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)

The expression of hepatocyte growth factor (HGF) receptor, encoded by the Met oncogene, is elevated in ovarian and a variety of cancers. Here we show that human ovarian cancer cells with high Met expression were more sensitive to the cell motility and invasion effect of HGF. Met down-regulation by small interfering RNAs or K252a resulted in reduced migration in response to HGF. The invasive/migratory phenotype activated by HGF can be blocked by specific inhibitors of the phosphatidylinositol-3-kinase (PI3K) cascade, inhibitor of p70(S6K), and also the expression of a dominant-negative Akt, demonstrating that HGF transmits the motogenic signal through PI3K and Akt to p70(S6K). A significant role for p70(S6K) in cell invasion is further supported by the observation that expression of constitutively active forms of p70(S6K) is sufficient to induce invasive and migratory phenotypes in ovarian cancer cells. Importantly, activation of p70(S6K) stimulated expression and proteolytic activity of matrix metalloproteinase (MMP)-9 and cellular invasion, whereas it had little effect on MMP-2, suggesting for the first time that MMP-9 up-regulation by p70(S6K) as a key step for HGF-induced invasion and migration. These data suggest that interfering p70(S6K) may provide a novel means of controlling tumor cell invasiveness.
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PMID:Activation of p70S6K induces expression of matrix metalloproteinase 9 associated with hepatocyte growth factor-mediated invasion in human ovarian cancer cells. 1646 1

Vascular endothelial growth factor (VEGF) has been identified to be important in tumor angiogenesis, which is essential for the growth, invasion, and metastasis of solid tumors. The aim of this study was to determine the effect of VEGF overexpression on the invasion of human epithelial ovarian cancer cells in vitro and the possible mechanism involved. The VEGF165 cDNA was transfected into ovarian tumor cell lines CAOV3 and COC1 to promote the expression of VEGF. The VEGF expression and matrix metalloproteinase (MMP)-2 activity were examined by RT-PCR, Western blot analysis and gelatin zymography. A modified Boyden chamber assay was used to test tumor cell invasion in vitro. All cells overexpressing VEGF displayed an enhanced in vitro invasiveness through Matrigel-coated filters with Boyden chamber invasion assay. MMP-2 mRNA and protein were significantly increased during VEGF165 cDNA transfection; MMP-2 activity was also increased. The invasion property of ovarian cancer cells was abrogated with VEGF neutralizing antibody. Our data indicated that the expression of VEGF gave impetus to the in vitro invasion of ovarian cancer cells by stimulating the production and functional activities of MMP-2, which may be a key component of VEGF in promoting ovarian cancer cell invasion. VEGF may constitute a novel therapeutic target for antiangiogenic cancer therapy.
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PMID:Enhanced in vitro invasiveness of ovarian cancer cells through up-regulation of VEGF and induction of MMP-2. 1652 67

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

E-cadherin plays an important role in maintaining tissue architecture. Loss of E-cadherin expression has often been associated with cancer metastasis. This study assessed the immuno-expression of E-cadherin and methylation of CDH1 and correlated them with clinical features in primary epithelial ovarian cancer. Moreover, epithelial ovarian cancer cell SKOV3 was used to explore the mechanism how the demethylating agent 5-Aza inhibited cancer metastasis. Of 80 patients with primary ovarian cancer, we found that decreased immunoexpression pattern of E-cadherin was associated with clinical stage, lymph node metastasis, and degree of differentiation. Methylation of CDH1 detected by MSP occurred frequently and was correlated with reduced expression of E-cadherin protein. 5-Aza treatment could lead to re-expression of functional E-cadherin, followed by decreased MMP-2 and MMP-9 activity and inhibition of cell invasion in SKOV3 cells. Therefore, we conclude that assessment of E-cadherin immunoreactivity or methylation of CDH1 may be a useful prognostic indicator in ovarian cancer, complementary to established prognostic factors. The mechanism underlying 5-Aza's anti-metastasis activity is associated with restored functional expression of E-cadherin and decreased MMPs activity. Correction of aberrant DNA methylation by 5-Aza may provide a new strategy for ovarian cancer prevention and therapy.
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PMID:Clinical evaluation of E-cadherin expression and its regulation mechanism in epithelial ovarian cancer. 1682 27

Recent studies using ovarian cancer cells have shown that the catecholamine hormones norepinephrine (norepi) and epinephrine (epi) may influence cancer progression by modulating the expression of matrix metalloproteinases (MMP) and vascular endothelial growth factor (VEGF). The purpose of this study is to determine if the stress hormone norepi can influence the expression of MMP-2, MMP-9, and VEGF in nasopharyngeal carcinoma (NPC) tumors by using three NPC tumor cell lines. The NPC cell lines HONE-1, HNE-1, and CNE-1 were treated with norepi. The effects of norepi on MMP-2, MMP-9, and VEGF synthesis were measured by ELISA; functional MMP activity was measured by the invasive potential of the cells using a membrane invasion culture system whereas functional activity of VEGF was analyzed using a human umbilical vein endothelial cell tube formation assay. Norepi treatment increased MMP-2, MMP-9, and VEGF levels in culture supernatants of HONE-1 cells, which could be inhibited by the beta-blocker propranolol. Norepi induced the invasiveness of all NPC cell lines in a dose-dependent manner, which was blocked by CMT-3, an MMP inhibitor, and propranolol. Norepi stimulated the release of functional angiogenic VEGF by HONE-1 cells as well. Finally, HONE-1 cells were shown to express beta-adrenergic receptors as did seven of seven NPC biopsies examined. The data suggest that catecholamine hormones produced by the sympathetic-adrenal medullary axis may affect NPC tumor progression, in part, through modulation of key angiogenic cytokines.
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PMID:Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells. 1707 56

Gonadotropin-releasing hormone (GnRH) receptor is present in 80% of ovarian cancer, and numerous studies have provided evidence for a role of GnRH in cell proliferation. In this study, the effect of GnRH on the invasion potential of ovarian cancer cells was investigated. In vitro migration and cell invasion assays with the ovarian cancer cell lines Caov-3 and OVCAR-3 revealed the biphasic nature of GnRH; low concentrations of GnRH agonist (GnRHa) increased the cell motility and invasiveness of these cells, but at increased concentrations, the stimulatory effect was insignificant. Reverse transcription-PCR, Western blot, and gelatin zymography showed that the expression of metastasis-related proteinases, matrix metalloproteinase (MMP)-2 and MMP-9, was up-regulated and activated by GnRHa. Moreover, we observed that GnRHa was able to transactivate the MMP-2 and MMP-9 promoters. The invasive/migratory phenotype activated by GnRHa can be blocked by specific inhibitors or neutralizing antibodies to MMP-2 and MMP-9. Knockdown of the GnRH receptor using small interfering RNA significantly inhibited the GnRH-induced MMP activation, invasion, and migration. In addition, we showed that the c-Jun NH(2)-terminal kinase, but not extracellular signal-regulated kinase 1/2 or p38 mitogen-activated protein kinase, signaling pathway was critical for GnRH-mediated up-regulation of MMP, cell invasion, and motility. These results indicate for the first time an expanded role for GnRH in other aspects of ovarian tumor progression, such as metastasis, via activation of MMP and the subsequent increase in cell migration and invasion.
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PMID:Gonadotropin-releasing hormone promotes ovarian cancer cell invasiveness through c-Jun NH2-terminal kinase-mediated activation of matrix metalloproteinase (MMP)-2 and MMP-9. 1710 27

The autocrine endothelin (ET)-1/endothelin A receptor (ET(A)R) pathway is an important regulator of several processes involved in ovarian cancer progression, and its overexpression is associated with aggressive disease. These features have led to the proposal of the ET(A)R receptor as a potential target for improving ovarian cancer treatment. In this study, we evaluated in vitro and in vivo the effects of ZD4054, an orally active antagonist that specifically binds ET(A)R, as monotherapy, and in combination with paclitaxel. In the human ovarian cancer ET(A)R-positive cell lines HEY, OVCA 433, SKOV-3, and A-2780, ZD4054 effectively inhibited the basal and ET-1-induced cell proliferation, associated with the inhibition of AKT and p42/44MAPK phosphorylation, and with increased apoptosis, through the inhibition of bcl-2 and activation of caspase-3 and poly(ADP-ribose) polymerase proteins. ZD4054 treatment also resulted in a reduction of ET(A)R-driven angiogenesis and invasive mediators, such as vascular endothelial growth factor, cyclooxygenase-1/2, and matrix metalloproteinase (MMP). The combination of ZD4054 and paclitaxel led to the potentiation of all these effects, indicating that ZD4054, by blocking the ET(A)R-dependent proliferative, invasive, and antiapoptotic signals, can enhance sensitivity to paclitaxel. In HEY ovarian cancer xenografts, ZD4054 significantly inhibited tumor growth to the same degree as paclitaxel. Furthermore, ZD4054-dependent tumor growth inhibition was associated with a reduction in proliferation index, microvessel density, and MMP-2 expression. Interestingly, the combination of ZD4054 and paclitaxel produced additive antitumor effects, with 40% of mice remaining tumor-free, supporting a rationale for the clinical use of ZD4054 as monotherapy or in combination with cytotoxic drugs.
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PMID:ZD4054, a specific antagonist of the endothelin A receptor, inhibits tumor growth and enhances paclitaxel activity in human ovarian carcinoma in vitro and in vivo. 1762 Apr 30

Degradation of collagen is required for the physiological remodelling of connective tissues during growth and development, as well as in wound healing, inflammatory diseases, and cancer cell invasion. In remodelling adult tissues, degradation of collagen occurs primarily through a phagocytic pathway. While various steps in this pathway have been characterized, the enzyme required to fragment collagen fibrils for phagocytosis has not been identified. Laser confocal microscopy, transmission electron microscopy and biochemical assays were used to show that degradation of collagen substrates by fibroblasts correlated with the expression of the membrane-bound metalloproteinase MT1-MMP (membrane-type 1 matrix metalloproteinase). The MT1-MMP was localized to sites of collagen cleavage on the cell surface and also within the cells. In contrast with MT1-MMP, the gelatinase MMP-2 was not required for collagen phagocytosis. Similar analyses of several ovarian cancer, breast cancer and fibrosarcoma cells indicated that highly metastatic cells also degrade collagen through a phagocytic pathway that is mediated by MT1-MMP. Collectively, these studies demonstrate a pivotal role for catalytically active MT1-MMP in preparing collagen fibrils for phagocytic degradation by normal and transformed cells.
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PMID:Phagocytosis of collagen by fibroblasts and invasive cancer cells is mediated by MT1-MMP. 1763 28

Malignant ascites is a major source of morbidity and mortality in ovarian cancer patients. It functions as a permissive reactive tumor-host microenvironment and provides sustenance for the floating tumor cells through a plethora of survival/metastasis-associated molecules. Using a syngeneic, immunocompetent model of peritoneal ovarian carcinomatosis in SP(-/-) mice, we investigated the molecular mechanisms implicated in the interplay between host secreted protein acidic and rich in cysteine (SPARC) and ascitic fluid prosurvival/prometastasis factors that result in the significantly augmented levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP). Ascitic fluid-enhanced ID8 invasiveness was mediated through VEGF via a positive feedback loop with MMP-2 and MMP-9 and through activation of alpha(v) and beta(1) integrins. Host SPARC down-regulated the VEGF-MMP axis at the transcriptional and posttranscriptional levels. In vitro, SPARC attenuated the basal as well as VEGF-induced integrin activation in tumor cells. SPARC inhibited the VEGF- and integrin-mediated ID8 proliferation in vitro and significantly suppressed their tumorigenicity in vivo. Relative to SP(+/+), SP(-/-) ascitic fluid contained significantly higher levels of bioactive lipids and exerted stronger chemotactic, proinvasive, and mitogenic effects on ID8 cells in vitro. SP(-/-) ascites also contained high levels of interleukin-6, macrophage chemoattractant protein-1, and 8-isoprostane (prostaglandin F(2)alpha) that were positively correlated with extensive infiltration of SP(-/-) ovarian tumors and ascites with macrophages. In summary, our findings strongly suggest that host SPARC normalizes the microenvironment of ovarian cancer malignant ascites through down-regulation of the VEGF-integrin-MMP axis, decreases the levels and activity of bioactive lipids, and ameliorates downstream inflammation.
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PMID:Normalization of the ovarian cancer microenvironment by SPARC. 1795 2

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