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)

In order to understand the ability of human ovarian cancers to degrade the basement membrane, we have studied the localization and activity of matrix metalloproteases (MMPs) 2 and 9, using in situ hybridization and quantificative zymography on sequential sections of tumor biopsies. We have related these data to expression of some of the controlling elements of the enzymes, namely tissue inhibitors of metastasis (TIMPs) and tumor necrosis factor (TNF). mRNA for MMP-2 was found in the majority of cases and localized to stromal areas with maximal expression adjacent to neoplastic areas. MMP-9 expression was associated with cells in epithelial and stromal areas, consistent with distribution of macrophages. Zymography revealed higher levels of MMP-9 activity in the ovarian cancer biopsy samples than in other cancers studied, but in contrast to our previous observations in breast and bladder cancer, there was no correlation between MMP levels and tumor grade. Nor was there any association between amount of TNF mRNA and levels of MMP enzymes. TIMP-I expression was localized to stromal areas adjacent to tumor epithelial cells as well as, in some cases, to epithelial cells. The pattern of TIMP-2 expression was similar to that of MMP-2. We conclude that the stromal elements of ovarian tumors express MMP-2 and 9 and their specific inhibitors, but these do not seem to be controlled by endogenous TNF in the tumor microenvironment.
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PMID:Expression and activity of MMPS and their regulators in ovarian cancer. 801 15

Matrix metalloproteinases (MMPs) are known to play an important role in cancer cell invasion by mediating the degradation of extracellular matrix proteins. The activity of such MMPs are regulated by tissue inhibitors of metalloproteinases (TIMPs). In this study, we investigated the immunohistochemical expression of MMP-2, MT1-MMP, TIMP-2, MMP-9, and TIMP-1 in 114 epithelial ovarian tumors (14 adenomas, 22 borderline tumors, and 78 adenocarcinomas). mRNA expression of MMP-2, MT1-MMP, and TIMP-2 was determined by RT-PCR in selected samples. The diffuse positive rates of MMP-2, MT1-MMP, TIMP-2, and MMP-9 in ovarian carcinomas were significantly higher than those in the borderline and in benign tumors. Conversely, the diffuse positive rate of TIMP-1 was higher in the benign and borderline ovarian tumors than that in ovarian carcinomas. The percentages of the cases with triple diffuse positive expression for MMP-2, MT1-MMP, and TIMP-2 within the same tumor was significantly higher in malignant tumors than those in borderline and in benign tumors. With respect to clinical stage, the triple diffuse positive rate in advanced-stage (stage II/III/IV) carcinomas was significantly higher than that in early-stage (stage I) carcinomas. A significantly higher triple diffuse positive rate was also observed in high-grade (grade 2/3) disease than in low-grade (grade 1) disease. Considerable levels of mRNA expression of MMP-2, MT1-MMP and TIMP-2 were detected in all selected samples that showed triple diffuse positive immunostaining, confirming the co-expression of MMP-2, MT1-MMP, and TIMP-2 at the transcriptional level within the same tumor. All cases with diffuse positive expression for MMP-9 showed regional or negative TIMP-1 expression. The diffuse positive rate of MMP-9 was significantly higher in ovarian carcinomas with lymph node metastasis than in those without lymph node metastasis. Our results suggest that the overexpression of MMP-2, MT1-MMP, TIMP-2, and MMP-9 and down-regulation of TIMP-1 may contribute to the development or enhanced growth capacity of ovarian tumors. Co-expression of MMP-2, MT1-MMP, and TIMP-2 within the same tumor seems to play an important role in the progression of ovarian cancer. Elevated MMP-9 expression together with low expression of TIMP-1 may also contribute to the lymph node metastasis of ovarian carcinoma cells.
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PMID:Expression of matrix metalloproteinases (MMP-2, MMP-9, MT1-MMP) and their inhibitors (TIMP-1, TIMP-2) in common epithelial tumors of the ovary. 1099 77

We measured the levels of the vascular endothelial growth factor (VEGF), matrix metalloproteinases type 2 and type 9 (MMP-2 and MMP-9) and tissue inhibitors of matrix metalloproteinase 1 and 2 (TIMP-1 and TIMP-2) in the plasma of patients with ovarian carcinoma (n=40), in other gynaecological pathologies (n=30) and in the plasma of healthy volunteers (n=26). MMP-2 and MMP-9 (pro and active forms) gelatinolytic activity was measured by zymography. Enzyme-linked immunosorbent assays (ELISA) were used to assay soluble VEGF and TIMPs. Preoperative plasma VEGF levels were significantly higher in patients with ovarian cancer than in healthy volunteers (P<0.0001) or patients with a benign gynaecological pathology (P<0.0001). The expression of pro-MMP-9 was higher in the plasma of ovarian cancer patients than in the plasma of women with non-malignant disease (P=0.01) or healthy women (P<0.0002). Pro-MMP-2 was detected in the plasma of ovarian cancer patients, but levels did not differ from those in non-malignant disease or healthy donor samples. Plasma TIMP-1 and TIMP-2 levels were significantly higher in patients with ovarian carcinomas than in healthy volunteers (P<0.0001 and P=0.006, respectively) or in the patients with a non-malignant pathology (P<0.0001 and P=0.002, respectively). Sub-group analysis showed that VEGF and pro-MMP-9 were higher in the plasma of patients with serous carcinomas than other histological types. Furthermore, plasma VEGF and pro-MMP-9 levels were higher in the plasma of cancer patients with thrombocytosis. Throughout the study, and in the univariate analysis, no correlation was found between the VEGF, MMP and TIMP levels. Only TIMP-1 was associated with a poor survival and mortality risk.
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PMID:Expression levels of vascular endothelial growth factor, matrix metalloproteinases 2 and 9 and tissue inhibitor of metalloproteinases 1 and 2 in the plasma of patients with ovarian carcinoma. 1293 75

The matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) have been associated with ovarian tissue remodelling and development of ovarian tumours. With respect to ovarian cancer, the majority of previous studies were performed on serous and mucinous tumours, and little is known about clear cell carcinoma, which shows unique characteristics among ovarian cancers. In the present study, we assessed the differences in the levels of MMP-2, MMP-9, TIMP-1 and TIMP-2 in the normal ovary and ovarian tumours of different histology, including clear cell carcinoma, using specific enzyme-linked immunosorbent assays. In malignant tumours, a prominent increase in pro-MMP-9 levels was observed compared with those of normal ovary and benign tumours, and pro-MMP-2 and TIMP-1 levels were moderately increased. In contrast, TIMP-2 levels were markedly decreased in malignant tumours compared with normal ovary with the exception of clear cell carcinoma, in which they were significantly elevated. Similar results were obtained by the organ culture of carcinoma tissue and normal ovary as well as in the cyst fluids of the tumours. Increased expression of TIMP-2 in clear cell carcinoma was also confirmed by Western blot analysis. Immunohistochemistry showed that TIMP-2 immunoreactivity was localized predominantly in epithelial cancer cells in clear cell carcinoma, while it was present mainly in stromal cells in the other histological types. Taken together, the present study shows that TIMP-2 expression is markedly increased in clear cell carcinoma of the ovary, suggesting a role of TIMP-2 in its unique characteristics among ovarian cancers.
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PMID:Increased expression of tissue inhibitor of metalloproteinase-2 in clear cell carcinoma of the ovary. 1297 Mar 94

Matrix metalloproteinases (MMPs) have been implicated in ovarian cancer progression. Among them, MMP-8 that degrades type I collagen may play a crucial role. The aim of our study was to determine MMP-8 expression and regulation in ovarian cancer and its association with other MMPs and tissue inhibitors of metalloproteinases (TIMPs). Tissue microarrays (TMAs) containing tissue cylinders from 302 patients were used for immunohistochemical studies. In addition, MMP-8 expression in vitro was analysed by a specific immunoassay and PCR-analysis. MMP-7 (81%), MMP-8 (95%), MT3-MMP (100%), TIMP-2 (100%), and TIMP-3 (96%) were expressed in all the OVCAs, but the staining intensities varied. MMP-3 (6%), MMP-9 (57%) and TIMP-1 (43%) expressions were more rarely detected. Only MMP-8 expression levels correlated with tumour grade (P<0.01), tumour stage (P<0.01), and a poor prognosis (P<0.05). MMP-8 protein and gene expression in vitro was found to be significantly upregulated by interleukin-1beta (IL-1beta, P<0.01). The data indicate that MMP-8 overexpression in OVCAs is regulated by IL-1beta and that pro-inflammatory cytokines may promote the invasive potential of ovarian cancer.
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PMID:Cytokine-regulated expression of collagenase-2 (MMP-8) is involved in the progression of ovarian cancer. 1460 36

Although matrilysin (MMP-7) is overexpressed in various malignancies, few studies have evaluated its role in epithelial ovarian cancer (EOC) invasion and metastasis. We report that the secretion of MMP-7 in EOC is stimulated significantly by vascular endothelial growth factor (VEGF) and interlukin-8 (IL-8). We also examined the in vivo expression of MMP-7 in EOC and its effects on the in vitro invasion and progelatinase activation. We report that MMP-7 is overexpressed in ovarian cancer cell lines and EOC surgical specimens. DOV13 cells incubated with active rhMMP-7 significantly increased cellular invasion and proMMP-2 activation. RhMMP-7 also showed the ability to activate proMMP-2 and proMMP-9 in immortalized ovarian epithelial cell (IOSE-29) conditioned medium. In addition, rhMMP-7 was able to activate progelatinase in a concentration-dependent manner in vitro. TIMP-2 or the generic MMP inhibitor-GM6001 inhibited both the activation of proMMP-2 and the increased invasion of DOV13 cells promoted by rhMMP-7. By incubation of MMP2-TIMP-2 complex with equal molar rhMMP-7, MMP-2 was dissociated from the complex and activated in a time-dependent manner, suggesting that TIMP-2 helps to keep the latency of MMP-2. TIMP-2 also showed inhibitory effects on the MMP-7 induced increase of gelatinolytic activity in DOV13 and IOSE-29 conditioned media. A strong co-localization of MMP-7 and MMP-2 was observed in DOV13 cells and ovarian carcinoma permanent tissue sections. These results indicate MMP-7 is overexpressed in malignant ovarian epithelium and suggest MMP-7 may facilitate tumor cell invasion in vivo partly through the induction of progelatinase activation.
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PMID:Matrilysin (MMP-7) promotes invasion of ovarian cancer cells by activation of progelatinase. 1552 95

Despite evidence that gonadotropins may facilitate peritoneal metastasis of ovarian cancer by increasing cell adhesion, the action and molecular mechanism of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in ovarian cancer invasion is not well characterized. In the present study, we investigated the effects of FSH and LH on the invasive activity and the expression of metastasis-related proteinases in human epithelial ovarian cancer by Western blot, zymography, reverse transcription-PCR (RT-PCR), ELISA, and Boyden chamber assay. Treatment with FSH or LH (10, 100, or 1,000 ng/mL) significantly increased the invasion of ovarian cancer cell lines, including BG-1, CaOV-3, and SKOV-3 cells but not OVCAR-3 cells. In addition, treatment of SKOV-3 cells with FSH or LH (100 or 1,000 ng/mL) enhanced the expression and activation of matrix metalloproteinases (MMP-2 and MMP-9) as shown by RT-PCR, gelatin zymography, and ELISA. Pretreatment with [(2R)-2-(hydroxamido-carbonylmethyl)-4-methylpentanoyl]-l-tryptophan methylamide (10 micromol/L), a total MMP inhibitor, and 3-(4-phenoxyphenylsulfonyl)-propylthiirane (20 micromol/L), a specific gelatinase inhibitor, neutralized the proinvasive effect of gonadotropins in SKOV-3 cells. In addition, the secretion of tissue inhibitor of metalloproteinases (TIMP-1 and TIMP-2) and plasminogen activator inhibitor-1 was significantly decreased by FSH and LH (100 or 1,000 ng/mL). We further showed that gonadotropins induced an increase in SKOV-3 invasiveness via the activation of protein kinase A (PKA) and phosphatidylinositol 3-kinase (PI3K) signaling pathways. Taken together, these results suggest that gonadotropins may contribute to ovarian cancer metastasis via activation of proteolysis and increase in invasion through the PKA and PI3K pathways.
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PMID:Gonadotropins activate proteolysis and increase invasion through protein kinase A and phosphatidylinositol 3-kinase pathways in human epithelial ovarian cancer cells. 1658 20

Tissue inhibitors of metalloproteinases (TIMPs) play key roles in maintaining homeostasis of the extracellular matrix by controlling matrix metalloproteinases (MMPs). In addition to their role in regulating MMPs, TIMPs have also been shown to have pluripotential effects on cell growth, apoptosis, and differentiation. The aim of this study was to evaluate TIMP-2 level in serous ovarian tumor tissues and to understand further the role of TIMP-2 protein in ovarian tumorigenesis. The expression of TIMP-2 was assessed by immunohistochemistry in a total of 57 ovarian specimens, including 5 normal ovaries, 12 benign serous cystadenomas, 20 serous borderline tumors, and 20 serous carcinomas. In addition, we transfected a TIMP-2 plasmid into the gynecologic cancer cell lines SKOV-3, 2774, and HeLa and then assayed cell growth, apoptosis, and MMP-2 activation. We found that TIMP-2 immunostaining was significantly more frequent in serous carcinomas, mainly in tumor epithelium, compared with cells of the other tissues studied. Tissue inhibitor of metalloproteinase-2 overexpression in ovarian cancer cells did not mediate proapoptosis, inhibited cisplatin-induced apoptosis, and induced MMP-2 expression. These findings suggest that TIMP-2 may function to favor tumor growth in serous ovarian tumorigenesis. Additional research is now needed to elucidate further the role of TIMP-2 in the biologic behavior of ovarian serous tumors.
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PMID:High expression of tissue inhibitor of metalloproteinase-2 in serous ovarian carcinomas and the role of this expression in ovarian tumorigenesis. 1678 92

Ovarian cancer is the most lethal of all gynecological cancers. Most deaths from ovarian cancer are due to widespread intraperitoneal metastases and malignant ascites. However, mechanisms of invasion in ovarian cancer remain poorly understood. In this study, we examined the effects of gonadotropin-releasing hormone (GnRH)-I (the classical mammalian GnRH), GnRH-II (a second form of GnRH), and GnRH receptor on invasion using two human ovarian carcinoma cell lines, OVCAR-3 and SKOV-3. Here we demonstrated that in OVCAR-3, GnRH-I and GnRH-II promoted cell invasion, whereas in SKOV-3, GnRH-I and GnRH-II inhibited cell invasion. Transfection of small interfering RNA to abrogate the gene expression of GnRH receptor reversed GnRH-I and GnRH-II-mediated invasion activities, suggesting that the same receptor, type I GnRH receptor, is essential for the effects of GnRH-I and GnRH-II in both OVCAR-3 and SKOV-3. Treatment of SKOV-3 cells with GnRH-I or GnRH-II resulted in a decrease in matrix metalloproteinase 2 but an increase in tissue inhibitor of metalloproteinase 2 secretions. In addition, we found that GnRH-I and GnRH-II interfered with activation of the phosphatidylinositol-3-kinase/AKT pathway that is well documented to stimulate proteolysis and invasion of ovarian cancer cells. Taken together, these observations suggest that GnRH-I and GnRH-II play key regulatory roles in ovarian tumor cell invasion and extracellular matrix degradation.
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PMID:Differential role of gonadotropin-releasing hormone on human ovarian epithelial cancer cell invasion. 1790 81

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

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