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)

Expression of CD44 standard form (CD44s) was evaluated by automated immunohistochemical analysis using the anti-CD44 A3D8 clone in 101 ovarian epithelial neoplasms including 82 primary tumors (64 carcinomas and 18 tumors of low malignant potential [LMP]), 9 lymph node metastases, 8 malignant ascites, and 2 peritoneal implants. Immunostaining was scored semiquantitatively. Tumors were graded according to the FIGO (International Federation of Gynecology and Obstetrics) classification system. Tumor stage and patient survival were determined from the patient records. While 9 of 18 LMP tumors expressed CD44s, only 15 of 64 carcinomas expressed it. In the carcinomas, univariate analysis revealed that decreased CD44s expression correlated with high tumor grade, advanced stage, and shortened survival. Loss of CD44s expression also was noted in the tumor cells in 8 of 9 lymph node metastases, 7 of 8 malignant ascites, and 1 of 2 implants. Multivariate analysis revealed that only tumor stage independently correlated with patient survival. Loss of CD44s expression determined by immunohistochemical analysis is more common in ovarian carcinomas than in LMP tumors; correlates with prognostic variables including tumor grade, stage, and survival; and may have an important role in the dissemination of ovarian cancer.
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PMID:Decreased CD44 standard form expression correlates with prognostic variables in ovarian carcinomas. 1144 42

The exact mechanisms by which serous ovarian cancer cells invade through their underlying basement membrane or are released from the surface of the ovary have yet to be elucidated. This process undoubtedly has a complex molecular basis that most likely involves multiple cell surface receptors, basement membrane components, intercellular adhesion molecules, and signaling from the cell [137]. One possible mechanism by which ovarian carcinoma tumor cells may alter their basement membrane is by the synthesis and secretion of proteolytic enzymes that degrade their basement membranes [88-94, 138]. Alternatively, metastatic ovarian carcinoma cells may decrease their synthesis and/or secretion of ECM molecules. Additional studies are required to determine whether the more aggressive behavior of malignant ovarian carcinoma cells, compared to normal ovarian epithelial cells, is related to an altered cellular response towards ECM molecules, perhaps due to alterations in adhesion molecules/receptors. A further elucidation of the mechanisms by which serous ovarian carcinoma cells regulate their expression of ECM molecules and adhesion molecules/receptors will help in our understanding of the invasion and metastasis of tumor cells. Members of several families of adhesion molecules have been described that seem to be important in the progression of ovarian carcinoma, including CD44, integrins, and E-cadherin. Due to the complexity of this disease, it is likely that other adhesion molecules will also be implicated in the adhesion, migration, invasion, growth, proliferation, and apoptosis of ovarian carcinoma cells. Our group and others have shown that CD44 and the beta 1 integrin subunit play fundamental roles in the adhesion and migration of ovarian carcinoma cells to mesothelial cells and their associated pericellular matrix. Subsequent to the initial adhesion, the ovarian carcinoma cells may migrate through the layer of mesothelial cells, penetrate through the underlying basement membrane, invade into the tissue, and establish a secondary site of growth. Further studies will be required in order to fully understand the relationship of each adhesion molecule and their ligand(s) in the progression of this disease. Once the adhesion molecules and their ligand(s) for each step of the progression of this disease have been identified, it should be possible to develop reagents that can inhibit these interactions. Then, when ovarian carcinoma cells can no longer interact with mesothelial cells and their associated ECM, the dissemination of ovarian carcinoma cells in vivo may be prevented.
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PMID:Adhesion molecules. 1177 59

Bikunin is a Kunitz-type protease inhibitor predominantly found in human amniotic fluid. In cancers, administration of bikunin may block tumor cell invasion by a direct inhibition of tumor cell-associated plasmin activity as well as by inhibiting urokinase-type plasminogen activator (uPA) expression at the gene and protein levels, possibly through suppression of CD44 dimerization and/or the MAP kinase signaling cascade. Treatment of cancer patients with bikunin may be beneficial in the adjuvant setting to delay the onset of metastasis development and/or in combination with cytotoxic agents to improve treatment efficacy in patients with advanced ovarian cancer.
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PMID:The protease inhibitor bikunin, a novel anti-metastatic agent. 1281 71

CD44 refers to a multifunctional family of type I transmembrane proteins. The CD44 gene contains at least 21 exons, 11 of which can be variably spliced and produce a variety of heavily glycosylated cell surface proteins, known as CD44 variant isoforms. These proteins have been implicated in many biological processes, such as cell adhesion, cell substrate, cell to cell interactions, including lymphocyte homing haemopoiesis, cell migration and metastasis. These abilities are of great importance in chronic inflammation and in cancer. Published data have shown that CD44 has the ability to recruit leucocytes to vascular endothelium at sites of inflammation, which is one of the first steps in the inflammatory response. In cancer, deregulation of the adhesion mechanisms increases the ability of tumor cells to metastasis. This behavior seems to be explained by the existing relationship between hyaluronan, a basic component of the extracellular matrix and CD44, which is its major cell surface receptor. There are CD44 variant isoforms which are expressed on different types of normal cells. In addition some isoforms are overexpressed on tumor cells including breast, cervical, endometrial and ovarian cancer. This property seems to be correlated with the metastatic potential of these cells. This review summarizes the available data on the possible prognostic role of the polymorphic CD44 protein family and its role as a tumor marker in gynaecological cancer.
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PMID:CD44 family and gynaecological cancer. 1475 31

Alternative splicing represents an important nuclear mechanism in the post-transcriptional regulation of gene expression, which is frequently altered during tumorigenesis. Previously, we have described marked changes in alternative splicing of the CD44 gene in ovarian and breast cancer. In the latter one we described also a specific induction of splicing factors during tumor development. Now we have focussed our studies on the expression profiles of splicing factors, including classical SR proteins, Tra2 and YB-1 in physiological and malignant ovarian tissues by RT-PCR and Western blot analysis. We detected changed expression pattern with higher levels of phosphorylated 30 kDa SR proteins as well as relatively high concentrations of hyperphosphorylated Tra2 protein isoforms in ovarian cancer. RT-PCR analysis revealed a marked induction of SC35 and ASF/SF2 as well as mRNA levels in malignant ovarian tissue. These results suggest gene-specific alterations of expression rather than a general induction of the splicing machinery. Together with previously performed functional studies of CD44 splicing these findings implicate that altered expression profiles of SR proteins, Tra2beta and YB-1 might be responsible for the known changes of alternative CD44 splicing in ovarian cancer.
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PMID:Expression of splicing factors in human ovarian cancer. 1506 51

To determine if the immunohistochemical expression of hyaluronan synthase (HAS) correlates with the clinicopathological manifestations or clinical outcomes of ovarian carcinoma, sections of tumor tissue from 33 ovarian cancer patients were immunostained by the avidin-biotin-peroxidase complex method using anti-HAS1, anti-HAS2, anti-HAS3 and anti-CD44 antibody. A section was defined as having positive expression when >50% of the tumor cells were intensely stained. The microvessel density, which was defined as the mean number of new vessels, was determined under light microscopy. In the 33 ovarian cancer cases, 12 cases had positive expression of HAS1, 21 cases had positive expression of HAS2 and 11 cases had positive expression of HAS3. The expression of HAS1, HAS2 and HAS3 was unrelated to the stage of disease. CD44 expression occurred more frequently in the HAS1-positive group than in the HAS1-negative group, but the expression of HAS2 and HAS3 was unrelated to CD44 expression. The microvessel density was higher in the HAS1-positive group than in the HAS1-negative group. But the microvessel density did not differ in relation to the expression of HAS2 and HAS3. In the 23 patients that received chemotherapy, the expression of HAS1, HAS2 and HAS3 was unrelated to the chemotherapy response. The overall survival time was longer in the HAS1-negative group than in the HAS1-positive group. However, the expression of HAS2 and HAS3 was unrelated to the overall survival time. These results suggest that HAS1 expression in ovarian cancer may be associated with disease progression through angiogenesis and is an independent predictor of patient survival.
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PMID:Hyaluronan synthase expression in ovarian cancer. 1537 93

We provided evidence previously that bikunin, a Kunitz-type protease inhibitor, can disrupt dimerization of CD44 proteins, which may result in suppression of receptor-mediated MAP kinase signaling. However, to what extent dimerization may alter ligand-induced signaling has not been documented. Given the recent recognition that some growth factor receptors can form heterodimers with CD44, the present study was undertaken to determine whether the CD44 and growth factor receptors (e.g., EGFR, FGFR, HGFR, VEGFR, TGF-betaRI, or TGF-betaRII) can form heterodimers in cancer cells and, if so, to investigate the potential functional consequences of such heterodimerization. We also examined whether bikunin can abrogate these heterodimerizations and inhibit CD44/growth factor-dependent signaling. Here, we show direct evidence for heterodimerization of CD44-FGFR and CD44-TGF-betaRI in human chondrosarcoma HCS-2/8 cells, CD44-EGFR complex in human glioma U87MG cells, and CD44-TGF-betaRI heterodimer in human ovarian cancer HRA cells. Coupling of CD44 and growth factor receptor may be selective, depending on a cell type. Bikunin does not alter the ligand binding, whereas functionally reduces heterodimerization between CD44 and growth factor receptors. The disruption of heterodimerization substantially reduces receptor-induced tyrosine phosphorylation and ERK1/2 activation. Taken together, our data suggest that bikunin-mediated suppression of heterodimerization between CD44 and growth factors may inhibit the agonist-promoted activation of the signaling pathway.
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PMID:Bikunin down-regulates heterodimerization between CD44 and growth factor receptors and subsequently suppresses agonist-mediated signaling. 1559 42

In this study, we have examined the interaction of hyaluronan (HA)-CD44 with IQGAP1 (one of the binding partners for the Rho GTPase Cdc42) in SK-OV-3.ipl human ovarian tumor cells. Immunological and biochemical analyses indicated that IQGAP1 (molecular mass of approximately 190 kDa) is expressed in SK-OV-3.ipl cells and that IQGAP1 interacts directly with Cdc42 in a GTP-dependent manner. Both IQGAP1 and Cdc42 were physically linked to CD44 in SK-OV-3.ipl cells following HA stimulation. Furthermore, the HA-CD44-induced Cdc42-IQGAP1 complex regulated cytoskeletal function via a close association with F-actin that led to ovarian tumor cell migration. In addition, the binding of HA to CD44 promoted the association of ERK2 with the IQGAP1 molecule, which stimulated both ERK2 phosphorylation and kinase activity. The activated ERK2 then increased the phosphorylation of both Elk-1 and estrogen receptor-alpha (ER alpha), resulting in Elk-1- and estrogen-responsive element-mediated transcriptional up-regulation. Down-regulation of IQGAP1 (by treating cells with IQGAP1-specific small interfering RNAs) not only blocked IQGAP1 association with CD44, Cdc42, F-actin, and ERK2 but also abrogated HA-CD44-induced cytoskeletal function, ERK2 signaling (e.g. ERK2 phosphorylation/activity, ERK2-mediated Elk-1/ER alpha phosphorylation, and Elk-1/ER alpha-specific transcriptional activation), and tumor cell migration. Taken together, these findings indicate that HA-CD44 interaction with IQGAP1 serves as a signal integrator by modulating Cdc42 cytoskeletal function, mediating Elk-1-specific transcriptional activation, and coordinating "cross-talk" between a membrane receptor (CD44) and a nuclear hormone receptor (ER alpha) signaling pathway during ovarian cancer progression.
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PMID:Hyaluronan-CD44 interaction with IQGAP1 promotes Cdc42 and ERK signaling, leading to actin binding, Elk-1/estrogen receptor transcriptional activation, and ovarian cancer progression. 1565 47

Dendritic cells (DCs) constitute very attractive vectors for cancer immunotherapy due to their ability to efficiently capture and present tumor antigens, which initiates tumor-directed T-cell responses. Because the initiation of cytotoxic anti-tumor immune responses requires the cross-presentation mechanism, antigen targeting to DCs represents a very important step in the chain of events that constitutes the cross-priming immune process. In the current study, we explored the ability of DCs loaded with antibody-coated melanoma and ovarian carcinoma tumor cells to cross-present tumor antigens to CD8+ T cells and elicit in vitro anti-tumor immune responses. Coating melanoma and ovarian cancer cells with monoclonal antibodies against different surface antigens (CD44, ME491, LFA-3, and CD24) expressed by the tumor cells promoted the cross-presentation of the tumor-associated antigens as MART-1, gp100, tyrosinase, and NY-ESO-1 by DCs to CD8+ T. These tumor antigen-specific CD8+ T-cell populations resulting from the DC-mediated cross-priming process were identified using specific immune tetramers and were a few fold larger than the ones generated using peptide-pulsed or apoptotic tumor cell-loaded DCs. The CD8+ T cells generated by DCs loaded with monoclonal antibody-coated tumor cells were cytotoxic against the primary melanoma and ovarian carcinoma cells. Thus, targeting monoclonal antibody-coated tumor cells to DCs is a novel method that opens new perspectives for immunotherapy strategies.
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PMID:Monoclonal antibodies targeted against melanoma and ovarian tumors enhance dendritic cell-mediated cross-presentation of tumor-associated antigens and efficiently cross-prime CD8+ T cells. 1636 99

Chronic inflammation is implicated in the pathophysiology of ovarian cancer. Tumor necrosis factor-alpha (TNF-alpha), a major inflammatory cytokine, is abundant in the ovarian cancer microenvironment. TNF-alpha modulates the expression of CD44 in normal T lymphocytes and CD44 is implicated in ovarian carcinogenesis and metastases. However, little is known about the role of TNF-alpha in CD44 expression of cancer cells. Recent clinical work using TNF-alpha inhibitors for the treatment of ovarian cancer makes the study of TNF-alpha interactions with CD44 crucial to determining treatment a success or a failure. We studied the effect of TNF-alpha on ovarian cancer cells viability, CD44 expression, and in vitro migration/invasion. Our results revealed that TNF-alpha differentially modulates the expression of CD44 in TNF-alpha-resistant ovarian cancer cells, affecting their in vitro migration, invasion, and binding to hyaluronic acid. TNF-alpha up-regulation of CD44 expression was dependent on the activation of c-Jun NH(2)-terminal kinase (JNK) and this activation was accompanied by an increase in their invasive phenotype. On the contrary, if TNF-alpha failed to induce JNK phosphorylation, the end result was down-regulation of both CD44 expression and the invasive phenotype. These results were confirmed by the use of JNK inhibitors and a TNF receptor competitive inhibitor.
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PMID:Tumor necrosis factor-alpha differentially modulates CD44 expression in ovarian cancer cells. 1690 92

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