UMLS:C1140680 - FACTA Search

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

There is growing evidence that chronic stress and other behavioral conditions are associated with cancer pathogenesis and progression, but the mechanisms involved in this association are poorly understood. We examined the effects of two mediators of stress, norepinephrine and epinephrine, on the activation of signal transducer and activator of transcription-3 (STAT3), a transcription factor that contributes to many promalignant pathways. Exposure of ovarian cancer cell lines to increasing concentrations of norepinephrine or epinephrine showed that both independently increased levels of phosphorylated STAT3 in a dose-dependent fashion. Immunolocalization and ELISA of nuclear extracts confirmed increased nuclear STAT3 in response to norepinephrine. Activation of STAT3 was inhibited by blockade of the beta1- and beta2-adrenergic receptors with propranolol, and by blocking protein kinase A with KT5720, but not with the alpha receptor blockers prazosin (alpha1) and/or yohimbine (alpha2). Catecholamine-mediated STAT3 activation was not inhibited by pretreatment with an anti-interleukin 6 (IL-6) antibody or with small interfering RNA (siRNA)-mediated decrease in IL-6 or gp130. Regarding the effects of STAT3 activation, exposure to norepinephrine resulted in an increase in invasion and matrix metalloproteinase (MMP-2 and MMP-9) production. These effects were completely blocked by STAT3-targeting siRNA. In mice, treatment with liposome-incorporated siRNA directed against STAT3 significantly reduced isoproterenol-stimulated tumor growth. These studies show IL-6-independent activation of STAT3 by norepinephrine and epinephrine, proceeding through the beta1/beta2-adrenergic receptors and protein kinase A, resulting in increased matrix metalloproteinase production, invasion, and in vivo tumor growth, which can be ameliorated by the down-regulation of STAT3.
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PMID:Neuroendocrine modulation of signal transducer and activator of transcription-3 in ovarian cancer. 1797 82

Matrix metalloproteinases (MMPs) are frequently expressed in malignant tumors and play an important role in tumor invasion and metastasis. The aim of this study was to evaluate role of serum MMP-2 and MMP-7 levels in patients with ovarian cancer. Serum levels of MMP-2 and MMP-7 were measured in 28 patients with ovarian carcinoma, 2 with borderline ovarian tumors, 10 with non-malignant gynecological disease and 30 healthy women by Enzyme-Linked Immunosorbent Assay (ELISA). Serum MMP-7 level was significantly (10.24+/-1.35 ng/ml) higher in the patients with ovarian malign tumors than healthy controls (3.29+/-1.64 ng/ml) (P<0.05). Postoperative levels of MMP-7 (7.68+/-1.17 ng/ml) were significantly lower in patients with malign ovarian tumors than those of preoperative level (10.24+/-1.35 ng/ml) (P<0.05). Serum MMP-2 levels were significantly lower in the patients with ovarian malign tumors (227.51+/-9.91 ng/ml) than those in the healthy controls (279.12+/-73 ng/ml) (P<0.05). There was no significant difference in serum levels of MMP-2 and MMP-7 in patients with benign ovarian disease when compared to healthy controls and patients with malignant disease (P>0.05). As a conclusion, MMP-7 can be a useful serum marker to show disease activity in malignant ovarian tumors.
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PMID:Clinical significance of serum MMP-2 and MMP-7 in patients with ovarian cancer. 1807 28

Matrix metalloproteinases (MMPs) are enzymes thought to be involved in tumor invasion. We hypothesized that MMP-2 and MMP-11 overexpression was associated with the aggressiveness of ovarian carcinoma. This study was performed on samples from 100 patients with stage III ovarian carcinomas treated surgically between 1990 and 2000. Immunohistochemical staining was performed on ovarian tumors and peritoneal implants using monoclonal antibodies. Overexpression was defined as more than 10% of cells expressing the marker. Multivariate analyses showed that only MMP-2 overexpression by cancer cells in peritoneal implants was associated with a significant risk of death by disease (hazard ratio, 2.65; 95% confidence interval, 1.41-4.97; P =.003). MMP-11 overexpression was not predictive of survival. These results suggest that MMP-2 overexpression by cancer cells in peritoneal implants and not in the primary ovarian cancer is predictive of ovarian cancer prognosis and more likely reflects the presence of particularly aggressive clones of cancer cells.
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PMID:Role of immunohistochemical overexpression of matrix metalloproteinases MMP-2 and MMP-11 in the prognosis of death by ovarian cancer. 1820 2

Most patients (80%) with ovarian cancer (OvCa) present with metastatic disease. Attachment of OvCa cells to peritoneum and omentum represents the first rate-limiting step for metastatic spread. Therefore, identifying factors regulating cell attachment in the abdominal cavity is critical to the development of therapeutic agents. We show here that MMP-2 expression was upregulated in OvCa cells upon attachment to their microenvironment. Downregulation of MMP-2 mRNA or pharmacological inhibition of MMP-2 proteolytic function, in both human OvCa primary cells and cell lines, reduced attachment of OvCa cells to a 3D organotypic model of metastatic OvCa, full human omentum or peritoneum, and in vivo to mouse peritoneum and omentum. Absence of MMP-2 in the host did not alter OvCa adhesion, as determined utilizing mice harboring homozygous null mutations in either the Mmp2 or Mmp9 genes. Conversely, adhesion induced upregulation of MMP-2 mRNA in OvCa cells. MMP-2 inhibition in OvCa cells through pharmacological or antibody treatment prior to i.p. dissemination in nude mice significantly decreased tumor growth and metastasis and extended survival. MMP-2 enhanced peritoneal adhesion of OvCa cells through cleavage of ECM proteins fibronectin (FN) and vitronectin (Vn) into small fragments and increased binding of OvCa cells to these FN and Vn fragments and their receptors, alpha5beta1 and alphaVbeta3 integrin. These findings indicate that MMP-2 expressed by metastatic OvCa cells functionally regulates their attachment to peritoneal surfaces.
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PMID:The initial steps of ovarian cancer cell metastasis are mediated by MMP-2 cleavage of vitronectin and fibronectin. 1834 Mar 78

The association between single nucleotide polymorphisms (SNPs) in the promoter region of MMP-2 and TIMP-2 genes and the risk of epithelial ovarian cancer was investigated. MMP-2 C-1306T, C-735T and TIMP-2 G-418C SNPs were genotyped by polymerase chain reaction-restrictive fragment length polymorphism (PCR-RFLP) analysis in 246 patients with epithelial ovarian cancer and 324 healthy women as control. Results showed no significant difference between the patient and control groups in allele or genotype distributions of MMP-2 C-1306T (P=0.55 and P=0.42). However, the frequencies of the C allele and the C/C genotype of the MMP-2 C-735T were significantly higher in ovarian cancer patients (80.7% and 66.7%) than those in healthy controls (75.5% and 55.9%). Compared with the T/T+C/T genotypes, the C/C genotype significantly increased the risk of ovarian cancer (OR=1.58, 95%CI=1.12-2.23). Stratification analysis showed that subjects carrying C/C genotype were significantly associated with the risk of endometrioid ovarian cancer and with ovarian cancer in subjects that were 50 or older, with odds ratio at 1.69 (95%CI=1.03-2.79) and 1.71 (95%CI=1.14-2.57), respectively. Haplotype analysis showed that the frequencies of four haplotypes (T(-1306)-T(-735), T(-1306)-C(-735), C(-1306)-T(-735) and C(-1306)-C(-735)) of MMP-2 C-1306T and C-735T were not significantly different between the patient and control groups (P=0.24). The allele and genotype frequencies of TIMP-2 G-418C were not significantly different between the patient and control groups (P=0.33 and P=0.47). But TIMP-2 -418G/G genotype was associated with a trend for endometrioid ovarian cancer by stratification analysis according to histological subtypes (OR=1.62, 95%CI=0.94-2.78). Thus, the study suggested that the C/C genotype of the C-735T SNP in the promoter region of MMP-2 gene may be a potential risk factor for epithelial ovarian cancer, but the C-1306T SNP may have no association with the risk of epithelial ovarian cancer. The TIMP-2 G-418C SNP may be associated with the risk of different histological subtypes of epithelial ovarian cancer.
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PMID:[Association of SNPs in the promoter of MMP-2 and TIMP-2 genes with epithelial ovarian cancer]. 1842 16

The objective of this study was to determine if the level of serum hyaluronan (HA), serum-derived HA-associated protein (SHAP)-HA complex, and urinary trypsin inhibitor (UTI) correlate with the clinical outcome of ovarian cancer patients. The relationship of metalloproteinase and its inhibitor with HA and the SHAP-HA complex was also examined. Serum and urine samples were obtained from 45 patients with ovarian cancer, 22 patients with benign ovarian tumors and 50 healthy women. Concentrations of serum HA and UTI were measured by an inhibitory sandwich enzyme-linked immunosorbent assay, and concentrations of the serum SHAP-HA complex were measured by a sandwich enzyme-linked immunosorbent assay. Concentrations of MMP-2, MMP-9 and TIMP-1 were measured by a one-step enzyme immunoassay. The levels of HA, SHAP-HA complex, MMP-9 and TIMP-1 were higher in the ovarian cancer group than in the benign ovarian tumor group. In ovarian cancer patients, the levels of HA, SHAP-HA complex and MMP-9 were higher in the stage III/IV group than in the stage I/II group, and the levels of SHAP-HA complex, MMP-9 and TIMP-1 were higher in the non-responder group than in the responder group. The serum concentration of SHAP-HA complex had a significant correlation with HA, MMP-9 and TIMP-1 in ovarian cancer patients. The patients with elevated SHAP-HA complex had a shorter disease-free survival compared with those with normal levels of SHAP-HA complex. The multiple regression analysis revealed that SHAP-HA complex is the significant independent variable for progression-free survival. The elevated level of SHAP-HA complex may indicate the prognosis of recurrence and reflect the tumor metastasis associated with MMP-9 in ovarian cancer patients.
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PMID:Role of serum-derived hyaluronan-associated protein-hyaluronan complex in ovarian cancer. 1842 83

The most common site (80%) of ovarian cancer metastasis is the omentum, a large (15 x 10 x 2 cm) peritoneal fold covering the small bowel. Because of the absence of model systems that accurately reproduce the microenvironment of the human omentum, the biological mechanism of early ovarian cancer metastasis is poorly understood. Using a new organotypic 3D culture of the omentum, we show that when cancer cells adhere, matrix-metalloproteinase (MMP)-2 is upregulated and proteolytically activated in these cells. The activated MMP-2 cleaves the matrix proteins fibronectin, vitronectin and collagen I into smaller fragments. The cleaved extra-cellular matrix (ECM) fragments then facilitate and accelerate cancer cell adhesion and invasion by binding to their cognate integrin receptors. In vivo inhibition of MMP-2 before adhesion by using a siRNA or a blocking antibody significantly reduced the number of metastasis and tumor weight in a xenograft mouse model. After metastasis had been established, blocking MMP-2 produced less of an effect. Our data identify tumor-derived proteolytically active MMP-2 as an early regulator of ovarian cancer metastasis.
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PMID:MMP-2 functions as an early response protein in ovarian cancer metastasis. 1922 81

This study was aimed to explore the role of stromal-derived factor 1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis in mediating the metastasis of ovarian cancer cells through activation of extracellular signal-regulated kinase-1/2 (ERK-1/2) signaling pathway. A highly metastatic ovarian cancer cell line, SKOV3, was used in the study. Intracellular calcium mobilization was detected by using laser scanning confocal fluorescence microscopy. Western blotting was used to detect the phosphorylation of ERK1/2 in SDF-1alpha-treated SKOV3 cells. Adhesion capability and matrix metalloproteinase (MMP) activity of ovarian cancer cells after exposure to SDF-1alpha were measured by adhesion assay and gelatin zymography. The results showed that SDF-1alpha induced rapid intracellular calcium mobilization in SKOV3 cells, as well as the phosphorylation of ERK-1/2. The adhesion of ovarian cancer cells to fibronectin and collagen IV was increased after SDF-1alpha treatment. An inhibitor of ERK-1/2 signaling, PD98059, could antagonize such effects of SDF-1alpha. SDF-1alpha could also increase the secretion of active MMP-2 and MMP-9. It was concluded that the SDF-1/CXCR4 axis played a critical role in the metastasis of human ovarian cancer by increasing the adhesion capability of cancer cells and the activity of MMP-2 and MMP-9 via ERK1/2 signaling pathway.
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PMID:The role of SDF-1/CXCR4 axis in ovarian cancer metastasis. 1951 23

There are several similarities between breast and ovarian cancer but anti-estrogen treatment is rarely used in ovarian cancer. We have previously shown that the most widely used anti-estrogen tamoxifen increased MMP-9 activity and endostatin generation in breast cancer. Here, we show that tamoxifen exposure of highly hormone responsive ovarian cancer cells decreased proliferation, and increased MMP-9 activity leading to increased levels of endostatin both in cell culture in vitro and in solid tumors of nude mice. Tamoxifen exposed tumors also exhibited significantly decreased tumor growth and vascularisation. Moreover, in ascites from ovarian cancer patients, MMP-9 was undetectable in majority of cases but a significant correlation of MMP-2 and endostatin was found. The effects on MMPs and endostatin generation are previously unknown mechanisms of estradiol and tamoxifen in ovarian cancer, which may have therapeutic implications in future anti-cancer options of hormone dependent ovarian cancer.
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PMID:Increased endostatin generation and decreased angiogenesis via MMP-9 by tamoxifen in hormone dependent ovarian cancer. 1994 23

Tumor-associated lymphatic endothelial cells (TLEC) could play a key role in the process of tumor metastasis. The aim of this study was to investigate the effect of TLECs that were isolated from human epithelial ovarian tumor (EOT) on ovarian cancer cell line CAOV-3 in vitro. First, TLECs in EOT were detected by immunochemistry and flow cytometry, then marked by lymphatic endothelial cell (LEC) marker LYVE-1, isolated by magnetic beads, and cultured in vitro. The cells were identified by immunostaining of LEC markers LYVE-1, Prox-1, Podoplanin, VEGFR-3, and pan-endothelial cell marker CD31. TLECs from EOT can be detected, cultured, and identified in vitro successfully. The effects of TLECs on invasion and migration of CAOV-3 cells were investigated by 12-well Boyden chamber; the proliferation effect was studied by counting the Trypan blue exclusion cell number. Furthermore, changes in MMP-2/9 secreted by CAOV-3 cells treated with TLEC were shown using real-time PCR and zymography, and TIMP-1/2 was detected by real-time PCR. In vitro, TLECs can enhance invasion and migration of CAOV-3 cells, but have no significant effect on proliferation. It was clear that the expression of MMP-9 increased and TIMP-2 decreased in CAOV-3 cells treated by TLECs, and the increasing of MMP-9 was confirmed by zymography. TLECs from EOT can enhance migration and invasion of human ovarian carcinoma cell line in vitro, and the possible mechanism was through activation of MMP-9/TIMP-2.
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PMID:Role of tumor-associated lymphatic endothelial cells in metastasis: a study of epithelial ovarian tumor in vitro. 2002 87

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