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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Key growth factor-receptor interactions involved in angiogenesis are possible targets for therapy of CNS tumors. Vascular endothelial growth factor (VEGF) is a highly specific endothelial cell mitogen that has been shown to stimulate angiogenesis, a requirement for solid tumor growth. The expression of VEGF, the closely related placental growth factor (PIGF), the newly cloned endothelial high affinity VEGF receptors KDR and FLT1, and the endothelial orphan receptors FLT4 and Tie were analyzed by in situ hybridization in normal human brain tissue and in the following CNS tumors: gliomas, grades II, III, IV; meningiomas, grades I and II; and melanoma metastases to the cerebrum. VEGF mRNA was up-regulated in the majority of low grade tumors studied and was highly expressed in cells of malignant gliomas. Significantly elevated levels of Tie, KDR, and FLT1 mRNAs, but not FLT4 mRNA, were observed in malignant tumor endothelia, as well as in endothelia of tissues directly adjacent to the tumor margin. In comparison, there was little or no receptor expression in normal brain vasculature. Our results are consistent with the hypothesis that these endothelial receptors are induced during tumor progression and may play a role in tumor angiogenesis.
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PMID:Expression of endothelial cell-specific receptor tyrosine kinases and growth factors in human brain tumors. 785 49

Angiogenesis is a key step in organ development and remodelling during embryogenesis or tissue regeneration. Some pathological events such as tumor growth or diabetic retinopathy also lead to angiogenesis formation. Several molecules have already been identified as promoting angiogenesis in vivo. We have recently purified a new angiogenic growth factor. Its unique specificity for vascular endothelial cells led us to provisionally name it vasculotropin (VAS) or vascular endothelial growth factor (VEGF) or vascular permeability factor (VPF). In vitro, despite a moderate action on proliferation, VAS/VEGF strongly stimulates cell migration. In vivo, VAS/VEGF is a potent inducer of angiogenesis and vascular permeability. Its central role in angiogenesis is emphasized by the observation that its immunoneutralization prevents tumor progression.
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PMID:Regulations of vasculatropin/vascular endothelial growth factor bioavailability. 795 29

Endocrine organs, such as the pancreatic islets of Langerhans, contain permeable, fenestrated endothelium that allows direct access of endocrine cells to the blood stream. Factors that control differentiation and maintenance of this highly specialized endothelium remain unknown. Vascular endothelial growth factor (VEGF) is a multifunctional growth factor that may be responsible for the homeostasis of endocrine endothelium; it is a selective mitogen for endothelial cells and is able to permeabilize endothelium. We have analyzed the expression of VEGF mRNA and protein in pancreatic islet cells of normal mice and during the different stages of tumor progression in a transgenic mouse model of beta-cell carcinogenesis. The 120-amino acid and the 164-amino acid isoforms of VEGF are expressed in normal islets of Langerhans and are moderately up-regulated during the stages of tumor development. Two high-affinity receptors for VEGF, flt-1 and flk-1, are expressed by endothelial cells both in normal islets and in the stages of tumorigenesis; these receptors are not up-regulated during this process. Our data raise the possibility that VEGF is involved in the maintenance of permeable endothelium in islets of Langerhans, an observation that may have implications for islet cell physiology and diabetes. While VEGF may also play an important role in the growth of new blood vessels during islet cell tumorigenesis, it cannot be the only factor required for the activation of tumor angiogenesis.
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PMID:Vascular endothelial growth factor and its receptors, flt-1 and flk-1, are expressed in normal pancreatic islets and throughout islet cell tumorigenesis. 861 12

Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF) is a multifunctional cytokine which potently stimulates angiogenesis in vivo. VEGF/VPF expression is elevated in pathological conditions including cancer, proliferative retinopathy, psoriasis and rheumatoid arthritis. The angiogenesis associated with human tumors is likely a central component in promoting tumor growth and metastatic potential. The regulation of VEGF/VPF expression during tumor progression may involve diverse mechanisms including activated oncogenes, mutant or deleted tumor suppressor genes, cytokine activation, hormonal modulators, and a particularly effective activator, hypoxia. Understanding the diverse mechanisms by which tumor cells overexpress VEGF/VPF, and which mechanisms are operating in specific tumor types is important for the design of effective anti-cancer therapies.
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PMID:Regulation of VEGF/VPF expression in tumor cells: consequences for tumor growth and metastasis. 884 88

Arteriovenous malformations (AVMs) are congenital lesions composed of abnormal vasculature, with no capillary component, and are clinically significant due to their tendency to spontaneously hemorrhage. The mechanisms regulating the genesis and progression of these lesions are unknown. In order to study the role of angiogenesis in AVMs, we have analyzed the expression of the endothelial cell mitogen vascular endothelial growth factor (VEGF) and a novel endothelial cell-specific receptor tyrosine kinase, Tie, by in situ hybridization and immunohistochemistry in these malformations and surrounding brain tissue. We have previously shown upregulation of Tie accompanying wound healing and tumor progression. In this study, we demonstrate significantly elevated levels of Tie mRNA and protein in AVM and surrounding brain vasculature. Upregulation of VEGF mRNA was observed in the cells of brain parenchyma adjacent to the AVM, and VEGF protein was detected in this tissue as well as in AVM endothelia. Normal brain, in comparison, expressed little or no Tie or VEGF. The significant upregulation of VEGF and Tie in AVMs may indicate some ongoing angiogenesis, possibly contributing to the slow growth and maintenance of the AVM, and could be of potential use in the therapeutic targeting of these lesions.
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PMID:Tie endothelial cell-specific receptor tyrosine kinase is upregulated in the vasculature of arteriovenous malformations. 893 95

Angiogenesis is a crucial process for tumor growth and metastasis regulated by the balance of positive and negative factors. Vascular endothelial growth factor (VEGF/VPF) is a specific mitogen for endothelial cells that has been shown to be overexpressed in a variety of tumors and other inflammatory diseases. To analyze the implication of VEGF/VPF during tumorigenesis, we have studied its expression at different stages of tumor development using the mouse skin carcinogenesis model. VEGF/VPF mRNA was induced in skin in vivo after 12-O-tetradecanoylphorbol-13-acetate treatment. Constitutive up-regulation of VEGF/VPF at the mRNA and protein levels was also observed in premalignant papillomas and, at a higher level, in squamous carcinomas, suggesting a correlation between VEGF/VPF expression and tumor progression. A direct positive correlation between VEGF/VPF mRNA expression and the level of activated H-ras gene was found in a series of cell lines representing different stages of epidermal tumor development. Consequently, a clone of one of these cell lines, HaCa4, which has lost most of its v-ras expression, down-regulated VEGF mRNA expression concomitantly with its metastatic potential. Direct evidence of H-ras involvement in VEGF induction was obtained when an immortalized mouse keratinocyte cell line transduced with a retrovirus carrying v-H-ras showed highly increased VEGF/VPF mRNA levels. These data show that in mouse skin carcinogenesis, the VEGF/VPF angiogenic stimulus occurs early during premalignant papilloma development and further increases at later stages. Moreover, we demonstrate that increasing the activated H-ras dose, a phenomenon that takes place sequentially throughout mouse skin tumor development, may play an additional role by facilitating malignant in vivo progression through the modulation of VEGF/VPF-mediated angiogenesis.
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PMID:Up-regulation of vascular endothelial growth factor/vascular permeability factor in mouse skin carcinogenesis correlates with malignant progression state and activated H-ras expression levels. 896 91

Hypoxia-induced neovascularization mediated by vascular endothelial growth factor (VEGF) contributes to tumor progression. Based on its effects when overexpressed in transient transfection assays, p53 has been proposed to repress VEGF transcription. To investigate this hypothesis, we have analyzed endogenous VEGF mRNA levels in Hep3B cells stably expressing an inducible p53-estrogen receptor fusion protein and in irradiated RKO cells expressing endogenous wild-type p53. In both cell lines, VEGF mRNA levels increased in response to hypoxia, either in the presence or absence of functional p53. Our data provide no evidence for a causal relationship between the loss of p53 activity and increased VEGF expression that is observed during tumor progression. Studies that attribute repressor functions to p53 based on analysis of cells transiently overexpressing this protein should be interpreted cautiously.
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PMID:p53 does not repress hypoxia-induced transcription of the vascular endothelial growth factor gene. 937 55

The infection of normal mouse mammary EF43 cells by a retroviral vector carrying either Fgf-3 (EF43.Fgf-3) or Fgf-4 (EF43.Fgf-4) cDNA resulted in the transformation of cells displaying different tumorigenic potentials in nude mice (A. Hajitou and C-M. Calberg-Bacq, Int. J. Cancer, 63: 702-709, 1995). EF43.Fgf-4 produced rapidly developing tumors at all sites of inoculation, whereas EF43.Fgf-3 produced slowly growing tumors only in the mammary fat pad. Cells infected with the vector carrying the selection gene alone (EF43.C) were not tumorigenic. The angiogenic properties of these cells were tested in an in vitro angiogenesis model using human umbilical vein endothelial cells (HUVECs) cultured at the surface of a type I collagen gel and their capacity to form tube-like structures on invasion of the gel. Only the conditioned medium (CM) of EF43.Fgf-4 induced an angiogenic morphotype in HUVECs. In parallel, the mRNA expression of matrix metalloproteinase 1 and c-ETS-1 was increased in the HUVECs displaying a differentiated phenotype, whereas the tissue inhibitor of matrix metalloproteinase 1 mRNA level was decreased. Recombinant human fibroblast growth factor 4 (FGF-4) did not induce an angiogenic phenotype in HUVECs by itself. By Western blot analysis, a high expression of vascular endothelial growth factor (VEGF) was detected in the EF43.Fgf-4 CM. This result was confirmed by Northern blot analysis of total RNA extracted from the three cell types; the steady-state level of VEGF mRNA was low and equivalent in EF43.C and EF43.Fgf-3, whereas it was strongly increased in EF43.Fgf-4. Culturing EF43 cells carrying only the selection gene with increasing concentrations of recombinant human FGF-4 resulted in a dose-dependent stimulation of VEGF. The induction of the angiogenic morphotype and the parallel modulations of the biosynthetic phenotype in HUVECs were completely suppressed by adding a neutralizing antibody directed against VEGF to EF43.Fgf-4 CM. Furthermore, inhibition of protein kinase C by bisindoylmaleimide suppressed the angiogenic phenotype induced by the CM of EF43.Fgf-4. Our results point to an indirect angiogenic activity of FGF-4 through the autocrine induction of VEGF secretion by EF43.Fgf-4 cells, an original signaling pathway that might be significant in tumor progression and metastasis.
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PMID:Angiogenesis by fibroblast growth factor 4 is mediated through an autocrine up-regulation of vascular endothelial growth factor expression. 940 72

Vascular endothelial growth factor (VEGF) is an angiogenic factor secreted by various tumors, including epithelial tumors of the ovary, and is involved in tumor progression and maintenance. The significance and function of other members of the VEGF family in the ovary has not yet been elucidated. In the present study, we have defined the expression of mRNA encoding VEGF-B, VEGF-C, and placenta growth factor (PIGF), compared with that of VEGF mRNA, in normal ovary and a range of ovarian epithelial tumors. Analysis by reverse transcription-PCR indicated that mRNA encoding VEGF (isoforms 121 and 165), VEGF-B (isoforms 167 and 186), and VEGF-C, but not PIGF, were present in all ovarian tissues examined. By in situ hybridization, neither VEGF-C nor PIGF transcripts were detected in any of the samples. The expression pattern of VEGF-B mRNA was generally similar to that of VEGF mRNA, in that transcripts were readily detected in the epithelial cells of all histologic types of ovarian carcinoma, but could not be detected in normal or benign tumor epithelium. Specific differences in the expression of the two genes were noted in areas of tumor necrosis, in which the expression of VEGF mRNA, but not VEGF-B mRNA, was further enhanced, and in a sample in which VEGF-B mRNA was strongly expressed in tumor-associated macrophages that did not hybridize with the riboprobe to VEGF mRNA. These results imply that a second member of the VEGF family, VEGF-B, may play a significant role in the angiogenesis, progression, and maintenance of ovarian carcinomas.
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PMID:Expression and localization of the vascular endothelial growth factor family in ovarian epithelial tumors. 942 98

The purpose of this study was to determine the angiogenic profile of human esophageal carcinomas. The expression of vascular endothelial growth factor (VEGF) was examined in 6 esophageal carcinoma cell lines and 119 human esophageal carcinoma tissues by Northern blot analysis and immunohistochemistry, respectively. Immunohistochemistry using antibodies against CD34 (endothelial cell specific) was carried out on archival specimens, and microvessels were quantitated by counting vessels in a x200 field in the most vascular area of the tumor. All of the cell lines constitutively expressed VEGF mRNA at various levels. A total of 71 of 119 (59.7%) tumors showed intense VEGF immunoreactivity in the cytoplasm of cancer cells. Vessel count was significantly higher in the VEGF-positive tumors than it was in the VEGF-negative tumors. VEGF expression correlated with the depth of tumor invasion, tumor stage, venous invasion, and lymphatic invasion. The survival rate of patients with high vessel density in the tumor was significantly worse than that of patients with low vessel density in the tumor. There was a tendency for poorer prognosis in the group with VEGF-positive tumors compared with that of the group with VEGF-negative tumors. Overall, these results suggest that VEGF is associated with tumor progression by stimulating angiogenesis in human esophageal carcinoma.
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PMID:Significance of vessel count and vascular endothelial growth factor in human esophageal carcinomas. 974 39


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