autocrine modulator of endothelial angiogenic responses to hepatocyte growth factor. 1450 Jul 21

Experimental studies of antiangiogenic or immune therapy of cancer have generated a great deal of optimism. However, the results of clinical testing of these therapies are below expectations. We hypothesized that the antitumor efficacy can be increased when immune destruction of tumor cell is combined with destruction of tumor vasculature by antiangiogenic drugs. In the present study the therapeutic efficacy of combined antiangiogenic and immune therapy has been tested against the highly aggressive, MHC class I negative murine RM1 prostate tumor. SU6668 was used as the antiangiogenic drug and recombinant murine B7.2-IgG fusion protein was used to stimulate T cell-mediated immune destruction of tumor cells. SU6668 is an inhibitor of the tyrosine kinase activity of three angiogenic receptors VEGFR2 (Flk-1/KDR), PDGFRbeta and FGFR1 that play a crucial role in tumor-induced vascularization. Our studies show that B7.2-IgG treatment of mice with established RM1 prostate tumors resulted in a significant inhibition of tumor growth. Both CD4+ and CD8+ T cells were responsible for this effect. SU6668 therapy substantially inhibited tumor vascularization and tumor growth. When tumor-bearing mice were treated with SU6668 in combination with B7.2-IgG, the antitumor effects were substantially higher than in mice treated separately with SU6668 or B7.2-IgG. Prolonged treatment of mice with SU6668 did not inhibit the immunoreactivity of T lymphocytes. On the contrary, T cells from mice treated with a combination of SU6668 and B7.2-IgG showed higher proliferative responses and cytokine production following anti-CD3 stimulation than T cells of mice treated separately with these modalities. These results indicate that antiangiogenic and immune therapies using SU6668 and B7.2-IgG are compatible and manifest complementary antitumor effects. Combined antiangiogenic and immune therapy might represent a new strategy for cancer treatment.
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PMID:Combined antiangiogenic and immune therapy of prostate cancer. 1613 14

The mitogenic signaling in mammalian cells is carried out mainly by growth factors that interact with receptors localized at the plasma membrane. Most of these receptors have a tyrosine kinase activity domain that is localized at the cytoplasmic region of the molecule. The interaction of the growth factors with the receptors, besides inducing the kinase activity of the receptor, activate signaling pathways the alter gene expression patterns and induce mitogenesis, or if deregulated are related to cancer. Among these receptors ERBB, VEGF, PDGF and IGF are attractive targets for directed therapies. ERBB receptors are frequently involved in the production of many types of cancers. Both, the over-expression of the growth factor and the receptor, besides mutations at the cytoplasmic tyrosine kinase domain contribute to constitutive signaling in human cancer. VEGF has a pivotal role in maintaining the tumor growth by facilitating growth of new blood vessels. Therefore, inhibition of tumor growth targeting of the tumor vasculature, by interfering with the activity of VEGFr is now a real alternative in combinatorial therapies. PDGF is a growth factor involved in growth of connective tissue and wound healing. Activating mutations of PDGFr have been found in gastrointestinal tumors and the autocrine signaling maintained by this receptor have been described in many tumors. Imatinib, and inhibitor of the tyrosine kinase activity of Bcr-Abl targets also the kinase of the PDGFr. Finally IGF-I an II have an important antiapoptotic and pro-mitogenic role in most tumors. Different inhibitors are now under clinical studies for the use in combination of chemotherapeutic drugs in the treatment of different tumors.
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PMID:Cell signalling: growth factors and tyrosine kinase receptors. 1663 20

Inhibition of tumor angiogenesis is a promising approach in cancer treatment. The purpose of this study was to evaluate the vascular response of human lung tumor xenografts in vivo to RO0281501, an inhibitor of tyrosine kinase receptors, including vascular endothelial growth factor receptor 2, fibroblast growth factor receptor, and platelet-derived growth factor receptor, using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Human non-small cell lung carcinoma (H460a) xenografts grown s.c. in athymic nu/nu mice were treated p.o. with the antiangiogenic agent RO0281501. Treatment-induced changes in tumor volume, epiphyseal growth plate thickness, and microvessel density assessed by CD31 immunohistochemistry were analyzed. Tumor vascular permeability and perfusion were measured in tumors using DCE-MRI with gadopentetate dimeglumine on a 1.5 T clinical scanner to assess vascular function. Treatment with RO0281501 resulted in significant growth retardation of H460a tumors. RO0281501-treated tumors showed histologic evidence of growth plate thickening and relatively lower microvessel density compared with the controls. Regarding DCE-MRI variables, the initial slope of contrast uptake and Ak(ep) were significantly decreased on day 7 of treatment. RO0281501 is a novel antiangiogenic/antitumor agent, which is active in the H460a xenograft model. Its effects on tumor vasculature can be monitored and assessed by DCE-MRI on a 1.5 T human MR scanner with clinically available gadopentetate dimeglumine contrast, which will facilitate clinical trials with this or similar agents.
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PMID:Preclinical evaluation of tumor microvascular response to a novel antiangiogenic/antitumor agent RO0281501 by dynamic contrast-enhanced MRI at 1.5 T. 1692 15

Clinical trials showing longer survival when chemotherapy is combined with antiangiogenic agents (AAs) have led to growing interest in designing combined modality protocols that exploit abnormalities in tumor vasculature. Approved agents include bevacizumab, a recombinant monoclonal antibody that binds to vascular endothelial growth factor, and two small molecule multitargeted tyrosine kinase inhibitors of angiogenesis (SU11248 and BAY-43-9006) that have been approved for therapy of renal cancer. Targeting tumor vasculature has a strong biological rationale in radiation therapy, and preclinical studies consistently show an increase in radiosensitization with combined treatment. Preclinical studies indicate that excessive damage to tumor vasculature can result in radioresistance in some situations, and early clinical data suggest that treatment sequencing may be important when combining AAs with radiation. Radiation itself appears to antagonize any hypoxia that can be induced by long-term administration of AAs. The optimal biological doses of AAs with radiotherapy are unknown, and surrogate markers of efficacy remain to be validated. Early clinical trials should therefore include studies designed to identify mechanisms of interaction and increases in tumor hypoxia. This review highlights preclinical and early clinical data that are relevant for clinical trial design. Optimal radiation planning and delivery is required to minimize the volume of irradiated normal organs and to establish safe dose-volume parameters for phase II-III clinical trials.
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PMID:Design of clinical trials of radiation combined with antiangiogenic therapy. 1747 Jun 89

The vascular endothelial growth factor-A (VEGF-A) signaling pathway, a key stimulant of solid tumor vascularization, is primarily dependent on the activation of the endothelial cell surface receptor VEGF receptor-2 (VEGFR-2). AZD2171 is an oral, highly potent small-molecule inhibitor of VEGFR tyrosine kinase activity that inhibits angiogenesis and the growth of human tumor xenografts in vivo. Here, we show pharmacodynamic changes in VEGFR-2 phosphorylation induced by AZD2171. In mouse lung tissue, a single dose of AZD2171 at 6 mg/kg inhibited VEGF-A-stimulated VEGFR-2 phosphorylation by 87% at 2 h with significant inhibition (>or=60%) maintained to 24 h. To examine inhibition of VEGFR-2 phosphorylation in tumor vasculature by immunohistochemistry, a comprehensive assessment of antibodies to various phosphorylation sites on the receptor was undertaken. Antibodies to the phosphotyrosine epitopes pY1175/1173 and pY1214/1212 were found suitable for this application. Calu-6 human lung tumor xenografts, from mice receiving AZD2171 or vehicle treatment (p.o., once daily), were examined by immunohistochemistry. A significant reduction in tumor vessel staining of phosphorylated VEGFR-2 (pVEGFR-2) was evident within 28 h of AZD2171 treatment (6 mg/kg). This effect preceded a significant reduction in tumor microvessel density, which was detectable following 52 h of AZD2171 treatment. These data show that AZD2171 is a potent inhibitor of VEGFR-2 activation in vivo and suggest that AZD2171 delivers therapeutic benefit in Calu-6 tumors by targeting vessels dependent on VEGFR-2 signaling for survival. In addition, this work highlights the utility of measuring either pY1175/1173 or pY1214/1212 on VEGFR-2 as a pharmacodynamic marker of VEGFR-2 activation.
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PMID:Acute pharmacodynamic and antivascular effects of the vascular endothelial growth factor signaling inhibitor AZD2171 in Calu-6 human lung tumor xenografts. 1769 17

Among children with relapsed or refractory neuroblastoma, the prognosis is poor and novel therapeutic strategies are needed to improve long-term survival. As with other solid tumors, high vascular density within neuroblastoma is associated with advanced disease, and therapeutic regimens directed against the tumor vasculature may provide clinical benefit. The receptor tyrosine kinase RET is widely expressed in neuroblastoma and is known to activate key signal transduction pathways involved in tumor cell survival and progression including Ras/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt. We investigated the effect of dual targeting of tumor cells and tumor endothelium with ZD6474, a small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor 2, epidermal growth factor receptor, and RET. ZD6474 inhibited the phosphorylation of RET in neuroblastoma cells and had a direct effect on tumor cell viability in seven neuroblastoma cell lines. In a human neuroblastoma xenograft model, ZD6474 inhibited tumor growth by 85% compared with treatment with vehicle alone. In contrast, no significant inhibition of tumor growth was observed after treatment with bevacizumab, an antihuman VEGF monoclonal antibody, or the epidermal growth factor receptor inhibitor erlotinib, either alone or in combination. Immunohistochemical analysis showed that ZD6474 treatment led to an increase in endothelial cell apoptosis along with inhibition of VEGF receptor-2 activation on tumor endothelium. In conclusion, dual targeting of tumor cells, potentially through RET inhibition, and tumor vasculature with ZD6474 leads to potent antitumor effects. This approach merits further investigation for patients with neuroblastoma.
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PMID:Potent antitumor effects of ZD6474 on neuroblastoma via dual targeting of tumor cells and tumor endothelium. 1824 71

Inhibitors of angiogenesis and radiation induce compensatory changes in the tumor vasculature both during and after treatment cessation. To assess the responses to irradiation and vascular endothelial growth factor-receptor tyrosine kinase inhibition (by the vascular endothelial growth factor tyrosine kinase inhibitor PTK787/ZK222854), mammary carcinoma allografts were investigated by vascular casting; electron, light, and confocal microscopy; and immunoblotting. Irradiation and anti-angiogenic therapy had similar effects on the tumor vasculature. Both treatments reduced tumor vascularization, particularly in the tumor medulla. After cessation of therapy, the tumor vasculature expanded predominantly by intussusception with a plexus composed of enlarged sinusoidal-like vessels containing multiple transluminal tissue pillars. Tumor revascularization originated from preserved alpha-smooth muscle actin-positive vessels in the tumor cortex. Quantification revealed that recovery was characterized by an angiogenic switch from sprouting to intussusception. Up-regulated alpha-smooth muscle actin-expression during recovery reflected the recruitment of alpha-smooth muscle actin-positive cells for intussusception as part of the angio-adaptive mechanism. Tumor recovery was associated with a dramatic decrease (by 30% to 40%) in the intratumoral microvascular density, probably as a result of intussusceptive pruning and, surprisingly, with only a minimal reduction of the total microvascular (exchange) area. Therefore, the vascular supply to the tumor was not severely compromised, as demonstrated by hypoxia-inducible factor-1alpha expression. Both irradiation and anti-angiogenic therapy cause a switch from sprouting to intussusceptive angiogenesis, representing an escape mechanism and accounting for the development of resistance, as well as rapid recovery, after cessation of therapy.
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PMID:Tumor recovery by angiogenic switch from sprouting to intussusceptive angiogenesis after treatment with PTK787/ZK222584 or ionizing radiation. 1878 5

Current clinical protocols favor a combination of antiangiogenic/antivascular compounds with classical chemotherapy. However, it remains unclear to what extent an antiangiogenic/antivascular therapy influences the delivery of chemotherapy. Therefore, the aim of the present study was to characterize the effects of the antiangiogenic tyrosine kinase inhibitor sunitinib on tumor microhemodynamics and delivery of chemotherapy. SF126 tumor cells were implanted subcutaneously into nude mice and were analyzed repeatedly by intravital microscopy. Treatment with sunitinib was initiated 7 days after implantation. To assess the effects of sunitinib on tumor vasculature and hemodynamics, we analyzed total and functional vessel densities, microvascular diameter, and microvascular blood flow rate. To study the delivery of chemotherapy, autofluorescent doxorubicin was systemically administered and its vascular delivery to the tumor tissue was quantified. Histological analysis included endothelial cell proliferation, pericyte coverage of tumor vessels, and tumor cell proliferation. Sunitinib significantly suppressed tumor growth by both antivascular and antiangiogenic effects. However, a number of tumor vessels escaped antiangiogenic therapy. Interestingly, in these surviving blood vessels sunitinib treatment resulted in an increased microvascular blood flow rate resulting in an improved delivery of chemotherapy via these blood vessels. Besides its potent antiangiogenic and antivascular efficacy, sunitinib treatment results in improved microhemodynamics and blood flow in tumor blood vessels that escape therapy leading to an improved vascular delivery of chemotherapy. These results provide the basis for a potential chemosensitizing effect of sunitinib.
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PMID:Effects of sunitinib on tumor hemodynamics and delivery of chemotherapy. 1910 89


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