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Query: UMLS:C1519670 (tumor angiogenesis)
 6,052 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis of hepatocellular carcinoma. Inhibition of VEGF receptors could theoretically reduce angiogenesis and tumor growth in hepatocellular carcinoma, but this remains to be proven with an experimental study. This study examined the angiogenesis-dependent and angiogenesis-independent activities of PTK787/ZK222584 (PTK787), a tyrosine kinase inhibitor of VEGF receptors, in nude mice bearing human hepatocellular carcinoma xenografts. The in vitro effects of PTK787 on proliferation, apoptosis, and cell cycle distribution in human hepatocellular carcinoma cell lines were also studied. Oral administration of PTK787 resulted in a significant reduction in tumor volume and microvessel formation of hepatocellular carcinoma xenografts in nude mice. PTK787 inhibited tumor cell proliferation in a dose-dependent manner and also induced tumor cells to undergo apoptosis both in vivo and in vitro. The proapoptotic response was associated with down-regulation of Bcl-2 and Bcl-x(L) expression and induction of cleavage of caspase-3. In addition, PTK787 induced growth arrest in hepatocellular carcinoma cells, which was associated with G1 arrest and partial G2-M block. This effect correlated with an increase in p21(WAF1/ CIP1) (p21) and p27KIP1 (p27) protein expression. In conclusion, this study showed that PTK787 is a potent inhibitor of tumor growth in hepatocellular carcinoma by both antiangiogenic effect and direct effects on tumor cell proliferation and apoptosis. Our data suggest that blockage of VEGF receptors may provide an effective therapeutic approach for human hepatocellular carcinoma.
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PMID:Both antiangiogenesis- and angiogenesis-independent effects are responsible for hepatocellular carcinoma growth arrest by tyrosine kinase inhibitor PTK787/ZK222584. 1586 64

The proangiogenic vascular endothelial growth factor-A (VEGF) is essential for the development of new tumor vessels. ZD6474 is a novel inhibitor of VEGF receptor-2 (VEGFR-2) tyrosine kinase activity, which also has additional activity against epidermal growth factor (EGF) receptor tyrosine kinase. The antitumor activity of different schedules of ZD6474 in a clinically relevant, metastasizing, murine renal cell carcinoma (RENCA) model was evaluated in this study. RENCA cells were inoculated into the left kidney of 24 mice (day 0). Daily ZD6474 (50 mg/kg p.o.) treatment was initiated 1 day or 10 days after tumor cell inoculation and continued until day 21. Following treatment, kidney weight and volume were assessed and blood vessel density determined by CD31 staining. Visible metastases in the lungs, spleen, and lymph nodes were quantified using a dissection microscope. In an additional study, animals were treated according to the same regimen and quantitative three-dimensional microvascular corrosion casting was performed to enable detailed assessment of the tumor vascular architecture. Therapy initiated on day 1 or day 10 resulted in a 79% and 59% reduction in primary tumor volume, a 79% and 60% reduction in the number of lung metastases, and a 58% and 59% reduction in vessel density of primary tumors compared with the control group, respectively. Corrosion casting proved a 5.4- and 3.2-fold lower vascular volume compared with untreated tumors, observations that paralleled with significant architectural alterations. In this RENCA model, ZD6474 was a highly active inhibitor of tumor angiogenesis, primary tumor growth and tumor metastasis.
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PMID:The VEGF receptor tyrosine kinase inhibitor, ZD6474, inhibits angiogenesis and affects microvascular architecture within an orthotopically implanted renal cell carcinoma. 1588 78

Vascular endothelial growth factor (VEGF) and its family members are important mediators of tumor angiogenesis. The multiple functions of the VEGF are mediated through complex and selective interactions between the ligands, their high-affinity tyrosine kinase receptors, and co-receptors (neuropilins). While these receptors are historically described as being exclusively expressed on endothelial cells, emerging evidence has documented expression of these receptors on a number of nonendothelial cells, including tumor cells. The VEGF receptors (VEGFR) have also been shown to be functional in a number of nonendothelial systems, where they may be targets for anti-VEGF therapy. This article will review the basic effects and interactions of the VEGFRs on endothelial cells and the evidence for their expression and function on tumor cells. The novel expression of VEGFRs on tumor cells contributes to the understanding of the complex roles of VEGF within the tumor microenvironment, potentially affecting both endothelial cells and tumor cells expressing the VEGFRs. This elucidation of VEGF activity may further refine antineoplastic regimens for solid malignancies.
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PMID:Vascular endothelial growth factor receptors: expression and function in solid tumors. 1616 58

Blockade of signaling through the epidermal growth factor receptor (EGFR) tyrosine kinase by inhibitors such as gefitinib (Iressa) can inhibit tumor angiogenesis and enhance responses to ionizing radiation. In this study, the ability of gefitinib to modulate intratumoral oxygenation was evaluated in human EGFR-expressing A431 squamous cell carcinoma xenografts using in vivo small animal positron emission tomography (PET) imaging with the hypoxia marker [(18)F]fluoroazomycin arabinoside (FAZA) and by the immunohistochemical detection of hypoxia-induced adducts of the 2-nitroimidazole, pimonidazole. Serial noninvasive PET imaging of A431 xenografts showed a significant reduction in FAZA uptake following treatment with 75 mg/kg/d of gefitinib [tumor to background ratio, 6.1 +/- 1.0 (pretreatment) versus 2.3 +/- 0.6 (posttreatment); P = 0.0004]. Similarly, ex vivo quantitation of FAZA uptake showed significantly reduced FAZA uptake in established A431 xenografts treated with gefitinib compared with vehicle control (tumor to blood ratio for controls versus gefitinib, 8.0 +/- 3.0 versus 2.7 +/- 0.8; P = 0.007; or tumor to muscle ratio controls versus gefitinib, 8.6 +/- 2.8 versus 2.6 +/- 1.0; P = 0.002). The effect of gefitinib treatment seemed to be independent of tumor size. In addition, gefitinib treatment reduced pimonidazole-binding in A431 xenografts measured after 5 and 8 days of gefitinib treatment compared with baseline and with tumors treated with vehicle alone. A strong correlation was observed between pimonidazole binding and FAZA uptake. Together, these findings show that gefitinib reduces intratumoral hypoxia.
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PMID:Modulation of intratumoral hypoxia by the epidermal growth factor receptor inhibitor gefitinib detected using small animal PET imaging. 1617 34

The multifunctional growth factor scatter factor/hepatocyte growth factor (SF/HGF) and its receptor tyrosine kinase c-Met have emerged as key determinants of brain tumor growth and angiogenesis. SF/HGF and c-Met are expressed in brain tumors, the expression levels frequently correlating with tumor grade, tumor blood vessel density, and poor prognosis. Overexpression of SF/HGF and/or c-Met in brain tumor cells enhances their tumorigenicity, tumor growth, and tumor-associated angiogenesis. Conversely, inhibition of SF/HGF and c-Met in experimental tumor xenografts leads to inhibition of tumor growth and tumor angiogenesis. SF/HGF is expressed and secreted mainly by tumor cells and acts on c-Met receptors that are expressed in tumor cells and vascular endothelial cells. Activation of c-Met leads to induction of proliferation, migration, and invasion and to inhibition of apoptosis in tumor cells as well as in tumor vascular endothelial cells. Activation of tumor endothelial c-Met also induces extracellular matrix degradation, tubule formation, and angiogenesis in vivo. SF/HGF induces brain tumor angiogenesis directly through only partly known mechanisms and indirectly by regulating other angiogenic pathways such as VEGF. Different approaches to inhibiting SF/HGF and c-Met have been recently developed. These include receptor antagonism with SF/HGF fragments such as NK4, SF/HGF, and c-Met expression inhibition with U1snRNA/ribozymes; competitive ligand binding with soluble Met receptors; neutralizing antibodies to SF/HGF; and small molecular tyrosine kinase inhibitors. Use of these inhibitors in experimental tumor models leads to inhibition of tumor growth and angiogenesis. In this review, we summarize current knowledge of how the SF/HGF:c-Met pathway contributes to brain tumor malignancy with a focus on glioma angiogenesis.
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PMID:Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis. 1621 9

Inhibition of tumor angiogenesis is an anticancer strategy in which neovasculature is targeted because tumor progression relies on neovascularization. The soluble, truncated form of vascular endothelial growth factor receptor-2 (VEGFR-2), sFLK-1, is a well-known inhibitor of endothelial cells. This kind of soluble receptor retains its high-affinity binding to VEGF, but cannot work with the receptor tyrosine transphosphorylation and activation of downstream signal transduction to induce endothelial proliferation due to the lack of the tyrosine kinase domain. Therefore, we tried to use this sFLK-1 as an inhibitor for malignant tumor gene therapy. In this study we transferred a soluble VEGFR-2 (sFLK-1) from embryo mouse liver by RT-PCR to PA317 cells through retroviral vector (pLXSN) and obtained stable expression. NIH3T3 cells were used for measuring the virus titer. The virus titer in this experiment was 2 x 10(7) CFU/ml. After 7 days of preparing subcutaneous tumor models bearing S180, MCF-7, and B16 cells in mice, respectively, 2 x 10(7) PFU of recombinant retroviruses were injected locally into the tumors the treatment groups. After treatment, the tumor size and weight were significantly smaller than that of control (p < 0.05). After autopsy, the metastasic focus numbers in the treatment groups were also less than control groups. We also measured VEGFR-2 expression in tumor tissues by Western blot to check if sFLK-1 had been integrated into the cells of tumor tissues. Expression in the treatment groups was significantly greater than that of control groups (p < 0.001). Microvessel density (MVD) and proliferative cell nuclear antigen (PCNA) were investigated to determine whether the Re-sFLK-1 fragment had the ability to inhibit tumor angiogenesis and proliferation in mice bearing S180 and MCF-7 cells. The results showed that MVD and PCNA in th e treatment groups werelower than in control groups. There were significant difference between treatment groups and control groups (p < 0.0001). The results indicated that retroviral-mediated sFLK-1 gene therapy in animal tumor models has significant therapeutic effect.
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PMID:Gene therapeutic exploration: retrovirus-mediated soluble vascular endothelial growth factor receptor-2 (sFLK-1) inhibits the tumorigenicity of S180, MCF-7, and B16 cells in vivo. 1626 43

Blockade of angiogenesis is a promising strategy to suppress tumor growth, invasion, and metastasis. Vascular endothelial growth factor (VEGF), which binds to tyrosine kinase receptors [VEGF receptors (VEGFR) 1 and 2], is the mediator of angiogenesis and mitogen for endothelial cells. Cyclooxygenase-2 (COX-2) plays an important role in the promoting action of nicotine on gastric cancer growth. However, the action of nicotine and the relationship between COX-2 and VEGF/VEGFR system in tumorigenesis remain undefined. In this study, the effects of nicotine in tumor angiogenesis, invasiveness, and metastasis were studied with sponge implantation and Matrigel membrane models. Nicotine (200 microg/mL) stimulated gastric cancer cell proliferation, which was blocked by SC-236 (a highly selective COX-2 inhibitor) and CBO-P11 (a VEGFR inhibitor). This was associated with decreased VEGF levels as well as VEGFR-2 but not VEGFR-1 expression. Topical injection of nicotine enhanced tumor-associated vascularization, with a concomitant increase in VEGF levels in sponge implants. Again, application of SC-236 (2 mg/kg) and CBO-P11 (0.4 mg/kg) partially attenuated vascularization by approximately 30%. Furthermore, nicotine enhanced tumor cell invasion through the Matrigel membrane by 4-fold and promoted migration of human umbilical vein endothelial cells in a cocultured system with gastric cancer cells. The activity of matrix metalloproteinases 2 and 9 and protein expressions of plasminogen activators (urokinase-type plasminogen activator and its receptor), which are the indicators of invasion and migration processes, were increased by nicotine but blocked by COX-2 and VEGFR inhibitors. Taken together, our results reveal that the promoting action of nicotine on angiogenesis, tumor invasion, and metastasis is COX-2/VEGF/VEGFR dependent.
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PMID:Nicotine induces cyclooxygenase-2 and vascular endothelial growth factor receptor-2 in association with tumor-associated invasion and angiogenesis in gastric cancer. 1631 86

SU5416, 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one, is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinase, Flk-1/KDR (fetal liver kinase 1/kinase insert domain-containing receptor), also known as VEGF receptor 2 (VEGFR2). It was the first VEGFR2 inhibitor to enter clinical trials for the treatment of colorectal and non-small cell lung cancers. Pre-clinical evaluation of SU5416 included studies related to the distribution, metabolism and excretion of this compound. These studies have provided information useful in understanding the disposition and metabolism of the indolinone class of chemicals, which has not been studied previously with therapeutic intent. The lessons we learned from SU5416 have been successfully applied in developing next generation indolinone compounds targeting tumor angiogenesis.
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PMID:Distribution, metabolism, and excretion of the anti-angiogenic compound SU5416. 1632 1

We have previously observed that the synthetic peptide corresponding to amino acids 31-45 (PCK3145) of PSP94 can reduce prostate tumor growth in vivo. Moreover, a recently concluded phase IIa clinical trial with patients with hormone refractory prostate cancer indicated that PCK3145 down-regulates the levels of plasma matrix metalloproteinase (MMP)-9, a MMP involved in metastasis and tumor angiogenesis. The purpose of our study was to investigate the molecular mechanisms of action of PCK3145 and whether this peptide could antagonize tumor neovascularization. We show that, in a syngeneic in vivo model of rat prostate cancer, the expression of endothelial cell (EC) specific CD31, a marker of tumor vessel density, was decreased by 43% in PCK3145-treated animals. In vitro, PCK3145 specifically antagonized in a dose-dependent manner the VEGF-induced ERK phosphorylation as well as the phosphorylation of the VEGFR-2 in cultured EC (HUVEC). These anti-VEGF effects were partly reproduced by pharmacological inhibitors such as PD98059 and PTK787, suggesting that PCK3145 inhibits the tyrosine kinase activity associated to VEGFR-2, which in turn prevents intracellular signalling through the MAPK cascade. Moreover, PCK3145 was also found to inhibit the PDGF-induced phosphorylation of PDGFR in smooth muscle cells. Finally, PCK3145 inhibited in vitro EC tubulogenesis and VEGF-induced MMP-2 secretion suggesting its potential implication as an antiangiogenic agent. Our study demonstrates that PCK3145 interferes with the tyrosine kinase activity associated with VEGF signalling axis in EC. The antiangiogenic properties of this peptide could be highly beneficial and exploited in novel antiangiogenic therapies, for patients with various cancers.
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PMID:A prostate secretory protein94-derived synthetic peptide PCK3145 inhibits VEGF signalling in endothelial cells: implication in tumor angiogenesis. 1633 3

The scientific rationale to block angiogenesis as a treatment strategy for human cancer has been developed over the last 30 years, but is only now entering the clinical arena. Preclinical studies have demonstrated the importance of the vascular endothelial growth factor (VEGF) pathways in both physiologic and pathologic angiogenesis, and have led to the development of approaches to block its role in tumor angiogenesis. Bevacizumab is an antibody to VEGF and has been shown to prolong survival when given with chemotherapy in the treatment of metastatic colorectal cancer (CRC). Although this is the first anti-angiogenic treatment to be approved for the treatment of human epithelial malignancy, a number of other approaches currently are in development. Soluble chimeric receptors to sequester serum VEGF and monoclonal antibodies against VEGF receptors have both shown considerable promise in the laboratory and are being brought into clinical investigation. A number of small-molecule tyrosine kinase inhibitors that have activity against VEGF receptors also are in clinical trials. Although these novel treatments are being pioneered in CRC, anti-angiogenic approaches also are being tested in the treatment of other gastrointestinal malignancies. Anti-VEGF therapy has shown promise in such traditionally resistant tumors as pancreatic cancer and hepatocellular carcinoma. This review will examine the preclinical foundation and then focus on the clinical studies of anti-VEGF therapy in gastrointestinal cancers.
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PMID:Anti-angiogenic treatment of gastrointestinal malignancies. 1637 90


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