UMLS:C0027627 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many studies have reported a close association between VEGF and tumor angiogenesis. The aim of the present study was to evaluate the effectiveness of gene therapy against cancer, including peritoneal metastasis, using a cDNA encoding a soluble type of Flt-1, one of the VEGF receptors. In a peritoneal metastasis model of MKN45 human gastric cancer cells, mice repetitively treated with intraperitoneal injections of HVJ-Fex, a type of HVJ-cationic liposome encapsulating a plasmid expressing soluble mFlt-1, exhibited smaller disseminated foci with fewer microvessels, thus resulting in a significantly longer survival period than the control mice. In another peritoneal metastasis model using HT1080S cells, a clone of HT1080 human fibrosarcoma cells stably transfected with hVEGF, treatments with HVJ-Fex also reduced the growth of disseminated foci without ascites formation. In conclusion, this study demonstrated that the peritoneal metastases of some cancers were largely dependent on VEGF, and that the repeated intraperitoneal transduction of a soluble flt-1 gene using HVJ-cationic liposomes suppressed peritoneal metastases, thereby contributing to a longer survival period.
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PMID:Soluble Flt-1 gene therapy for peritoneal metastases using HVJ-cationic liposomes. 1087 51

We recently developed a method for the isolation and purification of tumour-derived endothelium. In this study the phenotypic and functional properties of human tumour-derived microvascular endothelial cells (TdMEC) were examined. Endothelium obtained from human adrenal gland specimens (HAMEC) was used as a reference microvascular endothelial cell population. TdMEC formed a confluent monolayer with the typical morphological appearance of endothelium and were positive for endothelial markers such as Ulex-1 lectin, CD31 antigen, von Willebrand Factor and VE-cadherin. The addition of acidic Fibroblast Growth Factor (aFGF), basic FGF (bFGF) or Vascular Endothelial Growth Factor (VEGF) substantially improved proliferation of TdMEC; and kidney carcinoma derived endothelial cells were more responsive to FGFs, whereas glioblastoma derived endothelial cells greatly responded to VEGF TdMEC expressed high levels of the VEGF receptors, KDR/flk-1 and Flt-1, as shown by northern blot analysis. TdMEC expressed the adhesion molecules ICAM-1, VCAM-1 and E-selectin that could be further increased by exposing TdMEC culture to interleukin-1. All the TdMEC expressed interleukin-8 mRNA. These findings show that TdMEC in vitro maintain several of the features described for microvasculature. Thus, TdMEC represent a useful tool to study markers for tumor vasculature.
Clin Exp Metastasis 1999
PMID:Phenotypic and functional characteristics of tumour-derived microvascular endothelial cells. 1091 10

Vascular endothelial growth factor (VEGF) and its receptors, Flt-1 and flk-1(KDR), constitute an important angiogenic pathway which, under hypoxic conditions, is up-regulated in many solid tumours. We used the monoclonal antibody 11B5, specific for recognizing VEGF expression and the 'VEGF/flk-1(KDR) complex' on tumour endothelium, to assess free VEGF protein expression and VEGF/receptor activated microvessel density (aMVD) in a series of 104 inoperable locally advanced squamous cell carcinomas of the head and neck, treated with chemo-radiotherapy. High VEGF expression in cancer cells was strongly associated with high VEGF/receptor expression in the vasculature. The high VEGF expression and the aMVD were not associated with the standard microvessel density (sMVD), as assessed with the monoclonal antibody anti-CD31 and, were not detected in normal tissue. An increased sMVD, however, was significantly related with the expression thymidine phosphorylase (TP), and also with the nuclear accumulation of the oncoprotein p53, but neither p53 nor TP was associated with VEGF expression by cancer cells or VEGF/receptor complex aMVD. In 35% of cancer cases examined, more than 20% of the microvessels assessed with anti-CD31 also expressed the VEGF/KDR complex. The vasculature of the normal head and neck mucosa did not express the VEGF/KDR complex. There was no association between VEGF expression or VEGF/receptor complex aMVD and response to chemo-radiotherapy or patient's survival. It is concluded that activation of the angiogenic pathway VEGF/flk-1(KDR) is tumor specific in a subgroup of locally advanced squamous cell carcinomas of the head and neck. Selective destruction of this type of vasculature, using immunoconjugates directed against the VEGF/receptor complex, may prove therapeutically useful for patients with a high tumoral VEGF/flk-1(KDR) activated microvessel fraction.
Clin Exp Metastasis 2000
PMID:Tumor specific activation of the VEGF/KDR angiogenic pathway in a subset of locally advanced squamous cell head and neck carcinomas. 1144 62

A significant amount of research has been devoted to the chemical stabilization of synthetic ribozymes, in part, so that applications to systemic disease can be explored. A nuclease-stabilized synthetic hammerhead ribozyme, ANGIOZYME, has been developed which targets the mRNA encoding a vascular endothelial growth factor receptor, Flt-1. Because the stimulation of this receptor may contribute to tumor neovascularization and subsequent tumor growth and metastasis, we have explored the systemic use of ANGIOZYME to down regulate this receptor in a syngeneic model of metastatic cancer. We describe here the application of pharmacokinetic analysis to the selection of a dosing regimen for pharmacodynamic screening in this murine cancer model. These studies demonstrate that the appropriate application of pharmacokinetic analysis is necessary for the optimization of systemic pharmacodynamic studies using synthetic ribozymes.
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PMID:Ribozyme pharmacokinetic screening for predicting pharmacodynamic dosing regimens. 1147 55

In cloning tyrosine kinase genes in dog prostate cells, a fragment of the vascular endothelial growth factor (VEGF) receptor 1 or Flt-1 was sequenced. To test for a functional protein, Flt-1 antibodies were used to probe immunoprecipitated tyrosine phosphorylated proteins. Western blotting revealed a major 170-180 kDa band and a few bands below 116 kDa in dog prostate and human prostatic carcinoma PC-3 cells, with higher levels in PC-3. Similar results were obtained with human placental membranes used as a source of Flt-1. That the major Flt-1 tyrosine phosphorylated protein was likely VEGF-R1 and part of VEGF signaling pathways was shown by enhanced level of only this protein when PC-3 cells were exposed to VEGF. Accordingly specific cell surface receptor complexes, displaced by VEGF but not EGF and compatible with Flt-1 in size, were revealed by chemical cross-linking after 125I-VEGF binding. Similarly to the prostatic neuroproduct, gastrin-releasing peptide/bombesin, VEGF directly triggered the tyrosine phosphorylation of focal adhesion kinase and stimulated PC-3 cell motility. The titration of prostate tissue sections with VEGF-A antibodies revealed a confined staining in chromogranin A and/or serotonin positive neuroendocrine (NE) cells, including in primary tumors and lymph node metastases. Given that NE differentiation is associated with advanced disease, that NE cells are a significant source of VEGF in prostatic tumors, and that VEGF directly act on prostate cancer cells in vitro, VEGF-A may be more than angiogenic in prostate cancer and hence favor progression by affecting tumor cells.
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PMID:Vascular endothelial growth factor and signaling in the prostate: more than angiogenesis. 1203 75

Lung cancer is a major public health problem and the leading cause of cancer-related death worldwide. Its survival rates have changed little over the past 20 years. The best clinical benefit (ie, survival rates) with combination cytotoxic therapies in non-small-cell lung cancer (NSCLC) may have been reached. The need for improved survival rates in NSCLC has driven the development of novel, rationally designed, targeted therapies. Inhibitors of angiogenesis have been developed and are increasingly studied. Potential targets for therapy include inhibitors of vascular endothelial growth factor receptor, endogenous angiogenesis inhibitors, and cyclooxygenase inhibitors. Combining targeted molecules with traditional cytotoxic therapies usually results in lower required chemotherapy doses and fewer, less severe side effects. A number of ongoing randomized studies are underway to evaluate this idea. It is anticipated that these new targeted therapies will play an important role, along with cytotoxic and radiation therapies, in the management of metastatic disease.
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PMID:Angiogenesis inhibitors in lung cancer. 1204 42

Tumors require a blood supply for growth and hematogenous metastases. Until recently, most research in this area has focused on the role of angiogenesis, the recruitment of new vessels into a tumor from preexisting vessels. Previously, in a study of breast cancer (IBC), in which we used established inflammatory breast cancer (IBC) xenografts (WIBC-9) originating from a patient with IBC (Shirakawa et al., Cancer Res 2001:61:445-451), we reported observing vasculogenic mimicry (VM), a condition in which bloodstreams within cancer tissue are not accompanied by a lining of endothelial cells (ECs) (Shirakawa et al., Cancer Res 2002:62:560-566). In the present study, we examined 331 surgically resected breast cancer specimens for evidence of VM, using immunohistochemistry and laser-captured microdissection (LCM) followed by nested reverse transcriptase polymerase chain reaction (RT-PCR). Surprisingly, 7.9% (26 specimens) of the 331 specimens exhibited evidence of VM. Of these 26 VM specimens, 84.6% (22 specimens) exhibited pseudo-comedo formation. RT-PCR analysis of 8 microdissected typical VM specimens revealed expression of Tie-2, Flt-1, thrombin receptor and CD31 in 63, 50, 0 and 0% of specimens, respectively. In contrast, results of RT-PCR analysis of 8 specimens from non-VM tumors were negative for expression of these genes. The 26 VM cases tended to have a higher percentage of hematogenous recurrence (p = 0.059) and a lower percentage of 5-year survival (p = 0.071) than the 305 non-VM cases. However, there were no significant differences in tumor size, lymph node metastasis, estrogen receptors or progesterone receptors between the 2 groups (p > 0.1). Our results suggest that the existence of VM increases the likelihood of hematogenous metastases and is in inverse proportion to prognosis.
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PMID:Vasculogenic mimicry and pseudo-comedo formation in breast cancer. 1211 83

The pleura covers the lung parenchyma, chest wall, and diaphragm with a single layer of flat cells that are easy to genetically modify with adenovirus (Ad) vectors. Although intrapleural gene therapy has been used to treat intrapleural disorders, we hypothesized that it may also be used to deliver extracellular gene products to the lung parenchyma. In this context, this study is based on the concept that administration of adenovirus gene transfer vectors into the pleural cavity will mediate expression of gene products in mesothelial cells, and that the extracellular products produced by these genetically modified cells will reach the lung parenchyma. To assess this concept, Ad(beta)gal (expressing beta-galactosidase [beta-Gal]) or AdLuc (expressing luciferase) was administered into the right pleural cavity of BALB/c mice, as compared with intravenous injection via the jugular vein or the intratracheal route. Histologic assessment of lungs and pleural surface after intrapleural administration of Ad(beta)gal demonstrated beta-Gal expression limited to the pleural mesothelium and cells adjacent to the pleural surface. Right intrapleural administration of AdLuc showed higher level of luciferase in both the right and left lung (right vs. left, p > 0.8), compared with the intratracheal (p < 0.05) or intravenous routes (p < 0.02), that is, unilateral intrapleural administration is sufficient to transfer genes bilaterally to the pleura. To assess the ability of intrapleural gene transfer to modify lung parenchymal processes, CT26.CL25 tumor cells (3 x 10(5)) were injected via the jugular vein to generate tumor metastases in the lung parenchyma followed 24 hr later by administration to the right pleura of 5 x 10(8) PFU of Adsflt (an Ad "antiangiogenesis" vector expressing a soluble, secreted, extracellular portion of the Flt-1 receptor for vascular endothelial growth factor). Compared with phosphate-buffered saline, or the control vector AdNull (no transgene), mice receiving Adsflt by the intrapleural route had a marked suppression of tumor growth in the parenchyma of both lungs as assessed 12 days after tumor administration (p < 0.005). Treatment of preestablished lung metastases with Adsflt administered by the intrapleural route significantly improved long-term survival as compared with control animals (p < 0.0001). Thus, although intrapleural administration of an Ad vector encoding an intracellular protein mediates gene expression only in mesothelial cells and the local tissues, intrapleural delivery of a vector expressing a secreted protein can be used to modify processes throughout the lung parenchyma. In the context that intravascular gene transfer is an ineffective strategy to deliver gene products to the lung parenchyma, and that intratracheal administration is associated with alveolar inflammation secondary to host defenses against Ad vectors, these findings demonstrate that intrapleural administration represents a strategy that can be used to effectively deliver extracellular gene products to the lung parenchyma via a site that is readily accessible, and where inflammation against the vector will not have significant pathophysiologic consequences.
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PMID:Gene transfer to the pleural mesothelium as a strategy to deliver proteins to the lung parenchyma. 1221 68

Our laboratory has previously reported that natural killer (NK) cells bind to angiogenic microvessels in established cancer metastases. Vascular endothelial growth factor (VEGF) plays an important role in solid tumor angiogenesis by enhancing new blood vessel formation to transport nutrients and oxygen into tumors. Here we report that the human natural killer cell lines, NK-92 and YT, express the mRNA message and protein product for VEGF-B and its receptor, VEGFR-1/Flt-1. While stimulation of these cells by the potent angiogenic factor VEGF-A165, which also binds to VEGFR-1, does not alter the proliferation of the cells, it does increase adhesion to a model basement membrane-like extracellular matrix, Matrigel. VEGF-A165 also induces NK cell binding to human microvascular endothelial cells in newly forming but not established microvessels in vitro. These results suggest that human NK cells produce an angiogenic factor which may be involved in autocrine and paracrine regulations of angiogenesis. VEGF-A165 appears to stimulate NK cell adhesion to the microvasculature within established cancer metastases.
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PMID:Modulation of human NK cell lines by vascular endothelial growth factor and receptor VEGFR-1 (FLT-1). 1249 87

Angiogenesis is a process of development and of growth of new capillary blood vessels from pre-existing vessels. When pathological, it contributes to the development of numerous types of tumors, and the formation of metastases. In order to grow, carcinoma need new blood vessels to form so that they can feed themselves. Therefore, nowadays the concept according to which the development of cancer is angiogenesis dependent is generally recognized. This concept makes the control of tumoral angiogenesis one of the promising therapeutic ways in cancerology. The transition from the latent phase to the invasive and metastatic phase of a cancer is linked to what is called the angiogenic switch. It implies complex cellular and molecular interactions between cancerous cells, endothelial cells and the components of the extra-cellular matrix and namely the existence of specific proteins secreted by the tumoral cells able to stimulate the proliferation of capillary endothelial cells. Among them, VEGF, Vascular Endothelial Growth Factor was found in several types of tumors. It has shown a tumoral angiogenic activity in vitro and in vivo, and thus is a privileged target for the control of angiogenesis in an anti-tumoral goal. The role of VEGF in tumoral angiogenesis has been extensively studied. It has been proved to undergo as well autocrine as paracrine stimulation of tumoral angiogenesis. During the last few years, several members of the VEGF family have been described namely the VEGF-A, B, C, D, E and placenta growth factor (PlGF) among which VEGF-A (121 aminoacids) plays a role of prime importance in angiogenesis. VEGF is a 45 kDA glycoprotein, homodimeric, basic, and able to bind heparin. The three-dimensional structure of VEGF has been recently determined, by X-rays diffraction, and NMR spectroscopy. The different forms of the VEGF bind to receptors that exhibit a tyrosine-kinase activity (RTK). The specific action of the VEGF on the endothelial cells is mainly regulated by two types of RTK of the VEGF family, VEGFR1, or Flt-1, and VEGFR2, or KDR/Flk-1. Mutagenesis studies have shown that only a small number of VEGF residues are important and essential for the binding with RTK. Data described to date from the studies of VEGF/RTK interactions agree to the hypothesis that KDR receptor is the main human receptor responsible for the VEGF activity in both physiological and pathological vascular development, and VEGF-KDR signalling pathway has been validated as a priority target for the development of anti- and pro- angiogenic agents. Therefore angiogenesis mediated by VEGF constitutes a new target for anti-cancer therapy which has explored through different ways of intervention aiming at the blocking of the tumoral angiogenesis. The main ones are: -Struggle against the stroma degradation and invasion by the neo-vessels -Inhibition of activated endothelial cells. -Inhibition of angiogenic factors production and of their receptors. -Inhibition of the VEGF signal pathway, by peptides blocking the bond between VEGF and its receptors through the inhibition of intracellular transduction of VEGF signal. In conclusion, this bibliographic study allows to situate works of medicinal chemistry in the context of present knowledge concerning the vascular endothelial growth factor (VEGF) and its role in angiogenesis.
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PMID:Vascular endothelial cell growth factor (VEGF), an emerging target for cancer chemotherapy. 1267 5

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