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

Macrophages are supposed to play a key role in inflammatory and tumor angiogenesis. Their importance derives from (1) their ubiquitous presence in normal and especially inflamed tissues, (2) their potential to become activated in response to appropriate stimuli, and (3) their repertoire of secretory products. By release of proteases, growth factors (bFGF, GM-CSF, TGF-alpha, IGF-I, PDGF, VEGF/VPF, TGF-beta), and other monokines (IL-1, IL-6, IL-8, TNF-alpha, substance P, prostaglandins, interferons, thrombospondin 1), activated macrophages have the capability to influence each phase of the angiogenic process, such as alterations of the local extracellular matrix, induction of endothelial cells to migrate or proliferate, and inhibition of vascular growth with formation of differentiated capillaries. This review describes macrophage physiology and the influence of macrophage secretory products on the different phases of angiogenesis in vitro and in vivo.
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PMID:Macrophages and angiogenesis. 750 44

In primary malignant brain tumors increased vascularity and marked edema strongly suggest a possible role of the vascular endothelial growth factor/vascular permeability factor (VEGF/VPF). This was confirmed by earlier in situ hybridization studies, by analysis of the expression of the mitogen in different subsets of glioblastoma cells, and by the fact that the VEGF/VPF receptor flt-1 (fms-like tyrosine kinase) is up-regulated in tumor cells in vivo. To assess and quantify the expression of the VEGF/VPF gene and of the receptor gene, 26 surgical specimens of brain tumor tissue from 24 patients were analyzed. In most malignant gliomas, the expression level of the VEGF/VPF gene is elevated and can be increased up to 20- to 50-fold in comparison with low-grade tumors. Using polymerase chain reaction-based amplification, it could be shown that the messenger RNAs of three different VEGF/VPF forms are synthesized in tumor tissue samples. Northern blot studies revealed that in some samples a significant expression of the gene coding for placenta growth factor, a growth factor closely related to VEGF/VPF, was observed. In addition, using a radioreceptor assay it was possible to detect high VEGF/VPF-like activity in the cyst fluids of brain tumors, indicating the accumulation of the mitogen and permeability factor in brain tumor cysts. Further investigations revealed that astrocytoma and glioblastoma cells in culture express the VEGF/VPF gene and secrete the VEGF/VPF protein, whereas gene expression of the two known VEGF/VPF receptors, kinase insert domain-containing receptor and flt-1, could not be detected. These data support previous reports, which stated that VEGF/VPF acts as a paracrine growth and permeability factor in brain tumors and may contribute to tumor growth by initiating tumor angiogenesis.
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PMID:Detection and quantification of vascular endothelial growth factor/vascular permeability factor in brain tumor tissue and cyst fluid: the key to angiogenesis? 752 59

The growth of solid tumors in vivo beyond 1-2 mm in diameter requires induction and maintenance of an angiogenic response. This can occur through the release of various angiogenic growth factors from tumor cells. One such factor is vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), a secreted and specific mitogen for vascular endothelial cells. We show that one of the most commonly encountered genetic changes detected in human cancer, i.e., expression of mutant ras oncogenes, is associated with marked up-regulation of VEGF/VPF in transformed epithelial cells. Thus, elevation of the levels of both VEGF/VPF mRNA and secreted functional protein were detected in human and rodent tumor cell lines expressing mutant K-ras or H-ras oncogenes, respectively. Genetic disruption of the mutant K-ras allele in human colon carcinoma cells was associated with a reduction in VEGF/VPF activity. Furthermore, pharmacological disruption of mutant RAS protein function in H-ras transformed rat intestinal epithelial cells by treatment with L-739,749 (a protein farnesyltransferase inhibitor) caused a significant suppression of VEGF/VPF. The results suggest that dominantly acting ras oncogenes may contribute to the growth of solid tumors in vivo not only by a direct effect on tumor cell proliferation but also indirectly, i.e., by facilitating tumor angiogenesis. Hence, pharmacologically targeting mutant ras oncogenes could conceivably suppress solid tumor growth in vivo, in part, by inhibiting tumor-induced angiogenesis.
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PMID:Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. 755 32

We elucidated the relationship between vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), which is a potent angiogenic factor, and the growth of primary and metastatic tumors using an immunoneutralizing monoclonal antibody against human VEGF/VPF121. The monoclonal antibody, MV303, suppressed the growth of human umbilical vein endothelial cells (HUVEC) induced by VEGF/VPF121 or VEGF/VPF165 but did not inhibit its growth induced by basic fibroblast growth factor. MV303 inhibited the binding of 125I-VEGF/VPF121 to HUVEC. We examined the effects of MV303 on tumor angiogenesis using a membrane chamber packed with the human fibrosarcoma cell line HT-1080 and implanted s.c. into BALB/c mice. The neovascularization induced by HT-1080 was inhibited by the i.v. injection of MV303 at a dose of 100 micrograms/mouse. Furthermore, the growth of solid tumors of s.c. implanted HT-1080 in BALB/c nude mice was almost completely inhibited by the i.v. and s.c. administration of MV303 ten times from day 1 at a dose of 100 micrograms/mouse (T/C values of tumor volume at day 18 were 0.20 and 0.18, respectively). Tumor growth was suppressed when MV303 was administered, even from eight days after tumor inoculation. MV303 suppressed the increase in lung weight caused by experimental metastasis with i.v. inoculation of cultured HT-1080 cells to BALB/c nude mice. The life spans of the mice treated with MV303 were significantly prolonged. These results indicated that VEGF/VPF played an important role in both primary and metastatic tumor growth as a tumor angiogenesis factor. MV303, an immunoneutralizing monoclonal antibody against VEGF/VPF, potently inhibited both primary and metastatic tumor growth with no marked side effects.
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PMID:Inhibition of tumor growth and metastasis by an immunoneutralizing monoclonal antibody to human vascular endothelial growth factor/vascular permeability factor121. 758 91

Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is an endothelial cell-specific mitogen that is structurally related to platelet-derived growth factor (PDGF). Vascular endothelial growth factor/vascular permeability factor induces angiogenesis in vivo and may play a critical role in tumor angiogenesis. Using immunohistochemical analysis, the authors demonstrated the presence of VEGF/VPF protein in surgical specimens of glioblastoma multiforme and cultured glioma cells. By means of an enzyme-linked immunosorbent assay (ELISA) of cell supernatants, the authors showed that VEGF/VPF is variably secreted by all nine cultured human malignant glioma cell lines (CH-235MG, D-37MG, D-54MG, D-65MG, U-87MG, U-105MG, U-138MG, U-251MG, U-373MG) and by a single meningioma cell line (CH-157MN). An immunocytochemical survey of these cell lines revealed a cytoplasmic and cell-surface distribution of VEGF/VPF. In the U-105MG glioma cell line, VEGF/VPF secretion was induced with physiological concentrations of epidermal growth factor, PDGF-BB, or basic fibroblast growth factor, but not with PDGF-AA. Moreover, it was observed that activation of convergent growth factor signaling pathways led to increased glioma VEGF secretion. Similar results were obtained using these growth factor combinations in the D-54MG glioma cell line. The data obtained suggest a potential role for VEGF/VPF in tumor hypervascularity and peritumoral edema. These observations may lead to development of new therapeutic strategies.
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PMID:Vascular endothelial growth factor in human glioma cell lines: induced secretion by EGF, PDGF-BB, and bFGF. 771 13

Vascular permeability factor (VPF, also known as vascular endothelial growth factor or VEGF), is a potent microvascular permeability enhancing cytokine and a selective mitogen for endothelial cells. It has been implicated in tumor angiogenesis and ascites fluid accumulation. Since development of the destructive synovial pannus in rheumatoid arthritis (RA) is associated with changes in vascular permeability (synovial fluid accumulation), synovial cell hyperplasia, and angiogenesis, we examined synovial fluids (SFs) and joint tissue for the expression and local accumulation of VPF/VEGF. VPF/VEGF was detected in all of 21 synovial fluids examined and when measured by an immunofluorimetric assay, ranged from 6.9 to 180.5 pM. These levels are biologically significant, since < 1 pM VPF/VEGF can elicit responses from its target cells, endothelial cells. Levels of VPF/VEGF were highest in rheumatoid arthritis fluids (n = 10), with a mean value (+/- SEM) of 59.1 +/- 18.0 pM, vs. 21.4 +/- 2.3 pM for 11 SFs from patients with other forms of arthritis (p = 0.042). In situ hybridization studies that were performed on joint tissues from patients with active RA revealed that synovial lining macrophages strongly expressed VPF/VEGF mRNA, and that microvascular endothelial cells of nearby blood vessels strongly expressed mRNA for the VPF/VEGF receptors, flt-1 and KDR. Immunohistochemistry performed on inflamed rheumatoid synovial tissue revealed that the VPF/VEGF peptide was localized to macrophages within inflamed synovium, as well as to microvascular endothelium, its putative target in the tissue. Together, these findings indicate that VPF/VEGF may have an important role in the pathogenesis of RA.
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PMID:Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue. 800 92

The growth factor receptors expressed on endothelial cells are of special interest because of their potential to program endothelial cell growth and differentiation during development and neovascularization in various pathological states, such as wound healing and angiogenesis associated with tumorigenesis. Vascular endothelial growth factor ([VEGF] also known as vascular permeability factor) is a potent mitogen and permeability factor, which has been suggested to play a role in embryonic and tumor angiogenesis. The newly cloned FLT4 receptor tyrosine kinase gene encodes a protein related to the VEGF receptors FLT1 and KDR/FLK-1. We have here studied the expression of FLT4 and the other two members of this receptor family in human fetal tissues by Northern and in situ hybridization. These results were also compared with the sites of expression of VEGF and the related placenta growth factor (PlGF). Our results reveal FLT4 mRNA expression in vascular endothelial cells in developing vessels of several organs. A comparison of FLT4, FLT1 and KDR/FLK-1 receptor mRNA signals shows overlapping, but distinct expression patterns in the tissues studied. Certain endothelia lack one or two of the three receptor mRNAs. These data suggest that the receptor tyrosine kinases encoded by the FLT gene family may have distinct functions in the regulation of the growth/differentiation of blood vessels.
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PMID:The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells. 824 83

Angiogenesis is a critical factor in the growth, progression, and metastatic spread of solid tumors. Furthermore, angiogenesis has been correlated with prognosis in patients with ovarian cancer. The pathogenesis of the angiogenic events in ovarian cancer, however, are not well defined. Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is a multifunctional cytokine that has been shown to be an important regulator of tumor angiogenesis. The purpose of the present study was to define the expression of VPF/VEGF and its receptors flt-1 and KDR in ovarian tumors. Four specimens of normal ovarian cortex and 41 specimens of benign (4), borderline (8), and malignant (29) ovarian tumors were studied by in situ hybridization, and in some cases by immunohistochemical analysis. VPF/VEGF protein was also determined by an immunofluorometric assay in cyst fluids obtained from 11 patients, including 7 benign, 2 borderline, and 2 malignant tumors. VPF/VEGF mRNA and protein were expressed by the neoplastic cells in all of the malignant tumors evaluated, with the majority of tumors (28 of 29) showing strong expression of mRNA. Serous borderline tumors had variable VPF/VEGF mRNA expression, with two of six cases showing focal strong expression and four showing low-level expression. No definite expression of VPF/VEGF was seen in two cases of mucinous borderline tumors. No strong expression of VPF/VEGF mRNA was observed in normal ovarian cortex, including surface epithelium, or benign tumors. Substantially higher VPF protein concentrations were detected in cyst fluids of the two malignant (60, 440 pM) and two borderline tumors (210, 590 pM) than in the seven benign serous cysts (mean, 10 +/- 3 pM). In addition, microvascular endothelial cells strongly expressed mRNA of the VPF/VEGF receptors flt-1 and KDR and immunostained for VPF/VEGF protein in the majority of malignant and borderline tumors examined. These findings suggest that VPF/VEGF plays an important role in the angiogenesis associated with ovarian neoplasms.
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PMID:Strong expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in ovarian borderline and malignant neoplasms. 866 14

In the present study, we evaluated the effects of a neutralizing antivascular endothelial growth factor (anti-VEGF) antibody on angiogenesis and growth of tumor spheroids using an intravital microscopic technique permitting noninvasive, in vivo and in situ study of tumor angiogenesis and tumor growth in conscious mice. Tumor spheroids of the human rhabdomyosarcoma cell line A673, with a diameter between 600 and 1000 microns, were implanted in dorsal skinfold chambers inserted on Beige nude/xid mice. Tumor cells were prelabeled with a fluorescent vital dye [(5-(and-6)-((4-chloromethyl)benzoyl)amino)tetramethylrhodamine], which allowed estimation of the growth of the implanted tumor spheroids. Treatment (i.p.) with the monoclonal antibody A4.6.1, specific for VEGF, completely inhibited neovascularization of the microtumors and suppressed their growth to the extent that tumors implanted in treated animals leveled off at a volume less than 1 mm3, i.e., the anti-VEGF antibody dramatically changed the growth characteristics of the tumor line from being a rapidly growing malignancy to a dormant microcolony.
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PMID:Complete inhibition of angiogenesis and growth of microtumors by anti-vascular endothelial growth factor neutralizing antibody: novel concepts of angiostatic therapy from intravital videomicroscopy. 875 75

Several groups have shown that quantitation of tumor angiogenesis by counting blood vessels in primary breast cancer gives an independent assessment of prognosis. Poor prognosis is associated with high blood vessel counts. We have shown that the rate of cell division in endothelial cells is much higher in breast tumours than in normal breast. Breast cancer cell lines and primary human breast tumours express a wide range of vascular growth factors, including VEGF, placenta growth factor, pleiotrophin, TGF beta 1, acidic and basic FGF, and platelet-derived endothelial cell growth factor. Inhibiting angiogenesis by blocking vascular growth factors would be difficult with highly specific agents, but drugs with a broader spectrum of antagonism may be effective. We have developed several suramin analogues which are less toxic than suramin in vivo but more potent in inhibiting angiogenesis, and these have been developed for Phase I. A combination of anti-angiogenesis agents with drugs activated by hypoxia may also be useful, because anti-angiogenesis alone may not kill cells, whereas activation of hypoxic drugs could synergize. New endpoints may be necessary because inhibition of new blood vessel formation may not cause tumour regression. Thus, the endpoint of stable disease and biochemical assessment of inhibition of angiogenesis may be much more important in therapeutic studies and for drug development in the future. The prognostic importance of angiogenesis suggests that this should be a major new therapeutic target.
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PMID:Breast cancer angiogenesis--new approaches to therapy via antiangiogenesis, hypoxic activated drugs, and vascular targeting. 882 27


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