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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular permeability factor (VPF) is one of the most potent known inducers of microvascular hyperpermeability; in addition, it is a selective endothelial cell growth factor, hence its alternate name, vascular endothelial growth factor. VPF exerts its actions on the microvasculature by interacting with specific endothelial cell receptors. VPF is expressed by many transplantable animal tumors, by tumor cell lines in culture, and by certain normal cells in situ. The purpose of the present investigation was to determine whether and with what consistency VPF and its endothelial cell receptors are expressed in primary autochthonous human tumor of gastrointestinal tract origin, as determined by in situ hybridization and immunohistochemistry. Twenty-one primary adenocarcinomas (17 colon, 2 stomach, 1 small bowel, and 1 pancreas) were studied. The malignant epithelial cells expressed VPF mRNA strongly, in contrast to normal epithelium, hyperplastic polyps, and adenomas, which expressed little or no VPF mRNA. VPF expression was further increased in tumor cells immediately adjacent to zones of tumor necrosis; in such areas, occasional stromal cells also expressed VPF mRNA. In the ten colon carcinomas studied, tumor cells stained for VPF protein by immunohistochemistry. The endothelial cells of nearby stromal blood vessels also stained for VPF by immunohistochemistry and in addition expressed mRNAs encoding the VPF receptors flt-1 and kdr as determined by in situ hybridization. Endothelial cells away from the tumor did not stain for VPF and no definite mRNA expression for flt-1 or kdr was detected by in situ hybridization. The ganglion cells of the myenteric plexus of normal bowel expressed VPF mRNA and protein. These data indicate that primary autochthonous human tumors of gastrointestinal origin regularly express both VPF mRNA and VPF protein and that adjacent stromal vessels express mRNAs for both known VPF receptors. VPF is likely to contribute to tumor growth by promoting angiogenesis and stroma formation, both directly, through its action as an endothelial cell growth factor, and indirectly, by increasing vascular permeability, thereby leading to plasma protein extravasation, fibrin deposition, and the eventual replacement of the resulting matrix with vascularized stroma.
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PMID:Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract. 840 50

Vascular permeability factor (VPF), also known as vascular endothelial growth factor, is a dimeric M(r) 34,000-42,000 glycoprotein that possesses potent vascular permeability-enhancing and endothelial cell-specific mitogenic activities. It is synthesized by many rodent and human tumor cells and also by some normal cells. Recently we developed a sensitive and specific time-resolved immunofluorometric assay for quantifying VPF in biological fluids. We here report findings with this assay in guinea pigs and patients with both malignant and nonmalignant effusions. Line 1 and line 10 tumor cells were injected into the peritoneal cavities of syngeneic strain 2 guinea pigs, and ascitic fluid, plasma, and urine were collected at various intervals. Within 2 to 4 days, we observed a time-dependent, parallel increase in VPF, ascitic fluid volume, and tumor cell numbers in animals bearing either tumor line; in contrast, VPF was not detected in plasma or urine, even in animals with extensive tumor burdens. However, low levels of VPF were detected in the inflammatory ascites induced by i.p. oil injection. In human studies, high levels of VPF (> 10 pM) were measured in 21 of 32 effusions with cytology-documented malignant cells and in only seven of 35 effusions without cytological evidence of malignancy. Thus, VPF levels in human effusions provided a diagnostic test for malignancy with a sensitivity of 66% and a specificity of 80% (perhaps as high as 97% in that six of the seven cytology-negative patients with VPF levels > 10 pM had cancer as determined by other criteria). As in the animal tumor models, VPF was not detected in serum or urine obtained from patients with or without malignant ascites. Many nonmalignant effusions contained measurable VPF but, on average, in significantly smaller amounts than were found in malignant effusions. VPF levels in such fluids correlated strongly (p = 0.59, P < 0.001) with monocyte and macrophage content. Taken together, these data relate ascitic fluid accumulation to VPF concentration in a well-defined animal tumor system and demonstrate, for the first time, the presence of VPF in human malignant effusions. It is likely that VPF expression by tumor and mononuclear cells contributes to the plasma exudation and fluid accumulation associated with malignant and certain inflammatory effusions. The VPF assay may prove useful for cancer diagnosis as a supplement to cytology, especially in tumors that grow in the pleural lining but not as a suspension in the effusions that they induce.
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PMID:Vascular permeability factor (vascular endothelial growth factor) in guinea pig and human tumor and inflammatory effusions. 850 32

This review of angiogenesis aims to describe (a) stimuli that either elicit or antagonize angiogenesis, (b) the response of the vasculature to angiogenic or anti-angiogenic stimuli, i.e., processes required for the formation of new vessels, (c) aspects of angiogenesis relating to tissue remodeling and disease, and (d) the potential of angiogenic or antiangiogenic therapeutic measures. Angiogenesis, the formation of new vessels from existing microvessels, is important in embryogenesis, wound healing, diabetic retinopathy, tumor growth, and other diseases. Hypoxia and other as yet ill-defined stimuli drive tumor, inflammatory, and connective tissue cells to generate angiogenic molecules such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), transforming growth factor-beta (TGF-beta), platelet-derived growth factor (PDGF), and others. Natural and synthetic angiogenesis inhibitors such as angiostatin and thalidomide can repress angiogenesis. Angiogenic and antiangiogenic molecules control the formation of new vessels via different mechanisms. VEGF and FGF elicit their effects mainly via direct action on relevant endothelial cells. TGF-beta and PDGF can attract inflammatory or connective tissue cells which in turn control angiogenesis. Additionally, PDGF may act differently on specific phenotypes of endothelial cells that are engaged in angiogenesis or that are of microvascular origin. Thus phenotypic traits of endothelial cells committed to angiogenesis may determine their cellular responses to given stimuli. Processes necessary for new vessel formation and regulated by angiogenic/antiangiogenic molecules include the migration and proliferation of endothelial cells from the microvasculature, the controlled expression of proteolytic enzymes, the breakdown and reassembly of extracellular matrix, and the morphogenic process of endothelial tube formation. In animal models some angiogenesis-dependent diseases can be controlled via induction or inhibition of new vessel formation. Life-threatening infantile hemangiomas are a first established indication for antiangiogenic therapy in humans. Treatment of other diseases by modulation of angiogenesis are currently tested in clinical trials. Thus the manipulation of new vessel formation in angiogenesis-dependent conditions such as wound healing, inflammatory diseases, ischemic heart and peripheral vascular disease, myocardial infarction, diabetic retinopathy, and cancer is likely to create new therapeutic options.
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PMID:Angiogenesis: mechanistic insights, neovascular diseases, and therapeutic prospects. 852 Sep 66

Angiogenesis, the development of new capillaries, is tightly controlled by the balance of positive and negative regulatory pathways. A newly described angiogenic factor, vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), binds exclusively to endothelial cells and promotes their proliferation. Here we have studied the role of p53, a tumor suppressor, and v-Src, an oncogene on VEGF regulation. Wild-type p53 down-regulated endogenous VEGF mRNA level, as well as VEGF promoter activity, in a dose-dependent manner, whereas mutant forms of p53 had no effect. Overexpression of v-Src, known to up-regulate VEGF expression, activated a VEGF promoter-luciferase construct in a dose-dependent manner. Moreover, v-Src, in the presence of wt-p53, was unable to activate transcription of the VEGF promoter. Collectively, these data suggest that wild-type p53 may play a role in suppressing angiogenesis.
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PMID:Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. 852 8

We have investigated the hypoxia inducibility of vascular endothelial growth factor (VEGF) in multicellular tumor spheroids of HT29 cells using a monoclonal antibody to a fluorinated bioreductive drug, EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)aceta mide], a chemical probe for hypoxia. We have shown that VEGF expression is predominantly localized in interior spheroid cells that are sufficiently hypoxic to bioreductively activate the 2-nitroimidazole and produce immunologically detectable adducts of the EF5 compound. Northern blotting analyses demonstrated that VEGF165 is the predominant form of VEGF produced by HT29 cells and that the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate did not induce VEGF expression. This study demonstrates that VEGF expression is up-regulated in response to hypoxia and in the microenvironments found in human multicellular tumor spheroids. This investigation also illustrates the utility of the EF5 binding in multi-cellular tumor spheroids as a means of studying the expression and regulation of hypoxia-inducible genes.
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PMID:Mapping of the vascular endothelial growth factor-producing hypoxic cells in multicellular tumor spheroids using a hypoxia-specific marker. 852 17

At present the most used method to quantify tumor angiogenesis in human solid tumors is the count of intratumoral microvessels in the primary lesion. This method requires the use of specific markers to vascular endothelium and of immunohistochemical procedures to visualize microvessels. Several studies have found that intratumoral microvessel density (IMD) determined in the primary tumor is significantly associated with metastasis and prognosis in some solid neoplasia, particularly in operable breast carcinoma. The subjective evaluation of IMD made by two observers at the microscope is rapid and of low cost, but presents some difficulties, mainly the identification of the most vascularized area ("hot-spot") within each tumor. This method can be improved upon to attain a better reproducibility among different pathologists. For example, the use of a multiparametric computerized image analysis system (CIAS) seems to be a promising tool to improve accuracy, feasibility and reproducibility of microvessel counts, although there are still some open technical problems to completely automate its use. Angiogenic activity is the result of a balance between angiogenic stimuli and angio-inhibition. Therefore the determination of angiogenic peptides and/or natural angiogenesis inhibitors in the tumor tissue, serum, or urine of cancer patients seems to be a promising alternative to microvessel counting. At present it is possible to determine the expression of basic fibroblast growth factor (bFGF), vascular endothelial growth factor, and transforming growth factor beta using immunohistochemical methods. Serum and urine levels of bFGF can be assessed using an immunoenzymatic assay. Methods used to assess the expression and levels of urokinase-type plasminogen activator (uPA) or plasminogen activator inhibitor-1 (PAI-1) have also been developed, and correlate with angiogenic activity and prognosis of patients with breast cancer. Finally, some investigational methods to assess angiogenesis in vivo are presented and discussed. Angiogenesis is a very complex phenomenon. Thus it seems reasonable to hypothesize that its assessment by using concurrently several of the available methods may provide more valid, accurate, and comprehensive information on the angiogenic activity of each single tumor. For a reliable and reproducible assessment of angiogenesis for all of the assays, validation procedures and quality control protocols are mandatory.
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PMID:Novel methods for the determination of the angiogenic activity of human tumors. 853 66

Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) is an angiogenic cytokine expressed by many human and animal tumors. Hypoxia often up-regulates VPF/VEGF expression further. To better define the role of VPF/VEGF in tumor biology, we screened tumorigenic lines for those expressing minimal constitutive and hypoxia-inducible VPF/VEGF. Human melanoma SK-MEL-2 cells best fit these criteria and formed small, poorly vascularized tumors in immunodeficient mice. We transfected SK-MEL-2 cells stably with sense or antisense mouse VPF/VEGF cDNA or with vector alone. Cells transfected with sense VPF/VEGF (V+) expressed and secreted large amounts of mouse VPF/VEGF and formed well-vascularized tumors with hyperpermeable blood vessels and minimal necrosis in nude/SCID mice. Antisense-transfected VPF/VEGF (V-) cells expressed reduced constitutive VPF/VEGF and no detectable mouse VPF/VEGF, and formed small, minimally vascularized tumors exhibiting extensive necrosis. Vector-alone transfectants (N1 cells) behaved like parental cells. V+ cells formed numerous lung tumor colonies in SCID mice, approximately 50-fold more than N1 cells, whereas V- cells formed few or none. These experiments demonstrate that VPF/VEGF promotes melanoma growth by stimulating angiogenesis and that constitutive VPF/VEGF expression dramatically promotes tumor colonization in the lung.
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PMID:Expression of vascular permeability factor/vascular endothelial growth factor by melanoma cells increases tumor growth, angiogenesis, and experimental metastasis. 854 60

Tumour-secreted vascular endothelial growth factor (VEGF) exerts a number of effects which are important in tumour pathology, including stimulation of angiogenesis and permeabilisation of tumour-associated vasculature. In this study we have examined the possibility that VEGF may also play an autocrine role in tumour growth. Using reverse-transcriptase polymerase chain reaction (RT-PCR), the expression of VEGF was found in 15/15 human tumour cell lines examined, while the VEGF receptor KDR was detected only in three melanoma cell lines (MeWo and A375, both wild type and metastatic variant). Exogenously added VEGF (10ng/ml) was able to stimulate up to 40% increased proliferation of A375 M melanoma cells following a 48-h period of quiescence, suggesting that VEGF may indeed play a role in autocrine, as well as paracrine, stimulation of melanoma growth.
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PMID:Melanoma cell lines express VEGF receptor KDR and respond to exogenously added VEGF. 855 90

Biopsies from 25 juvenile nasopharyngeal angiofibromas (JNAs) and respective normal inferior turbinates were examined and compared. The expression patterns of the messenger RNAs (mRNAs) for various growth factors possibly involved in the growth of mesenchymal cells, as well as angiogenesis and fibrosis, were also compared. These growth factors included insulin-like growth factor II (IGF-II), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), transforming growth factors-beta1 (TGF-beta1) and platelet-derived growth factors (PDGF-A and PDGF-B). Quantification of mRNA coding for proto-oncogenes and suppressor genes related to proliferation (i.e., c-myc, c-fos, p53) was also undertaken. Tumor and turbinates expressed similar levels of bFGF, VEGF, TGF-beta1, c-myc, c-fos, and PDGF-A mRNAs. The presence of TGF-beta1 protein was confirmed by immunohistochemistry in several structures that characterize the lesions of JNA, which suggests that TGF-beta1 may play a role in the development of the fibrous component of this tumor. PDGF-B and p53 were overexpressed (i.e., twice the mean level found in turbinates) in 50% and 32% of JNAs, respectively but there was no statistical significance when compared with controls. Statistically significant increased expression of IGF-II mRNA was observed in JNA (P = .04). IGF-II mRNA levels were correlated to p53 (P = .05) and PDGF-B (P = .034), indicating a possible synergistic action of such factors in JNA. The results of this study suggest that IGF-II might be a potential growth regulator of nasopharyngeal angiofibromas.
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PMID:Expression of growth factors, proto-oncogenes, and p53 in nasopharyngeal angiofibromas. 858 52

One event that accompanies glioma progression is the upregulation of angiogenesis. Low-grade gliomas are moderately vascularized tumors whereas high-grade gliomas show prominent microvascular proliferations and areas of high vascular density. To analyze the molecular mechanisms underlying glioma angiogenesis, we studied the expression of vascular endothelial growth factor (VEGF) and its tyrosine kinase receptors VEGFR-1 and VEGFR-2 during normal brain development and glioma-induced angiogenesis. Our results suggest a paracrine control of angiogenesis and endothelial cell proliferation that is tightly regulated and transient in the embryonic brain, switched off in the normal adult brain, and turned on in tumor cells (VEGF) and the host vasculature (VEGFR-1 and -2) during tumor progression. It is unknown how VEGF and VEGF receptors are upregulated during glioma angiogenesis, but there is recent evidence that VEGF as well as endogenous inhibitors of angiogenesis could be under control of the tumor suppressor genes p53 and VHL.
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PMID:Angiogenesis in malignant gliomas. 858 68


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