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

Previously, we induced vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) secretion in glioma cell lines by using physiologic concentrations of epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), or platelet-derived growth factor-BB (PDGF-BB). We hypothesized that VEGF/VPF might enhance the blood supply required for the unregulated growth of tumors, and that it acts as the central mediator of tumor angiogenesis. The objective of this study was to determine whether the expression of VEGF/VPF by meningiomas is regulated by growth factors or sex hormones. By means of an enzyme-linked immunosorbent assay of CH-157MN meningioma cell supernatants, we demonstrated that EGF and bFGF similarly induce VEGF secretion by CH-157MN meningioma cells. At the maximum concentrations of EGF (50 ng/mL) and bFGF (50 ng/mL) used in this study, VEGF secretion was induced to 140% to 160% above baseline constitutive secretion. PDGF-BB homodimer did not enhance VEGF secretion significantly. Estradiol (up to 10(-7) mol/L), progesterone (up to 10(-5) mol/L), or testosterone (up to 10(-5) mol/L) did not stimulate or inhibit VEGF secretion in CH-157MN meningioma cells (p > 0.05). Furthermore, we demonstrated that dexamethasone decreased VEGF secretion to 32% of baseline constitutive secretion. This might explain the effect of corticosteroids in alleviating peritumoral brain edema in meningiomas. These results suggest that VEGF secretion in CH-157MN meningioma cells is mainly regulated by growth factors and corticosteroids, but not by sex hormones. Understanding the regulation of VEGF/VPF secretion in meningiomas might contribute to the development of a new therapeutic strategy.
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PMID:Regulation of vascular endothelial growth factor secretion in human meningioma cells. 1008 66

Vascular endothelial growth factor (VEGF) is a key regulator of developmental, physiological, and tumor angiogenesis. Upregulation of VEGF expression by hypoxia appears to be a critical step in the neovascularization of solid cancers. The VEGF mRNA is intrinsically labile, but in response to hypoxia the mRNA is stabilized. We have systematically analyzed the regions in the VEGF mRNA that are responsible for its lability under normoxic conditions and for stabilization in response to hypoxia. We find that the VEGF mRNA not only contains destabilizing elements in its 3' untranslated region (3'UTR), but also contains destabilizing elements in the 5'UTR and coding region. Each region can independently promote mRNA degradation, and together they act additively to effect rapid degradation under normoxic conditions. Stabilization of the mRNA in response to hypoxia is completely dependent on the cooperation of elements in each of the 5'UTR, coding region, and 3'UTR. Combinations of any of two of these three regions were completely ineffective in responding to hypoxia, whereas combining all three regions allowed recapitulation of the hypoxic stabilization seen with the endogenous VEGF mRNA. We conclude that multiple regions in the VEGF mRNA cooperate both to ensure the rapid degradation of the mRNA under normoxic conditions and to allow stabilization of the mRNA in response to hypoxia. Our findings highlight the complexity of VEGF gene expression and also reveal a mechanism of gene regulation that could become the target for strategies of therapeutic intervention.
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PMID:Hypoxic regulation of vascular endothelial growth factor mRNA stability requires the cooperation of multiple RNA elements. 1019 46

Vascular endothelial growth factor (VEGF) is a major inducer of tumor angiogenesis and an important prognostic factor in breast cancer. Hypoxia is an important inducer of VEGF expression but less is known of the role of hormones in VEGF regulation. We have studied the regulation of VEGF, VEGF-B, VEGF-C, and VEGF-D mRNAs in human MCF-7 and mouse S115 breast carcinoma cells stimulated by estrogens and androgens, respectively. VEGF, VEGF-B, and VEGF-C were expressed in both cell lines, whereas VEGF-D was expressed only in S115 cells. Addition of estradiol (E2) caused a biphasic increase of VEGF mRNA in MCF-7 cells and led to accumulation of the VEGF protein in the culture medium. The VEGF-B mRNA was not affected, while a decrease occurred in VEGF-C mRNA. Similarly, testosterone upregulated the expression of VEGF mRNA in the S115 cells. Experiments with actinomycin D and cycloheximide suggested that estrogen induction of VEGF mRNA is dependent on the synthesis of new mRNA and increased mRNA half-life. The antiestrogen ICI 182.780 inhibited E2 stimulation of VEGF, suggesting that the effect was mediated by the estrogen receptor. In contrast, the antiestrogens tamoxifen and toremifene which inhibit MCF-7 cell growth in vivo and in vitro did not inhibit estrogen effect but induced VEGF mRNA expression when used alone. The antiandrogen cyprosterone acetate inhibited T induction of VEGF mRNA in S115 cells, thus suggesting that activation of androgen receptor must be involved in the increase of VEGF mRNA. Our results suggest that both estrogen and androgen stimulate the expression of VEGF by increasing gene transcription and mRNA stability. In addition, the antiestrogens tamoxifen and toremifene also increased VEGF expression. Estrogen and androgen induction of VEGF expression and promotion of new vessel formation may be an important paracrine mechanism by which these hormones contribute to the early phase of tumor growth of hormonal cancer.
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PMID:Vascular endothelial growth factors are differentially regulated by steroid hormones and antiestrogens in breast cancer cells. 1037 15

Vascular endothelial growth factor (VEGF) is a specific mitogen for vascular endothelial cells and has been implicated in tumor angiogenesis. Okadaic acid, an inhibitor of protein phosphatases 1 and 2A, is a non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoter in two-stage carcinogenesis experiments in mouse skin. To elucidate the role of VEGF in the angiogenesis of these experimental tumors, the effect of okadaic acid on VEGF gene expression was examined. In NIH 3T3, Rat1, HeLa, and A431 cells, VEGF mRNA was upregulated by 5- to 10-fold after incubation with okadaic acid. Furthermore, the amount of VEGF protein in the culture medium was significantly increased after stimulation with okadaic acid. Interestingly, okadaic acid-induced upregulation of VEGF mRNA was not suppressed by protein kinase C (PKC) inhibitor or by tumor necrosis factor alpha blocking antibody, although TPA-induced VEGF upregulation was strongly suppressed by PKC inhibitor. Our results indicate that okadaic acid is a new and potent inducer of VEGF, suggesting the involvement of VEGF as an angiogenic factor during multistep carcinogenesis in vivo.
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PMID:Okadaic acid stimulates the expression of vascular endothelial growth factor gene. 1055 13

With increasing size tumors are continually dependent on a functional blood vessel system to guarantee the supply with oxygen and nutrients. Vascular endothelial growth factor (VEGF) is a key mediator not only of developmental but also of hypoxia-mediated and tumor-induced angiogenesis. Gene therapy using antisense VEGF with the aim to inhibit tumor angiogenesis may be a successful strategy for the treatment of highly vascular and invasive malignant gliomas. We investigated whether retrovirus producer cells encoding antisense VEGF can be used for in vivo gene transfer. The full length mouse VEGF164 cDNA was cloned in a sense and antisense direction into the retroviral expression vector pLEN. pLEN-VEGF (sense) and pLEN-FGEV (antisense) expression vectors were used to transfect the packaging cell line GP + E86 and to establish ecotropic virus producer cell lines. GP + E86:LEN-FGEV (#5) cells showed high expression of antisense VEGF mRNA, whereas GP+ E86:LEN-VEGF (#8) showed high expression of sense VEGF mRNA and active VEGF protein. Co-implantation of GS-9L cells with retrovirus producing cells containing the antisense VEGF construct into the brains of syngeneic rats showed a statistically significant inhibition of tumor growth and prolongation of survival time, while co-implantation of retrovirus producer cells containing the sense VEGF expression vector resulted in an increasing tumor growth and reduced survival time of the rats compared to control animals. Histological analysis of the tumors co-implanted with GP + E86:LEN-FGEV (#5) cells showed the suppression of angiogenesis, high degree of necrosis and no evidence of a significant immune response. Expression of antisense VEGF mRNA in these tumors was confirmed by in situ hybridization analysis. This is the first report demonstrating the potential utility of virus producer cells as in vivo gene transfer vehicles for antisense VEGF gene therapy of malignant gliomas.
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PMID:Retrovirus producer cells encoding antisense VEGF prolong survival of rats with intracranial GS9L gliomas. 1057 19

We have shown previously that the VEGF system plays a crucial role in regulation of tumor angiogenesis during the development of estrogen-induced prolactin-secreting pituitary tumors in Fisher 344 rats. Studies also suggested that both endothelial and non-endothelial cells expressed VEGF. However, several questions concerning the VEGF signals in regulation of estrogen-induced angiogenesis in rat pituitary remained unanswered. VEGF exists in a number of isoforms in human and rodent tissue (i.e., VEGF206h/205r, VEGF189h/188r, VEGF165h/164r, VEGF145h/144r and VEGF121) that differ in their molecular masses and biological activities. The VEGF isoforms bind with two tyrosine-kinase receptors, KDR/flk-1 and flt-1. In addition, VEGF165 binds with a newly identified co-receptor, neuropilin-1, which is expressed in human endothelial cells and several types of non-endothelial cells including tumor cells. The present study was undertaken to elucidate which isoforms of VEGF are predominantly expressed in normal Fisher 344 rat pituitaries, estrogen-induced prolactin secreting rat pituitary tumors and in prolactin secreting rat pituitary tumor cell line (GH3 cell line). To identify the isoform, RT-PCR with primer pairs derived from exon 1 and exon 8 of the VEGF gene, cloning, sequencing and Western blot analysis were performed. The status of neuropilin-1 in the rat pituitaries (normal and transformed) and GH3 pituitary tumor cell line has also been investigated using RT-PCR and Western blot analysis. These studies demonstrate that normal rat pituitaries, estrogen-induced rat pituitary tumors and GH3 pituitary tumor cells expressed VEGF164 and co-receptor, neuropilin-1. The VEGF164 was the predominant form in all of these cells. The VEGF164 and neuropilin-1 mRNA and protein levels were significantly higher in the estrogen-induced pituitary tumors and GH3 tumor cell line, as compared to normal pituitary. The data suggest that both VEGF164 and neuropilin-1 may actively participate in modulation of tumor angiogenesis and the development of pituitary tumors in Fisher 344 rats.
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PMID:Overexpression of vascular endothelial growth factor164 and its co-receptor neuropilin-1 in estrogen-induced rat pituitary tumors and GH3 rat pituitary tumor cells. 1063 67

A possible link between oncogenes and tumor angiogenesis has been implicated by the finding that expression of various oncogenes, particularly mutant ras, can lead to a marked induction of a potent paracrine stimulator of angiogenesis, vascular endothelial growth factor (VEGF). We sought to determine how oncogenic ras induction of VEGF is mediated at the molecular level and whether the mechanisms involved differ fundamentally between transformed epithelial cells and fibroblasts. Our results suggest that in a subline (called RAS-3) of immortalized nontumorigenic rat intestinal epithelial cells (IEC-18) that acquired a tumorigenic phenotype upon transfection of mutant ras, up-regulation of VEGF occurs in the absence of an autocrine growth factor circuit. The expression of VEGF mRNA and protein by RAS-3 cells was strongly suppressed in the presence of LY294002, an inhibitor of phosphatidylinositol 3'-kinase, but remained largely unaffected in the same cells treated with an inhibitor (PD98059) of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MKK/MEK-1). This is consistent with the observation that overexpression of a constitutively activated mutant of MEK-1 (AN3/ S222D) in the parental IEC-18 cells did not result in up-regulation of VEGF production. The impact of mutant ras on VEGF expression was also significantly amplified at high cell density, conditions under which RAS-3 cells became less sensitive to LY294002-induced VEGF down-regulation. In marked contrast to cells of epithelial origin, ras-transformed murine fibroblasts (3T3RAS) up-regulated VEGF in a manner that was strongly inhibitable by MEK-1 blockade (ie. treatment with PD98059), whereas these cells were relatively unaffected by treatment with the phosphatidylinositol 3'-kinase inhibitor LY294002. In addition, VEGF was up-regulated by 2-3-fold in NIH3T3 cells overexpressing mutant MEK-1. Collectively, the data suggest that the stimulatory effect of mutant ras on VEGF expression is executed in a nonautocrine and cell type-dependent manner and that it can be significantly exacerbated by physiological/ environmental influences such as high cell density.
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PMID:Oncogenes and tumor angiogenesis: differential modes of vascular endothelial growth factor up-regulation in ras-transformed epithelial cells and fibroblasts. 1066 5

Tumor angiogenesis is an essential step for tumor cell growth, progression and metastasis. Vascular endothelial growth factor (VEGF) is mitogen specific for endothelial cells, and therefore is believed to play a key role in tumor angiogenesis. However, the mechanisms underlying the regulation of VEGF expression remain virtually unknown and the only major regulator of VEGF expression has been reported to be hypoxia. Recently, it was reported that a mutant p53 in#duced the expression of VEGF mRNA, and that wild-type p53 down-regulated endogenous VEGF mRNA levels. In contrast, it has also been reported that mutant ras oncogenes were associated with the marked up-regulation of VEGF in transformed epithelial cells. Based on these results, we performed a retrospective study of the p53 and K-ras genes status and VEGF gene expression in the tumor tissues from 181 patients with non-small cell lung cancer using SSCP, sequencing, RT-PCR and immunohistochemical techniques. Forty-six carcinomas (25.4%) were evaluated as having high VEGF expression, and 135 tumors (74.6%) had low VEGF expression. Of the 181 primary NSCLC studied, 63 carcinomas (34.8%) contained mutations of p53, whereas only 14 carcinomas (7.7%) had mutations of K-ras. There were no significant relationships between VEGF expression and p53 status or each mutant exon of p53. In contrast, a significant difference was found between VEGF expression and K-ras status. Of the 14 tumors with mutant K-ras genes, 7 cases (50.0%) had high VEGF expression whereas only 39 of the 167 tumors with wild-type K-ras (23.4%) had high VEGF expression (p=0.0278). The mean VEGF conservation rate for the 14 tumors with mutant K-ras genes was 0.77+/-0.58 and the rate of the 167 tumors with wild-type K-ras genes was 0.49+/-0.46 (p=0. 0350). Moreover, the overall survival rate of patients with high VEGF expression was lower than patients with low VEGF expression (45.7% vs 60.7%, p=0.0419). On the other hand, there was no significant difference in the overall survival rate between patients with a mutant p53 and those with a wild-type p53; there was also no difference in the overall survival between patients with a mutant K-ras and those with a wild-type K-ras. The Cox regression model analysis indicated that three variables, VEGF status, K-ras status and nodal status, were found to be significant indicators for prognosis (p=0.0236, p=0.0172 and p<0.0001, respectively). Our data suggest that a high expression of VEGF in lung cancer may be associated with a poor prognosis. This may be a clue to improving lung cancer diagnoses and therapies aimed at inhibiting tumor angiogenesis due to VEGF.
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PMID:The K-ras gene regulates vascular endothelial growth factor gene expression in non-small cell lung cancers. 1067 82

Upregulation of vascular endothelial growth factor (VEGF) expression induced by hypoxia is crucial event leading to neovascularization. Cyclooxygenase-2, an inducible enzyme that catalyzes the formation of prostaglandins (PGs) from arachidonic acid, has been demonstrated to be induced by hypoxia and play role in angiogenesis and metastasis. To investigate the potential effect of COX-2 on hypoxia-induced VEGF expression in prostate cancer. We examined the relationship between COX-2 expression and VEGF induction in response to cobalt chloride (CoCl2)-simulated hypoxia in three human prostate cancer cell lines with differing biological phenotypes. Northern blotting and ELISA revealed that all three tested cell lines constitutively expressed VEGF mRNA, and secreted VEGF protein to different degrees (LNCaP > PC-3 > PC3ML). However, these cell lines differed in the ability to produce VEGF in the presence of CoCl2-simulated hypoxia. CoCl2 treatment resulted in 40% and 75% increases in VEGF mRNA, and 50% and 95% in protein secretion by LNCaP and PC-3 cell lines, respectively. In contrast, PC-3ML cell line, a PC-3 subline with highly invasive, metastatic phenotype, exhibits a dramatic upregulation of VEGF, 5.6-fold in mRNA and 6.3-fold in protein secretion after treatment with CoCl2. The upregulation of VEGF in PC-3ML cells is accompanied by a persistent induction of COX-2 mRNA (6.5-fold) and protein (5-fold). Whereas COX-2 expression is only transiently induced in PC-3 cells and not affected by CoCl2 in LNCaP cells. Moreover, the increases in VEGF mRNA and protein secretion induced by CoCl2 in PC-3ML cells were significantly suppressed following exposure to NS398, a selective COX-2 inhibitor. Finally, the effect of COX-2 inhibition on CoCl2-induced VEGF production was reversed by the treatment with exogenous PGE2. Our data demonstrate that VEGF induction by cobalt chloride-simulated hypoxia is maintained by a concomitant, persistent induction of COX-2 expression and sustained elevation of PGE2 synthesis in a human metastatic prostate cancer cell line, and suggest that COX-2 activity, reflected by PGE2 production, is involved in hypoxia-induced VEGF expression, and thus, modulates prostatic tumor angiogenesis.
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PMID:Upregulation of vascular endothelial growth factor by cobalt chloride-simulated hypoxia is mediated by persistent induction of cyclooxygenase-2 in a metastatic human prostate cancer cell line. 1091 14

We have quantified the expression of all 4 isoforms of vascular endothelial growth factor (VEGF) mRNA in non-small-cell lung cancer (NSCLC) using a new kinetic quantitative PCR method, real-time quantitative (RTQ) RT-PCR, and investigated the association between VEGF expression at the mRNA and protein levels and the clinicopathologic variables, tumor angiogenesis, patient survival and timing of relapse. Surgical tumor specimens from 72 NCSLC patients (37 squamous-cell carcinomas, 35 adenocarcinomas) were examined. Twenty-eight patients had stage I, 10 stage II and 34 stage IIIA or IIIB disease. Total VEGF mRNA (all 4 isoforms) was quantified by RTQ RT-PCR, while VEGF protein expression and microvessel number in tumors were assessed immunohistochemically. VEGF mRNA was detected in all 72 tumor samples at significantly higher levels than in adjacent normal tissue. Tumoral VEGF mRNA levels correlated strongly with the VEGF protein staining score and microvessel count. Adenocarcinomas showed significantly higher VEGF mRNA expression and a higher protein staining score than squamous-cell carcinomas. High tumoral VEGF mRNA expression was associated with advanced (IIIA or IIIB) tumor stage, lymph node metastasis, high tumoral microvessel counts, short patient survival (<24 months) and early relapse (<12 months), while a high VEGF protein staining score was associated with high tumoral microvessel counts, short patient survival and early relapse. Patients with high tumoral levels of both VEGF mRNA and protein had significantly shorter survival and earlier relapse. In multivariate analysis, the VEGF protein staining score and nodal status were the most important independent predictors of survival and recurrence. We conclude that RTQ RT-PCR is a sensitive method for detecting and quantifying VEGF mRNA expression in NSCLC and that the expression levels of total VEGF mRNA and protein in NSCLC are strongly associated with histologic type, tumor angiogenesis, survival and timing of relapse. High VEGF expression in adenocarcinomas may contribute to their greater metastatic potential.
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PMID:Correlation of total VEGF mRNA and protein expression with histologic type, tumor angiogenesis, patient survival and timing of relapse in non-small-cell lung cancer. 1110 90


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