Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0027627 (metastases)
103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased expression of the hepatocyte growth factor (HGF) receptor (c-met) and urokinase type plasminogen (uPA) correlated with the development and metastasis of cancers. To investigate the role of HGF/c-met signaling on metastasis in cancer cells stimulated with HGF, we examined the effects of a specific MEK1 inhibitor (PD98059) and a p38 MAP kinase inhibitor (SB203580) on HGF-induced uPA expression in pancreatic cancer cell lines, L3.6PL and IMIM-PC2. Pretreatment of PD98059 decreased HGF-mediated phosphorylation of extracellular receptor kinase (ERK), uPA secretion and expression of matrix metalloproteinases (MMP-2 and MMP-9) in a dose-dependent manner. In contrast, SB203580 pretreatment increased HGF-stimulated ERK phosphorylation, uPA secretion and expression of MMPs. SB203580 also reversed the inhibition of HGF-mediated ERK activation and uPA secretion in the PD98059-pretreated cells. These results suggest that ERK activation by HGF might play important roles in the metastasis of pancreatic cancer and the p38 MAPK pathway also involved in the HGF-mediated uPA secretion and metastasis by regulation of ERK pathway.
Clin Exp Metastasis 2003
PMID:Growth factor-dependent activation of the MAPK pathway in human pancreatic cancer: MEK/ERK and p38 MAP kinase interaction in uPA synthesis. 1459 83

To systematically identify genes related to invasion a three-dimensional multicellular matrix invasion assay was used to classify human tumor cell lines as stromal invasion positive or stromal invasion negative. Cells from two of the primary cell types of the stromal compartment [endothelial cells (HMVEC) and myofibroblasts (HDF)] were assayed for invasion into tumor cell clusters (breast carcinoma, ovarian carcinoma, prostate carcinoma, lung carcinoma, and melanoma). Four tumor cell lines (MDA-MB231, SKOV-3, A375, and MEL624) scored invasion positive, and four tumor cell lines (LNCaP, DU145, PC3, and A549) scored invasion negative. Serial analysis of gene expression (SAGE) libraries generated from the tumor cell lines were analyzed by GeneSpring Hierarchical clustering, t test, and chi(2) test. Clusters emerged that reflected the behavior in the cell culture assay. Of the 47 most highly differentially expressed genes, 30 were selected for confirmation by real-time PCR, and 9 had good correlation with normalized serial analysis of gene expression tag counts. The strongest correlations were for bone marrow stromal antigen 2, stathmin-like 3, tumor necrosis factor receptor superfamily member 5, and hepatocyte growth factor tyrosine kinase substrate. In situ hybridization of metastatic and nonmetastatic ovarian cancer demonstrated selective expression of bone marrow stromal antigen 2 and tumor necrosis factor receptor superfamily member 5 in the metastatic disease. This combination approach appears to be a powerful tool for identifying genes that may be useful as diagnostic markers and/or as therapeutic targets for invasive solid tumors.
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PMID:Identification of genes expressed in malignant cells that promote invasion. 1469 11

Hepatocyte growth factor (HGF), a cytokine involved in tumorigenesis and most metastases, initiates cell migration by binding to the protooncogene c-Met receptor. In epithelial carcinoma cells, c-Met activation causes the breakdown of E-cadherin cell-cell contacts leading to cell spreading. While the breakdown of E-cadherin contacts is immediate, HGF-induced migration requires transcription. To test the hypothesis that this de novo mRNA synthesis includes cancer cell-specific transcripts, we performed subtraction hybridization to isolate HGF-induced transcripts from an endometrial epithelial carcinoma cell line, RL95-2 (RL95), known to migrate but not to proliferate with HGF treatment. One novel cDNA we call Mig-7 is induced by HGF in endometrial epithelial carcinoma cell lines RL95 and HEC-1A before migration ensues. Ovarian, oral squamous cell, and colon metastatic tumors but not normal tissues express Mig-7. HGF did not induce Mig-7 in normal primary endometrial epithelial cells. In addition, blocking antibodies to alphavbeta5 integrin inhibited HGF induction of Mig-7 in RL95 cells. Most importantly, Mig-7-specific antisense oligonucleotides inhibited scattering of RL95 cells in vitro. These results are the first to demonstrate that Mig-7 expression may be used as a cancer cell-specific target to inhibit cell scattering.
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PMID:HGF and ligation of alphavbeta5 integrin induce a novel, cancer cell-specific gene expression required for cell scattering. 1469 35

Met, the receptor for hepatocyte growth factor (HGF), is activated in human cancer by both ligand-dependent and -independent mechanisms. We engineered a soluble Met receptor (decoy Met) that interferes with both HGF binding to Met and Met homodimerization. By lentiviral vector technology, we achieved local or systemic delivery of decoy Met in mice. We provide evidence that in vivo expression of decoy Met (1) inhibits tumor cell proliferation and survival in a variety of human xenografts, (2) impairs tumor angiogenesis by preventing host vessel arborization, (3) suppresses or prevents the formation of spontaneous metastases, and (4) synergizes with radiotherapy in inducing tumor regression, without (5) affecting housekeeping physiological functions in the adult animal.
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PMID:Targeting the tumor and its microenvironment by a dual-function decoy Met receptor. 1526 Nov 36

The competitive inhibitory effects of NK4 (a specific hepatocyte growth factor (HGF)-antagonist) on the interaction between HGF and the c-Met/HGF receptor has been shown in HGF-mediated invasion of some distinct types of human cancer cells. Furthermore, NK4 has inhibitory effects on the angiogenic pathways driven by basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), as well as by HGF. In this study, to evaluate the therapeutic efficacy of adenoviral-mediated NK4 gene treatment, we employed animal models of peritoneal metastasis using two gastric cancer cell lines, the strongly c-Met expressing MKN45 cell line and the weakly c-Met-expressing cell line, TMK1. In both models, the total number and weight of peritoneal tumours per mouse and ascites treated early with AxCANK4 (administered 3 times 2, 7 and 12 days after the tumour inoculation) were significantly reduced compared with those treated with phosphate-buffered solution (PBS) and AxCALacZ (P < 0.05). In Factor-VIII-related-antigen-stained sections from peritoneal metastatic tumours, the inhibition of intratumour vessels was observed in tissues from tumours of MKN45 and TMK1 treated with AxCANK4. We also compared the therapeutic effect of early AxCANK4 treatment with that of late treatment (at 7, 12 and 17 days). Peritoneal metastases and ascites treated late with AxCANK4 showed less of an improvement than those treated early with AxCANK4 in both models. In addition, the inhibitory effect of cisplatin (CDDP) on peritoneal metastasis was significantly enhanced by AxCANK4, suggesting that the combination of intraperitoneal (i.p.) chemotherapy with NK4 gene therapy might be effective, even in cases of advanced peritoneal metastasis from gastric cancer. To conclude, these results show clearly that NK4 gene therapy inhibits peritoneal metastases from gastric cancer, regardless of the level of c-Met/HGF receptor expression in the tumour cells, and especially in the early stages of peritoneal metastasis.
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PMID:Adenoviral-mediated gene transduction of the hepatocyte growth factor (HGF) antagonist, NK4, suppresses peritoneal metastases of gastric cancer in nude mice. 1534 89

Hepatocyte growth factor (HGF), the ligand for the c-met proto-oncogene product, is a multifunctional protein that enhances tumor cell motility, extracellular matrix invasion, and mitogenic or morphogenic activities of various cell types. In this study we examined the expression of the c-Met receptor in human oral squamous cell carcinoma (SCC) in vivo and in vitro to explore its relationship to tumor progression and invasiveness. Biopsy specimens of human oral SCC were immunohistochemically stained for c-Met. Nearly all primary oral SCC lesions and lymph node metastases consistently showed intense staining for c-Met, whereas normal oral mucosa showed faint to negative staining only on basal cells. In a panel of human oral SCC cell lines, we found a strong correlation between the levels of c-Met expression and the cells' response to HGF in motility and invasion assays. Sensitivity to HGF also correlated with the expression of the c-Met 9-kb mRNA. When the non-invasive HOC-605 cell line, which expresses a low level of c-Met receptor, was transfected with an expression plasmid containing human c-met cDNA, the transfectant cells showed motile and invasive responses to HGF. Immunostaining and immunoprecipitation studies demonstrated that E-cadherin and c-Met were physically associated at SCC cell-cell junctions, suggesting a direct role for c-Met in induction of junctional integrity. Importantly, HGF caused a rapid elevation of unbound beta-catenin, suggesting its availability for nuclear signal transduction and triggering of cell motility and invasiveness. Thus, overexpression of c-Met may facilitate disruption of E-cadherin junctions. Collectively, these results suggest that HGF/c-Met signaling is a common event in oral SCC that may trigger phenotype modulation and enhanced invasion and metastasis.
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PMID:Overexpression of c-met in oral SCC promotes hepatocyte growth factor-induced disruption of cadherin junctions and invasion. 1537 30

Receptor tyrosine kinases play an important role in malignant transformation of epithelial cells by activating signal transduction pathways important for proliferation, invasion and metastasis. In a pilot study (n = 40), we evaluated expression of the c-Met and Her2/neu receptor tyrosine kinases and the c-Met ligand hepatocyte growth factor/scatter factor (HGF/SF) in primary breast cancers and their lymph node metastases using both conventional immunohistochemistry and confocal immunofluorescence. Neither c-Met and HGF/SF nor Her2/neu expression correlated with established prognostic factors such as age, lymph node involvement, estrogen receptor (ER), progesterone receptor (PR), tumor size, or grade. Both staining methods confirmed a significant correlation between c-Met overexpression and a high risk of disease progression. Furthermore, among tumors with c-Met overexpression, only 50% also overexpress Her2/neu, thus identifying a subset of patients with aggressive disease in addition to Her2/neu. Median disease-free survival in patients with c-Met overexpressing tumors was 8 months compared to 53 months when c-Met expression was low (p = 0.037; RR = 3.0). This significant impact of c-Met on tumor aggressiveness independent of Her2/neu was also confirmed by multivariate analysis. In conclusion, the role of c-Met expression as a prognostic variable and consequently as an interesting target for novel therapeutic approaches deserves further analysis in a larger cohort of patients.
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PMID:C-Met overexpression in node-positive breast cancer identifies patients with poor clinical outcome independent of Her2/neu. 1545 88

Scatter factor (SF), also known as hepatocyte growth factor, is ubiquitously present in the extracellular matrix of tissues in the form of an inactive precursor (pro-SF). In order to acquire biological activity, pro-SF must be cleaved by specific proteases present on the cell surface. The mature form of SF controls invasive cues in both physiological and pathological processes through activation of its receptor, the Met tyrosine kinase. By substituting a single amino acid in the proteolytic site, we engineered an unprocessable form of pro-SF (uncleavable SF). Using lentivirus vector technology, we achieved local or systemic delivery of uncleavable SF in mice. We provide evidence that (a) uncleavable SF inhibits both protease-mediated pro-SF conversion and active SF-induced Met activation; (b) local expression of uncleavable SF in tumors suppresses tumor growth, impairs tumor angiogenesis, and prevents metastatic dissemination; and (c) systemic expression of uncleavable SF dramatically inhibits the growth of transplanted tumors and abolishes the formation of spontaneous metastases without perturbing vital physiological functions. These data show that proteolytic activation of pro-SF is a limiting step in tumor progression, thus suggesting a new strategy for the treatment or prevention of the malignant conversion of neoplastic lesions.
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PMID:An uncleavable form of pro-scatter factor suppresses tumor growth and dissemination in mice. 1554 93

Identification of genes that are expressed in a cancer cell-specific manner can provide markers for detection, diagnosis, and disease progression. We have previously reported that receptor tyrosine kinase ligands in concert with ligation of alphavbeta5 integrin induce expression of Mig-7 restricted to carcinoma cells. Because of this highly specific expression, we hypothesized that Mig-7 could be used as a marker of occult tumor cells. The objective of this study was to begin to test this hypothesis by generating Mig-7 specific antisera and RT-PCR methods for detection of Mig-7 expression in tissues and blood from cancer patients as compared to those from normal subjects. By immunohistochemistry and by RT-PCR, we detected Mig-7 mRNA in lymph nodes from 7 out of 9 (77.8%) endometrial carcinoma xenograft mice but not from any of the 5 negative control animals. Mig-7 expression was more specific than Met expression, the RTK that binds Scatter factor and is used as a marker of poor progression, in endometrial carcinoma as compared to normal endometrial tissue samples. In 87.3% of tumors from various tissues including breast, lung, colon and ovary, we detected Mig-7 expression. Blood samples from untreated metastatic cancer patients also displayed Mig-7 mRNA in contrast to a lack of expression in chemotherapy treated or normal individuals. In conclusion, we report the first immunohistochemical and RT-PCR assays for Mig-7 and discuss its highly specific localization to cancer cells in contrast to an absence in normal cells. Our preliminary data indicate that Mig-7 may be a potential early marker of migrating and circulating carcinoma cells.
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PMID:Carcinoma cell-specific Mig-7: a new potential marker for circulating and migrating cancer cells. 1558 99

BACKGROUND: Increases in urokinase-like plasminogen activator (uPA) activity are reported to be amongst the earliest events occurring in remnant liver following partial hepatectomy in rats, and have been proposed as a key component of the regenerative response. Remodelling of the extracellular matrix, conversion of single chain hepatocyte growth factor to the active two-chain form and a possible activation of a mitogenic signalling pathway have all been ascribed to the increased uPA activity. The present study aimed to determine whether similar early increases in uPA activity could be detected in the remnant liver following resection of metastatic tumours in surgical patients. RESULTS: Eighteen patients undergoing partial hepatectomy for the removal of hepatic metastases secondary to primary colonic tumours were studied. Increased plasminogen activator activity was found in the final liver samples for the group of patients in whom the resection size was at least 50%. For smaller resections, the increased activity was not observed. The increased activity did not correlate with the age of the patient or with the time between the start of resection and the end of the operation. There was, however, a negative correlation between plasminogen activator activity and the time for which blood supply to the liver was clamped. CONCLUSIONS: Our findings are in accordance with those from experimental animal models and show, for the first time, that rapid increases in plasminogen activator activity can occur following similarly large liver resection in humans. Thus, increases in plasminogen activator activity are an early event in the remnant liver following major liver resection in man. Our observations provide support for the contention that increases in plasminogen activators play a key role in the initiation of hepatic regeneration in man.
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PMID:Early increases in plasminogen activator activity following partial hepatectomy in humans. 1561 75


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