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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stromal cells are essential for the progression of many cancers including ovarian tumors. Stromal cell-epithelial cell interactions are important for tumor development, growth, angiogenesis, and metastasis. In the current study, the effects of normal ovarian bovine stromal cells on ovarian tumor progression was investigated. The hypothesis tested is that ovarian stromal cells will alter the onset and progression of ovarian tumors. Conditioned medium from normal bovine ovarian surface stromal cells was found to stimulate the growth of normal ovarian surface epithelium and had no effect on the growth of human tumor cell lines SKOV3 and OCC1. Human ovarian cancer cell lines, SKOV3 and OCC1, were injected subcutaneously into nude mice to examine tumor progression. Tumor growth in the nude mice was dramatically reduced when normal ovarian surface stromal cells were co-injected with SKOV3 or OCC1 cells. Similar results were obtained with normal bovine or human ovarian stromal cells. In contrast, irrelevant testicular stromal cells and epithelial cells had no effect on tumor growth in the nude mouse. Histological examination of these tumors revealed a characteristic stromal cell component adjacent to epithelial cell colonies. Sections of these tumors were hybridized with species specific genomic probes using fluorescence in situ hybridization to identify cell populations. Epithelial cells were shown to be of human origin (i.e. SKOV3 or OCC1), but stromal cells were found to be primarily murine in origin (i.e. host tissue). No detectable bovine cells were observed in the tumors after one week post-injection. Results suggest that stromal cells are an essential component of ovarian tumors. Interestingly, normal ovarian stromal cells had the ability to inhibit tumor growth, but were not able to survive long-term incubation at the tumor site. The developing tumor appears to recruit host (i.e. murine) stromal cells to invade the tumor and support its growth. In summary, normal ovarian stromal cells can inhibit ovarian tumor progression and the developing tumors recruit adjacent host stroma to become "tumor stroma". The tumor stroma likely develop an altered phenotype that cooperates with the tumorigenic epithelial cells to help promote the progression of ovarian cancer.
Mol Cell Endocrinol 2001 Apr 25
PMID:Stromal-epithelial interactions in the progression of ovarian cancer: influence and source of tumor stromal cells. 1132 14

The CRE (cyclic AMP response element)-transcription factor complex plays a critical role in response to hormonal signals for cell proliferation, differentiation, and apoptosis. We have reported previously that the CRE-transcription factor decoy oligonucleotide specifically slows tumor cell proliferation and inhibits CRE- and Ap-1-directed transcription in vivo (Park et al., 1999). We have investigated the effect of inhibiting CRE-directed transcription on ovarian cancer cell growth. Here, we report that CRE-decoy oligonucleotide treatment results in the inhibition of cell growth and a marked reduction in the expression of the regulatory and catalytic subunits of protein kinase A and the type I and type II protein kinase A holoenzymes. Growth inhibition was accompanied by changes in cell morphology, appearance of apoptotic nuclei, and DNA fragmentation. In addition, MMP-9 (matrix methalloproteinase-9) activity was markedly reduced in CRE-decoy treated cells. Indirect immunofluorescence revealed that CRE-decoy oligonucleotide treatment promoted export of the CRE-binding protein, CREB, from the nucleus to the cytoplasm, while importing the catalytic subunit of protein kinase A from the cytoplasm to the nucleus. The results indicate that the decoy oligonucleotide, by binding specifically to CRE-transcription factors, interferes with CRE-directed transcription in vivo. These results show a critical role for CRE-directed transcription in ovarian cancer cell growth. Thus, the CRE-decoy oligonucleotide may provide a powerful means to combat ovarian cancer.
Mol Cell Biochem 2001 Feb
PMID:Apoptosis, growth arrest and suppression of invasiveness by CRE-decoy oligonucleotide in ovarian cancer cells: protein kinase A downregulation and cytoplasmic export of CRE-binding proteins. 1133 Aug 38

We performed genome-wide linkage analysis in 58 patients and nine unaffected members among 28 families with no mutation in BRCA1 or BRCA2, employing a set of 410 microsatellite markers. We initially screened the whole genome, including the X chromosome, by a non-parametric method using the GENEHUNTER program. As a result, chromosome 3p22-p25 showed a suggestive score for linkage [LOD = 3.49 and non-parametric LOD (NPL) = 2.77 at D3S3611] based on a multipoint analysis. Additionally, based on a two-point analysis using dense markers, this 3p22-p25 region showed a P-value < 0.05 at 10 markers and there is suggestive evidence for linkage at two markers within approximately 19 cM (NPL = 2.60 and 2.49 at D3S1597 and D3S3611, respectively). To explore whether the candidate gene in this 3p22-p25 region contributed to carcinogenesis of familial ovarian cancer in a similar fashion to the tumor suppressor gene, we performed loss of heterozygosity (LOH) analysis. It was observed that the frequency of LOH at four markers in this region was >50% only in tumor tissues from patients with no mutation in BRCA1 or BRCA2, not in those with a BRCA1 mutation.
Hum Mol Genet 2001 Jun 15
PMID:Localization of a novel susceptibility gene for familial ovarian cancer to chromosome 3p22-p25. 1144 Sep 95

Interest in inhibin as a marker of ovarian malignancy was stimulated by the description of elevated immunoreactive inhibin levels in the sera of patients with granulosa cell tumours. Several groups have confirmed the value of serum inhibin in the diagnosis and follow-up of patients with this uncommon malignancy. Immunoreactive inhibin levels are also frequently elevated in patients with mucinous cystadenocarcinoma and less frequently in other forms of ovarian tumour. Assay of sera using the specific dimeric inhibin assays has shown that ovarian tumours are able to secrete dimeric inhibin particularly inhibin B. The less specific alpha-subunit directed assays, however, most frequently show elevated concentrations. Used in combination with CA125 as a dual tumour marker, it appears in principle that inhibin can be a useful diagnostic agent. Immunohistochemistry for the inhibin subunits has been reported with increasing frequency as a helpful method to assess suspected ovarian stromal cell tumours. Its diagnostic accuracy for other types of ovarian adenocarcinoma appears less reliable. Expression of the inhibin subunit mRNAs has been demonstrated in a variety of ovarian malignancies. The observation that inhibin levels are elevated in ovarian cancer has stimulated studies of their relevance to the molecular pathogenesis of these malignancies. Findings to date have been largely negative with no evidence for activating mutations of the FSH receptor or of the post-receptor signalling pathway proteins.
Mol Cell Endocrinol 2001 Jun 30
PMID:The inhibins and ovarian cancer. 1145 84

The telomerase RNA-protein complex responsible for maintenance of telomeric DNA at chromosome ends, is usually inactive in most primary somatic human cells, but is specifically activated with in vitro immortalization and during tumorigenesis. Although expression of the RNA component of telomerase appears to be constitutive, the expression pattern of human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, is correlated with measured enzyme activity. In particular, a >80% concordance has been reported between telomerase activity and hTERT mRNA expression in ovarian tumors. Accordingly, to learn more about the mechanism regulating hTERT gene expression in ovarian carcinoma, we have performed a detailed analysis of the 5'-flanking promoter region of the hTERT gene. We have reported previously the isolation and analysis of a 5.8-kb genomic fragment containing the human hTERT gene promoter (M. Tzukerman et al., Mol. Biol. Cell, 11: 4381-4391, 2000). Deletion analysis of this promoter was carried out using transient transfection of promoter-reporter constructs in four different telomerase-expressing, ovarian carcinoma-derived cell lines, the tumorigenic properties of which have been characterized, and was compared with telomerase-negative primary human fibroblasts and nontransformed ovarian epithelial cells. These assays have shown that the hTERT promoter is inactive in telomerase-negative cells and is active in telomerase-positive cell lines. A core promoter of 283 bp upstream of the transcription initiation site (TI) was found to be sufficient for maximum promoter activity, suggesting the presence of inhibitory elements within the larger promoter sequence. Gel shift analysis of the core promoter using nuclear extracts from the ovarian and control cell lines revealed specific transcription factor binding using extracts from telomerase-positive cells. Among the binding elements, we identified two E-boxes (CACGTG) as well as a novel element (MT-box), which we identified recently in a number of differentiation systems. Site-directed mutagenesis was used to introduce mutations into this novel transcription factor binding element. These mutations significantly affect the transcriptional activity of hTERT promoter in a cell type-specific manner and suggest that the transcription factors that bind to the E-box and the novel element cooperatively function as major determinants of hTERT expression and telomerase activity in ovarian cancer. Further comparison of promoter activity, telomerase activity, and telomere length among the different ovarian cancer cells indicated that a threshold level of telomerase activity is apparently sufficient to protect telomere integrity and permit the immortal state of the different ovarian cancer cell lines.
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PMID:Human telomerase reverse transcriptase promoter regulation in normal and malignant human ovarian epithelial cells. 1145 3

The majority of ovarian tumors are derived from the single layer of epithelial cells on the surface of the ovary termed the ovarian surface epithelium (OSE). Stromal cell-OSE interactions are postulated to be an important aspect of normal OSE biology and the biology of ovarian cancer. Transforming growth factor beta (TGFbeta) has been shown to often be a mesenchymal cell-derived growth factor that mediates stromal cell-epithelial cell interactions in a variety of different tissues. The current study investigates the expression and action of TGFbeta isoforms (TGFbeta1, TGFbeta2, and TGFbeta3) in OSE and the underlying stroma in both normal bovine and human tumor tissues. Normal bovine ovaries are similar to human ovaries and are used as a model system to investigate normal OSE and stromal cell functions. All three TGFbeta isoforms and their receptor, transforming growth factor beta receptor type II (TGFbetaRII), proteins were found to be detected in the OSE from normal bovine ovaries using immunohistochemistry. Ovarian stromal tissue also contained positive immunostaining for TGFbeta isoforms and TGFbetaRII. RNA was collected from normal bovine OSE and ovarian stromal cells to examine TGFbeta gene expression. TGFbeta1, TGFbeta2, and TGFbeta3 transcripts were detected in both freshly isolated and cultured bovine OSE and stromal cells by a sensitive quantitative polymerase chain reaction assay. TGFbeta1 and TGFbeta2 mRNA levels were found to be present at similar levels in freshly isolated OSE and stroma. Interestingly, TGFbeta3 mRNA levels were significantly higher in freshly isolated OSE than stromal cells. All but TGFbeta3 mRNA in OSE increased when the cells were cultured. Observations indicate that normal bovine OSE and stroma cells express the three TGFbeta isoforms in vivo and in vitro. Human ovarian tumors from stage II, stage III and stage IV cases were found to express TGFbeta1, TGFbeta2, TGFbeta3 and TGFbetaRII protein primarily in the epithelial cell component by immunohistochemistry analysis. The stromal cell component of the human ovarian tumors contained little or no TGFbeta or TGFbetaRII immunostaining. TGFbeta actions on bovine OSE and stromal cells were also investigated. TGFbeta was found to inhibit the growth of OSE, but not stromal cells. To further examine the actions of TGFbeta on OSE, the expression of two growth factors previously shown to be expressed by OSE were analyzed. TGFbeta1 was found to stimulate the expression of both keratinocyte growth factor (KGF) and kit ligand/stem cell factor (KL) by bovine OSE. Therefore, TGFbeta actions on OSE will likely promote a cascade of cell-cell interactions and cellular responses involving multiple growth factors. The effects of regulatory agents on TGFbeta expression by the bovine OSE were examined. Transforming growth factor alpha (TGFalpha) stimulated TGFbeta1 expression, TGFbeta1 stimulated TGFbeta2 expression, and follicle stimulating hormone (FSH) stimulated TGFbeta3 expression. These results demonstrate that TGFbeta isoforms are regulated differently by the regulatory agents tested. In summary, all the TGFbeta isoforms are differentially expressed by the OSE and TGFbeta appears to have an important role in regulating OSE and possibly stromal-OSE interactions. A complex network of endocrine and paracrine interactions appears to influence the expression and actions of TGFbeta on OSE. Abnormal expression and/or action of TGFbeta is postulated to in part be involved in the onset and progression of ovarian cancer.
Mol Cell Endocrinol 2001 Sep
PMID:Expression and action of transforming growth factor beta (TGFbeta1, TGFbeta2, TGFbeta3) in normal bovine ovarian surface epithelium and implications for human ovarian cancer. 1151 49

The adenovirus (Ad) is a useful vector for cancer gene therapy due to its unparalleled gene transfer efficiency to dividing and quiescent cells. Primary cancer cells, however, often have highly variable or low levels of the requisite coxsackie-adenovirus receptor (CAR). Also, assessment of gene transfer and vector persistence has been logistically difficult in human clinical trials. We describe here two novel bicistronic adenoviral (Ad) vectors, AdTKSSTR and RGDTKSSTR, which contain the herpes simplex virus thymidine kinase gene (TK) for molecular chemotherapy and bystander effect. In addition, the viruses contain the human somatostatin receptor subtype-2 gene (SSTR2), the expression of which can be noninvasively imaged. We enhanced the infectivity of RGDTKSSTR by genetically incorporating the RGD-4C motif into the HI-loop of the fiber. This allows the virus to circumvent CAR deficiency by binding to alpha(v)beta(3) and alpha(v)beta(5) integrins, which are highly expressed on most ovarian cancers. The expanded tropism of RGDTKSSTR results in increased infectivity of purified primary ovarian cancer cells and allows enhanced gene transfer in the presence of malignant ascites containing anti-Ad antibodies. RGDTKSSTR may be a useful agent for treating ovarian cancer in clinical trials.
Mol Ther 2001 Sep
PMID:An adenovirus with enhanced infectivity mediates molecular chemotherapy of ovarian cancer cells and allows imaging of gene expression. 1154 13

Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are members of the phospholipid growth factor family. A major limitation in the field to date has been a lack of receptor subtype-specific agonists and antagonists. Here, we report that dioctylglycerol pyrophosphate and dioctylphosphatidic acid are selective antagonists of the LPA(1) and LPA(3) receptors, but prefer LPA(3) by an order of magnitude. Neither molecule had an agonistic or antagonistic effect on LPA(2) receptor. Consistent with this receptor subtype selectivity, dioctylglycerol pyrophosphate inhibited cellular responses to LPA in NIH3T3 fibroblasts, HEY ovarian cancer cells, PC12 pheochromocytoma cells, and Xenopus laevis oocytes. Responses elicited by S1P in these cell lines that endogenously express S1P(1), S1P(2), S1P(3), and S1P(5) receptors were unaffected by dioctylglycerol pyrophosphate. Responses evoked by the G protein-coupled receptor ligands acetylcholine, serotonin, ATP, and thrombin receptor-activating peptide were similarly unaffected, suggesting that the short-chain phosphatidates are receptor subtype-specific lysophosphatidate antagonists.
Mol Pharmacol 2001 Oct
PMID:Short-chain phosphatidates are subtype-selective antagonists of lysophosphatidic acid receptors. 1156 40

Urokinase plasminogen activator (uPA) has been implicated in the metastatic potential of ovarian carcinomas of surface epithelial origin. The SKOV-3 human ovarian cancer cell line was tested for uPA secretory responses (enzyme immunoassay of conditioned media) after treatments with sex steroids, human menopausal gonadotropins (hMG), or gonadotropin-releasing hormone (GnRH). Secretion of uPA during a 6-h incubation was unaffected by testosterone, estradiol-17beta, hMG, or GnRH. Progesterone, at supraphysiological concentrations, suppressed uPA secretion; this reaction was not altered by the progesterone receptor antagonist RU486 or the transcriptional inhibitor actinomycin D. It appears that progesterone exerted a direct biophysical effect on the plasma membrane manifested by an interference with shedding of uPA in exocytotic vesicles. Finally, invasion of SKOV-3 cells into Matrigel was inhibited by progesterone. We suggest that progesterone can disrupt the fluid dynamics of plasma membranes and thereby invoke an antitumorigenic action via inhibition of proteolytic secretions.
J Steroid Biochem Mol Biol 2001 Aug
PMID:High-dose progesterone inhibition of urokinase secretion and invasive activity by SKOV-3 ovarian carcinoma cells: evidence for a receptor-independent nongenomic effect on the plasma membrane. 1156 43

One of the major problems with ovarian cancer treatment is the clinical development of resistance to cisplatin. Considerable efforts have been directed toward the identification of biological and pharmacological agents that would reverse drug resistance to cisplatin. ALLnL is an inhibitor of the proteasome that can inhibit the ubiquitin-proteasome pathway, which plays an essential role in many processes in cell life. We have recently shown that ALLnL, at concentrations that do not appear harmful, has significantly enhanced DNA platination and decreased DNA repair of cisplatin-DNA adducts in human A2780/CP70 ovarian carcinoma cells. These activities of proteasome inhibition were also associated with substantially increased cisplatin toxicity in these cells. In this communication, we demonstrate that treatment of A2780/CP70 cells with ALLnL blocks cisplatin-induced ERCC-1 mRNA expression in a concentration- and time-dependent manner, as measured by Northern blot analysis. In addition, we showed that the cisplatin-dependent increase in steady-state levels of ERCC-1 mRNA was prevented by pretreatment with lactacystin, a potent and specific inhibitor of proteasome. These results suggest that the effect of proteasome inhibition on cisplatin cytotoxicity, DNA platination, and DNA repair of cisplatin adducts in ovarian cancer cells may be through down-regulating ERCC-1 expression.
Res Commun Mol Pathol Pharmacol
PMID:Proteasome inhibition suppresses cisplatin-dependent ERCC-1 mRNA expression in human ovarian tumor cells. 1158 65


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