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

Production of vascular endothelial growth factor (VEGF) by cancer cells at invasive and metastatic sites is an important aspect of tumor angiogenesis. Although known primarily as a mitogen and a vascular permeability factor (VPF) for endothelial cells, VEGF/VPF has been proposed to induce the expression of procoagulant factors in endothelial cells. In this study, we have explored the ramifications of VEGF induction of tissue factor (TF) in human umbilical vein endothelial cells (HUVECs) and subsequent activation of progelatinase A. Within 3 hr of incubation with VEGF/VPF, endothelial cells accelerate TF generation as measured using chromogenic substrate assays for coagulation factors Xa and thrombin. Incubation of VEGF/VPF-pre-treated cells with prothrombin and factors X, Va, and VIIa at 37 degrees C and subsequent generation of thrombin resulted in activation of secreted endothelial progelatinase A as demonstrated by gelatin zymography. Anti-thrombin III or antibodies to TF inhibited thrombin generation and progelatinase A activation. VEGF/VPF also directly increased HUVEC secretion of interstitial collagenase, tissue inhibitor of metalloproteinases (TIMP-1) and, to a lesser extent, gelatinase A. The effect of thrombin on endothelial proliferation in serum-free media was examined. Thrombin was a growth factor for HUVECs at a lower dose than that required for progelatinase A activation. Whereas TIMP-2 abrogated thrombin-induced progelatinase A activation, it had no significant effect on thrombin-induced endothelial cell growth. We propose that an early step in tumor angiogenesis involves VEGF-induced thrombin generation and increased MMP production with subsequent activation of endothelial progelatinase A and degradation of the underlying basement membrane.
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PMID:Vascular endothelial growth factor induces tissue factor and matrix metalloproteinase production in endothelial cells: conversion of prothrombin to thrombin results in progelatinase A activation and cell proliferation. 949 49

Bladder tumors are characterized by markedly increased angiogenesis when compared to the normal urothelium (NU) from which they are derived. Here, we use both cultured cells and immunohistochemistry to demonstrate a primary regulatory role for thrombospondin-1 (TSP-1), a potent inhibitor of angiogenesis, in the development of bladder tumor angiogenesis. Secretions from bladder cancer (CA) cells stimulated endothelial cell migration and corneal neovascularization, whereas those from NU cells were inhibitory. The antiangiogenic activity of NU cells was primarily due to secreted TSP-1 because neutralizing antibodies completely relieved the inhibition. Neutralizing antibodies to several putative angiogenesis inducers identified vascular endothelial growth factor (VEGF) and, to a lesser extent, basic fibroblast growth factor as the primary inducers secreted by bladder cancer cells. The secretion of TSP-1 by low- and high-grade cancer cells was reduced >94% when compared to NU cells, and this loss of inhibitory TSP-1 accounted for the development of an angiogenic phenotype because both NU cells and cancer cells secreted similar levels of total stimulatory activity and VEGF. Immunohistochemistry showed that TSP-1 was significantly reduced in all grades of bladder cancer when compared to NU, whereas VEGF staining remained relatively constant. Taken together, these data suggest that down-regulation of TSP-1 secretion is a key event in the switch from an antiangiogenic to an angiogenic phenotype, which occurs early in the development of bladder cancer.
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PMID:Molecular mediators of angiogenesis in bladder cancer. 951 19

Targeted disruption of the single mutant K-ras allele in two human colorectal carcinoma cell lines (DLD-1 and HCT-116) leads to loss of tumorigenic competence in nude mice with retention of ability to grow indefinitely in monolayer culture. Because expression of the mutant K-ras oncogene in these cell lines is associated with marked up-regulation of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), we sought to determine whether this potent angiogenesis inducer plays a role in K-ras-dependent tumorigenic competence. Transfection of a VEGF121 antisense expression vector into DLD-1 and HCT-116 cells resulted in suppression of VEGF/VPF production by a factor of 3- to 4-fold. The VEGF/VPF-deficient sublines, unlike the parental population or vector controls, were profoundly suppressed in their ability to form tumors in nude mice for as long as 6 months after cell injection. In contrast, in vitro growth of these sublines was unaffected, thus demonstrating the critical importance of VEGF/VPF as an angiogenic factor for HCT-116 and DLD-1 cells. Transfection of a full-length VEGF121 cDNA into two nontumorigenic mutant K-ras knockout sublines resulted in a weak but detectable restoration of tumorigenic ability in vivo in a subset of the transfectants, with no consistent change in growth properties in vitro. The findings indicate that mutant ras-oncogene-dependent VEGF/VPF expression is necessary, but not sufficient, for progressive tumor growth in vivo and highlight the relative contribution of oncogenes, such as mutant K-ras, to the process of tumor angiogenesis.
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PMID:Impact of oncogenes in tumor angiogenesis: mutant K-ras up-regulation of vascular endothelial growth factor/vascular permeability factor is necessary, but not sufficient for tumorigenicity of human colorectal carcinoma cells. 952 Apr 13

To examine the association of vascular endothelial growth factor (VEGF) expression with tumor angiogenesis, survival and thymidine phosphorylase/platelet-derived endothelial cell growth factor (dThdPase/PD-ECGF) expression in human colorectal cancer, immunohistochemical studies were performed on 136 cases of resected colorectal cancer specimens using antibodies for VEGF, KDR, CD34 and dThdPase/PD-ECGF. Fifty-nine cases (43%) were evaluated as positive for VEGF staining and 71 cases (52%) were evaluated as positive for dThdPase/PD-ECGF staining. The expression of VEGF correlated significantly with vessel counts and the expression of dThdPase/PD-ECGF (P = 0.01 and 0.01, respectively). Cox proportional hazards model analysis showed that vessel counts and VEGF expression were significant and independent prognostic factors, but that KDR expression was not.
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PMID:Association of vascular endothelial growth factor expression with tumor angiogenesis, survival and thymidine phosphorylase/platelet-derived endothelial cell growth factor expression in human colorectal cancer. 957 Mar 76

Endothelial cells involved in tumor angiogenesis, wound healing, and inflammation are predominantly of microvascular origin and are functionally distinct from large vessel-derived endothelial cells which have been largely used for in vitro vascular research. To overcome the problems commonly involved in the culture of microvascular endothelial cells, including unreliable isolation techniques and low cell yields, we developed a simplified protocol for the selective cultivation of human dermal microvascular endothelial cells (HDMEC) obtained from neonatal foreskins, based on the transient, endothelial cell-specific induction of E-selection by tumor necrosis factor-alpha (TNF-alpha). Subconfluent primary cultures, consisting of a mixture of endothelial cells, fibroblasts, and keratinocytes, were treated with TNF-alpha for 6 h, and HDMEC were isolated by their selective binding to magnetic beads coupled with anti-E-selection monoclonal antibody. After two immunomagnetic purification steps, a homogenous population of HDMEC was obtained which showed typical cobblestone morphology, expressed CD31 and von Willebrand factor, proliferated in response to vascular endothelial growth factor, upregulated the expression of intercellular adhesion molecule-1 and vascular adhesion molecule-1 in response to TNF-alpha, and formed capillary-like tubes in a three-dimensional collagen type I matrix. This simple technique may facilitate a more widespread use of microvascular endothelial cell cultures obtained from different human or animal organs for functional in vitro studies.
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PMID:A simple immunomagnetic protocol for the selective isolation and long-term culture of human dermal microvascular endothelial cells. 957 Sep 15

Angiogenesis is a critical determinant of tumor growth. Tumor cells produce or induce angiogenic molecules that act specifically on endothelial cells (ECs) but also release angiostatic molecules. Thus, tumor angiogenesis represents a net balance between positive and negative regulators of neovascularization. Sera from patients with breast or gastrointestinal cancers were evaluated for their capacity to selectively modulate the proliferation of human umbilical vein ECs; sera from 15 of 78 (19%) breast cancer patients and 8 of 53 (15%) gastrointestinal cancer patients induced human umbilical vein EC growth, whereas sera from 4 of 78 (5%) breast cancer patients and 1 of 53 (2%) gastrointestinal cancer patients inhibited EC proliferation. Growth-stimulatory sera were significantly more frequent among postmenopausal (14 of 53) than premenopausal (1 of 25) breast cancer patients; inhibitory activity was observed in 3 of 25 premenopausal patients versus 1 of 53 postmenopausal individuals. The half-life of serum-stimulating and -inhibiting factors seemed to differ, because stimulatory activity but not inhibitory activity was decreased at 5 days after surgery. The levels of vascular endothelial growth factor were elevated in about 45% of patients with growth-stimulatory sera, whereas the serum inhibition of EC growth was found to be due, at least in part, to high levels of soluble thrombospondin.
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PMID:Evaluation of the balance between angiogenic and antiangiogenic circulating factors in patients with breast and gastrointestinal cancers. 960 80

Tumor growth and metastasis are angiogenesis-dependent processes initiated and regulated by a number of cytokines. Vascular endothelial growth factor (VEGF) is a potent angiogenic protein with a selective mitogenic effect on vascular endothelial cells, known to be involved in physiological (embryogenesis) and pathophysiological (rheumatoid arthritis, tumor) angiogenesis. An increased expression of matrix metalloproteinase type IV collagenase has been reported in invading endothelial cells in vitro and in malignant cells, degrading structures of the basement membranes in various human malignancies. In the present study we investigated the expression of the genes for type IV collagenase and vascular endothelial growth factor (VEGF) in 40 cases of primary non-small-cell lung cancer (NSCLC). Specimens were immunostained by an antibody directed against VEGF and mRNA transcripts of VEGF and type IV collagenase were localized by non-radioactive in situ hybridization. VEGF mRNA was detected in 33 neoplasms, while in 23 cases transcripts of the type IV collagenase gene were visualized by digoxigenin-labeled cDNA probes. Transcripts of both mRNAs were detected in malignant cells. Furthermore, anti-VEGF immunostaining was present in newly formed microvessels close to the atypical cells, and mRNA of type IV collagenase was present in stromal cells adjacent to the tumor. A statistically significant correlation was found between the expression of type IV collagenase and VEGF (P = 0.0061). These data suggest a double role for type IV collagenase in the metastatic process of NSCLC: (1) facilitating the invasion of tumor cells by the proteolytic cleavage of the basement membrane and (2) similarly supporting the endothelial cell invasion essential for tumor angiogenesis. Furthermore, our findings sustain the hypothesis that metastatic spread and angiogenesis are associated with a clonal expansion of highly angiogenic and invasive tumor cell clones.
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PMID:Expression of type IV collagenase correlates with the expression of vascular endothelial growth factor in primary non-small cell lung cancer. 962 Feb 25

A single-chain antibody phage display library was constructed from spleen cells of mice immunized with a soluble form of a human vascular endothelial growth factor (VEGF) receptor, kinase insert domain-containing receptor (KDR). After two rounds of biopanning, >90% of the clones recovered were specifically reactive to KDR. Subsequent selection identified two clones that blocked VEGF binding to KDR. The clones were expressed in Escherichia coli and purified as soluble single-chain Fv (scFv) antibodies. The affinities of the scFv for binding to KDR were determined by BIAcore analysis (2.1 x 10(-9)-5.9 x 10(-9) M). One scFv, p1C11, was shown to inhibit VEGF-induced KDR phosphorylation and VEGF-stimulated DNA synthesis in human umbilical vein endothelial cells. There is much experimental evidence to suggest that the VEGF/KDR/Flk-1 pathway plays an important role in tumor angiogenesis, a process that is essential for tumor growth and metastasis. The antibodies discussed here, which block VEGF binding to KDR, have potential clinical application in the treatment of cancer and other diseases where pathological angiogenesis is involved.
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PMID:Inhibition of vascular endothelial growth factor-induced receptor activation with anti-kinase insert domain-containing receptor single-chain antibodies from a phage display library. 969 43

Dynamic studies of Gd-based contrast agents in magnetic resonance imaging (MRI) are increasingly being used for tumor characterization as well as for therapy response monitoring. Because detailed knowledge regarding the pathophysiological properties, which in turn are responsible for differences in contrast enhancement, remains fairly undetermined, it was the aim of this study to: (a) examine the association of standard and pharmacokinetic analysis of time-intensity curves in dynamic MRI with histomorphological markers of tumor angiogenesis [microvessel density (MVD) and vascular endothelial growth factor (VEGF)]; and (b) determine the ultimate value of a histomorphological and a dynamic MRI approach by the correlation of those data with disease outcome in patients with primary cancer of the uterine cervix. Pharmacokinetic parameters (amplitude, A; exchange rate constant, k21) and standard parameters [the maximum signal intensity increase over baseline (SI-I) and the steepest signal intensity-upslope per second (SI-U/s)] were calculated from a contrast-enhanced dynamic MRI series in 37 patients with biopsy-proven primary cervical cancer. On the surgical whole mount specimens, histomorphological markers of tumor angiogenesis (MVD and VEGF) were compared to MRI-derived parameters. For MRI and histomorphological data, Kaplan-Meier survival curves were calculated and compared using log-rank statistics. A significant association was found between MVD and A (P < 0.01) and SI-I (P < 0.05). No significant relationships were observed between VEGF expression and all dynamic MRI parameters. Kaplan-Meier curves based on k21 and SI-U/s showed that tumors with high k21 and SI-U/s values had a significantly (P < 0.05 and 0.001, respectively) worse disease outcome than did tumors with low k21 and SI-U/s values. None of the histomorphological gold standard markers for assessing tumor angiogenesis (MVD and VEGF) had any significant power to predict patient survival. It is concluded that in patients with uterine cervical cancer: (a) the pathophysiological basis for differences in dynamic MRI is MVD but not VEGF expression; (b) a functional, dynamic MRI approach (both standard and pharmacokinetic analysis) may be better suited to assess angiogenic activity in terms of patient survival than are the current histomorphological-based markers of tumor angiogenesis; and (c) compared with standard analysis, a simple pharmacokinetic analysis of time-intensity curves is not superior to assess MVD or patient survival.
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PMID:Uterine cervical carcinoma: comparison of standard and pharmacokinetic analysis of time-intensity curves for assessment of tumor angiogenesis and patient survival. 972 67

We have established a line of transgenic mice expressing the A. victoria green fluorescent protein (GFP) under the control of the promoter for vascular endothelial growth factor (VEGF). Mice bearing the transgene show green cellular fluorescence around the healing margins and throughout the granulation tissue of superficial ulcerative wounds. Implantation of solid tumors in the transgenic mice leads to an accumulation of green fluorescence resulting from tumor induction of host VEGF promoter activity. With time, the fluorescent cells invade the tumor and can be seen throughout the tumor mass. Spontaneous mammary tumors induced by oncogene expression in the VEGF-GFP mouse show strong stromal, but not tumor, expression of GFP. In both wound and tumor models the predominant GFP-positive cells are fibroblasts. The finding that the VEGF promoter of nontransformed cells is strongly activated by the tumor microenvironment points to a need to analyze and understand stromal cell collaboration in tumor angiogenesis.
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PMID:Tumor induction of VEGF promoter activity in stromal cells. 975 19


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