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Query: UMLS:C1140680 (ovarian cancer)
 28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Neovascularisation plays a crucial role in solid tumor growth and metastasis formation. Our previous studies showed that theophylline and theobromine suppressed cutaneous neovascular reaction induced in mice by human blood leukocytes, and lung as well as ovarian cancer cells. Here, we investigated the in vivo effect of theobromine on angiogenic activity of human urothelial cell line HCV-29, v-raf transfected (mouse cutaneous assay), and the in vitro effect of this drug on VEGF, tPA, uPA and PAI mRNA expression in these cells (RT-PCR method). Theobromine suppressed angiogenesis induced in mice by HCV-29-v-raf cells, inhibited VEGF mRNA expression, and had no effect on transcription of uPA and tPA in these cells. HCV-29-v-raf transfectants do not display transcripts of PAI, in the presence or the absence of theobromine.
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PMID:Inhibitory effect of theobromine on induction of angiogenesis and VEGF mRNA expression in v-raf transfectants of human urothelial cells HCV-29. 985 Jul 31

The expression level of interleukin-8 (IL-8) directly correlates with the progression of human ovarian carcinomas implanted into the peritoneal cavity of nude mice, but the mechanism of induction is unknown. Because hypoxia induces expression of vascular endothelial growth factor/vascular permeability factor, which, like IL-8, is an angiogenesis-regulating molecule, we determined whether hypoxic conditions could regulate the expression of IL-8. Surgical specimens of human ovarian carcinomas were prepared for immunohistochemical and in situ hybridization analysis. Elevated levels of IL-8 mRNA and protein were found in tumor cells adjacent to necrotic zones. In vitro exposure of human ovarian carcinoma cell lines SKOV3 i.p.1 and Hey-A8 to hypoxia resulted in a time-dependent increase in steady-state levels of IL-8 mRNA (Northern blot) and in increased production and secretion of IL-8 protein (ELISA). Hypoxia-mediated transient induction of IL-8 expression could be ascribed to both an increase in IL-8 mRNA stability and transcriptional activation of the IL-8 gene promoter. Detailed functional analysis of the IL-8 promoter revealed that the sequence between -133 and -98 bp relative to the transcription initiation site was primarily responsible for IL-8 gene transcriptional activation by hypoxia. Point-mutated luciferase reporter studies indicated that AP-1 and NF-kappaB-like factor binding elements were mainly responsible for hypoxia-induced increase in IL-8 gene expression in human ovarian cancer cells, and that IL-8 transcription activation by hypoxia required the cooperation of NF-kappaB and AP-1 binding sites.
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PMID:Hypoxia-induced elevation in interleukin-8 expression by human ovarian carcinoma cells. 1058 5

We determined whether inhibition of the catalytic tyrosine kinase activity of the receptors for vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) inhibits the formation of malignant ascites and the progressive growth of human ovarian carcinoma cells implanted into the peritoneal cavity of nude mice. The novel protein tyrosine inhibitor PTK 787 was evaluated in two models of human ovarian cancer: Hey-A8 cells, which express low levels of VEGF/VPF and grow as solid tumor foci on the surface of peritoneal organs, and SKOV3 i.p.1 cells, which express high levels of VEGF/VPF and grow as solid peritoneal tumors and ascites. Treatment of nude mice by daily oral administration of 50 mg/kg PTK 787 was not effective against Hey-A8 tumors. In sharp contrast, it significantly inhibited growth of SKOV3 i.p.1 cells and formation of ascites, significantly increasing survival of mice with the implants. Tumor-induced vascular hyperpermeability in the peritoneum of tumor-bearing mice was inhibited by PTK 787, which accounted for its inhibition of ascites formation. Our results suggest that blockade of the VEGF/VPF receptor may be an efficient strategy to inhibit formation of malignant ascites and growth of VEGF/VPF-dependent human ovarian carcinomas.
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PMID:Inhibition of malignant ascites and growth of human ovarian carcinoma by oral administration of a potent inhibitor of the vascular endothelial growth factor receptor tyrosine kinases. 1067 74

Ascites formation is often observed in ovarian cancer patients. Vascular permeability factor (VPF) may induce ascites formation. We established an animal model of ascites formation and re-accumulation by i.p. transplantation of a human ovarian adenocarcinoma cell line, NOS2, into nude mice. The formation of ascites was observed after 10 days of tumor inoculation and continued for up to 4 weeks. In the ascitic fluid, biologically active VPF was detected. The repeated i.p. administration of an immunoneutralizing monoclonal antibody (MAb) to VPF, MV833, significantly inhibited the formation of ascites throughout the experiments. Re-accumulation of ascites occurred quickly in control mice after aspiration of ascites and these mice died within 20 days. MV833 again inhibited the re-accumulation of ascites and significantly prolonged the life span of mice without any side effect. These results indicate that VPF plays an important role in the accumulation of ascites induced by ovarian cancer and an anti-VPF MAb is a new specific drug to suppress the formation and re-accumulation of ascites. This MAb may contribute to ameliorating quality of life of cancer patients as well as prolong their survival.
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PMID:Suppression of ascites formation and re-accumulation associated with human ovarian cancer by an anti-VPF monoclonal antibody in vivo. 1076 48

Recent evidence suggests that vascular endothelial growth factor (VEGF) expression is up-regulated by oxidative stressors through activation of hypoxia-inducible Factor 1 (HIF-1). To investigate whether this is a general phenomenon, we studied the effects of the sulfhydryl reagent arsenite on VEGF expression in human ovarian cancer cells. Arsenite potently induces the production of reactive oxygen species (ROS) in several cell systems and directly interacts with sulfhydryl groups of cellular thiols. We report that arsenite induces VEGF mRNA and protein levels in normoxic H134 and OVCAR-3 cells. Arsenite also increases HIF-1alpha protein levels, suggesting a role for HIF-1 in the induction of VEGF expression. Pretreatment with the ROS inhibitors catalase and mannitol attenuated arsenite-induced ROS production, but did not affect induction of VEGF mRNA and HIF-1alpha protein. In contrast, pretreatment with the thiol antioxidants glutathione or N-acetylcysteine completely abrogated both effects, whereas a potentiation was observed by depletion of intracellular glutathione. These results demonstrate that arsenite-induced VEGF mRNA and HIF-1alpha protein expression is independent of increased ROS production but critically regulated by the cellular reduced glutathione content. In addition, these data suggest the involvement of a thiol-sensitive mechanism in the regulation of VEGF mRNA expression and HIF-1alpha protein in human ovarian cancer cells.
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PMID:Induction of vascular endothelial growth factor expression and hypoxia-inducible factor 1alpha protein by the oxidative stressor arsenite. 1164 98

Vascular endothelial growth factor (VEGF) is a heparin-binding, dimeric polypeptide with potent mitogenic effects on endothelial cells. VEGF expression has also been reported in ovarian epithelial tumors (OETs), which may be associated with gonadotropin stimulatioin. We recently reported that most OETs, including OET cell lines, express gonadotropin receptors. Here we studied VEGF mRNA expression in 141 OET and 35 benign ovarian samples using reverse transcriptase polymerase chain reaction and in situ hybridization (ISH). We also studied VEGF production by OET cell lines under stimulation of gonadotropins. AO (serous carcinoma), low malignant potential (LMP; SV40-transformed borderline tumor) and ML-5 (SV40-transformed cystadenoma) cells were examined for VEGF protein production under the regulation of gonadotropins in vitro. The biologic function of VEGF was confirmed by using bovine endothelial growth assay. Whereas VEGF was not detected in benign ovarian surface epithelium or in ovarian epithelial inclusions, it was detected in both epithelial and stromal compartments of OETs. For VEGF epithelial expression, only 5% of ovarian cystadenomas and 30% of borderline tumors were positive for VEGF detection by ISH, whereas VEGF mRNA signal was detected in 80% of ovarian carcinoma cases. This increment of VEGF expression in ovarian carcinomas was statistically significant compared with benign and borderline tumors. Within ovarian carcinomas, the percentage of VEGF-positive cells was significantly associated with the grade of cancer but not with cancer cell types or cancer stages. Both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) stimulated the expression of VEFG(165) in AO cells in a dose-dependent manner. Maximal induction was obtained for FSH at dose of 40 mIU/ml and for LH at 50 mIU/ml after 48 hr of culture. Compared with the nonstimulated cells, VEGF level was significantly elevated in both LMP and AO cells after stimulation of gonadotropins. Furthermore, the induction of VEGF expression was significantly stronger in carcinoma cells than in borderline OET cells. These observations suggest that VEGF may play a role in the development of ovarian cancer and that the elevated gonadotropins, as found in menopause and in most ovarian cancer patients after surgery, could accelerate tumor growth and tumor recurrence by inducing VEGF expression in OETs.
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PMID:VEGF expression and enhanced production by gonadotropins in ovarian epithelial tumors. 1177 59

Recently we have demonstrated that sodium arsenite induces the expression of hypoxia-inducible factor 1alpha (HIF-1alpha) protein and vascular endothelial growth factor (VEGF) in OVCAR-3 human ovarian cancer cells. We now show that arsenic trioxide, an experimental anticancer drug, exerts the same effects. The involvement of phosphatidylinositol 3-kinase and mitogen-activated protein kinase (MAPK) pathways in the effects of sodium arsenite was investigated. By using kinase inhibitors in OVCAR-3 cells, both effects of sodium arsenite were found to be independent of phosphatidylinositol 3-kinase and p44/p42 MAPKS but were attenuated by inhibition of p38 MAPK. A role for p38 in the regulation of HIF-1alpha and VEGF expression was supported further by analysis of activation kinetics. Experiments in mouse fibroblast cell lines, lacking expression of c-Jun N-terminal kinases 1 and 2, suggested that these kinases are not required for induction of HIF-1alpha protein and VEGF mRNA. Unexpectedly, sodium arsenite did not activate a HIF-1-dependent reporter gene in OVCAR-3 cells, indicating that functional HIF-1 was not induced. In agreement with this hypothesis, up-regulation of VEGF mRNA was not reduced in HIF-1alpha(-/-) mouse fibroblast cell lines. Altogether, these data suggest that not HIF-1, but rather p38, mediates induction of VEGF mRNA expression by sodium arsenite.
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PMID:Evidence for a role of p38 kinase in hypoxia-inducible factor 1-independent induction of vascular endothelial growth factor expression by sodium arsenite. 1248 58

Metastasis or progression of ovarian cancer cells is known to be due to the action of various angiogenic factors. We determined the expression of thymidine phosphorylase/platelet-derived endothelial cell growth factor (TP/PD-ECGF) and vascular endothelial growth factor (VEGF) in cell lines established from 3 serous adenocarcinomas, 3 clear cell carcinomas and 2 mucinous carcinomas of the human ovary. TP activity and the TP mRNA level were much higher in the serous adenocarcinoma cells than in the clear cells and mucinous carcinoma cells, and TP expression was extremely low in the clear cell carcinoma cells. Expression of VEGF mRNA was variable, but not significantly different between the 3 histological types of ovarian cancer. In vivo angiogenesis in the ovarian cancer cells was evaluated by the dorsal air sac assay and revealed that SHIN-3 and HRA serous adenocarcinoma cells, which have high levels of TP expression, induced angiogenesis, while KK clear cell carcinoma cells with low TP expression, did not. The degree of ovarian-cancer-induced angiogenesis seemed to be independent of expression of VEGF in the cells. To confirm that the serous adenocarcinoma-induced angiogenesis is dependent on TP levels, a potent and specific inhibitor of TP was administered orally to mice implanted with a chamber containing SHIN-3 or HRA cells. The TP inhibitor significantly inhibited the angiogenesis induced by the serous adenocarcinoma cells. These results suggest that the angiogenic potency of ovarian cancer cells differs with the histological type and is controlled by expression of TP/PD-ECGF, not by VEGF, and that TP-mediated angiogenesis may be the main factor responsible for progression or metastasis of ovarian serous adenocarcinomas.
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PMID:Thymidine phosphorylase-mediated angiogenesis regulated by thymidine phosphorylase inhibitor in human ovarian cancer cells in vivo. 1268 60

Ovarian cancer is the most lethal gynecological malignancy and the fifth most common cause of cancer in women. It is characterized by diffuse peritoneal carcinomatosis and often by large volumes of i.p. ascites. Because vascular endothelial growth factor (VEGF), also known as vascular permeability factor, increases vascular permeability and stimulates endothelial cell growth, its role in ovarian cancer has been evaluated in a number of studies. However, questions remain regarding the ability of VEGF alone to cause ascites formation and the ability of VEGF blockade to inhibit the growth of disseminated cancer. We have used retroviral technology to create cell populations that overproduce VEGF and report that enforced expression of VEGF by ovarian carcinoma cells dramatically reduces the time to onset of ascites formation. In fact, even tumor-free peritoneal overexpression of VEGF, created by using adenoviral vectors, is sufficient to cause ascites to accumulate. We have found that systemic administration of the VEGF-Trap, a recently described high-affinity soluble decoy receptor for VEGF, prevents ascites accumulation and also inhibits the growth of disseminated cancer. Remarkably, much as is observed in s.c. tumor models, VEGF blockade results in dramatic remodeling of the blood vessels in disseminated ovarian carcinoma. The potent effects of the VEGF-Trap in reducing both ascites and tumor burden suggest that it will be of value in a regimen for treatment of women with ovarian cancer and ascites.
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PMID:Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. 1465 57


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