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)

Malignant transformation of murine and human cells is commonly associated with increased--GlcNAc beta 1-6Man alpha 1-6Man beta--branching in asparagine-linked oligosaccharides. Somatic mutations and drugs which block expression of the beta 1-6 branched oligosaccharides are potent inhibitors of tumor cell invasion and metastasis in animal models. This suggests that the oligosaccharides are required for metastasis to occur and therefore their increased presence in primary tumors may be diagnostic of metastatic disease. Although antibodies to the beta 1-6 branched portion of the oligosaccharides are not available, a plant lectin leukoagglutinin (L-PHA) has been shown to bind specifically to this structure. L-PHA lectin histochemistry was performed on paraffin sections of human breast and colon tissues. All breast carcinomas and epithelial hyperplasia with atypia showed significantly increased L-PHA staining compared to fibroadenomas and hyperplasia without atypia. In histological sections of colon, adenomas showed a small but significant increase in L-PHA staining compared to normal colonic epithelium, while carcinomas showed greatly increased reactivity. In addition, Dukes stage C tumors showed higher levels of L-PHA staining than stage A tumors. These results demonstrate that L-PHA-reactive beta 1-6 branched N-linked oligosaccharides are consistently increased in neoplasias of human breast and colon and that the level of L-PHA staining correlates with the pathological staging of the diseases.
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PMID:Beta 1-6 branched oligosaccharides as a marker of tumor progression in human breast and colon neoplasia. 826 56

Increased--GlcNAc beta 1-6Man alpha 1-6Man beta--branching in asparagine-linked oligosaccharides has been observed in murine and human tumor cells and has recently been linked to enhanced metastatic potential in experimental tumor models. Leukoagglutinin (L-PHA) requires the beta 1-6-linked lactosamine antenna (beta 1-6 branch) for high affinity binding and was used in this study to quantitate these structures on glycoproteins separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Normal rodent tissues and cell lines were used to standardize the experimental conditions required to quantitate beta 1-6-branched oligosaccharide structures and the glycosyltransferase activity which initiates the synthesis of the antenna, beta 1-6 N-acetylglucosamine (GlcNAc)-transferase V (EC 2.4.1.155). Secondly, the levels of L-PHA-reactive oligosaccharide were compared in a series of benign and malignant human breast biopsies. Normal human breast tissue and benign lesions showed low expression but 50% of the primary malignancies examined showed significantly elevated L-PHA reactivity. GlcNAc transferase V activities in the human breast carcinomas and in normal murine tissues correlated with the levels of L-PHA reactive oligosaccharide in the tissues. GlcNAc transferase V showed similar ranges of activities, differing by approximately 5-fold between high and low expressing mouse tissues; fibroblasts with and without an activated H-ras oncogene; and low and high expressing human breast carcinomas. The results show that beta 1-6 branching in asparagine-linked oligosaccharides is dependent on tissue-specific regulation of GlcNAc transferase V activity. Secondly, a subset of human breast malignancies showed elevated levels of beta 1-6-branched oligosaccharides compared to benign samples, suggesting that further studies are warranted to determine whether the presence of these oligosaccharides is associated with metastatic disease and reduced patient survival time.
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PMID:Oncodevelopmental expression of--GlcNAc beta 1-6Man alpha 1-6Man beta 1--branched asparagine-linked oligosaccharides in murine tissues and human breast carcinomas. 252 56

From the highly metastatic in vivo-passaged Friend leukemia cells (FLC), WGA-resistant (WR) tumor cell variants were selected. These WR FLC had lost their capacity to metastasize when injected i.v. or s.c. into DBA/2 mice. We have characterized the plasma membrane glycoproteins of the different FLC types by: (i) metabolic labelling with (3H)-galactose; (ii) surface labelling with galactose oxidase-borohydride; (iii) direct binding of (125I)-lectins on glycoproteins separated by SDS-PAGE. The ensemble of these approaches showed that the 100- to 200-kDa glycoproteins of in vivo-passaged FLC and WR FLC exhibited a very similar distribution of the terminal galactose in their oligosaccharide moieties. In contrast, the expression of terminal sialic acid was reduced in WR FLC with respect to in vivo-passaged counterparts as appreciated by: (i) binding experiments with (125I)-WGA; (ii) cathodic shift of the 100- to 200-kDa glycoproteins in 2-dimensional electrophoresis studies, and (iii) thiobarbituric acid assay after FLC treatment with neuraminidase. Moreover, binding experiments with (125I)-LPHA, (125I)-ConA and (125I)-WGA (after Smith degradation) indicated that, in the 100- to 200-kDa region, virtually identical asparagine-linked tri- or tetra-antennary complex-type oligosaccharides were expressed in both cell types. We conclude that the sialylation of high-molecular-weight surface glycoproteins (particularly in the 150-kDa region) is strongly associated with the metastatic potential of FLC, especially to the liver.
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PMID:Hyposialylation of high-molecular-weight membrane glycoproteins parallels the loss of metastatic potential in wheat-germ agglutinin-resistant Friend leukemia cells. 291 Aug 24

Increased sialylation and branching of asparagine-linked oligosaccharides have recently been associated with both neoplastic transformation and the metastatic phenotype. Swainsonine, an inhibitor of Golgi alpha-mannosidase II blocks the synthesis of sialylated tri- and tetraantennary asparagine-linked oligosaccharides and results in the expression of hybrid-type oligosaccharides at the cell surface. Both the lymphoid tumor line MDAY-D2 and B16F10 melanoma cells were less metastatic when grown in swainsonine (0.3 micrograms/ml) for 48 h prior to injection of the cells into the lateral tail veins of mice. The addition of swainsonine (2.5 micrograms/ml) to the drinking water of the mice further reduced the incidence of lung colonization by B16F10 melanoma cells. MDAY-D2 tumors removed from mice on swainsonine-supplemented drinking water showed a loss of leukoagglutinin-binding complex-type oligosaccharides similar to that of tumor cells cultured in medium containing swainsonine. The growth rate of s.c. MDAY-D2 tumors was not reduced by the addition of swainsonine to the drinking water of the host; however, when mice were given two i.p. injections of the interferon-inducing agent polyinosinic:polycytidylic acid in addition to swainsonine, the primary tumor grew at a reduced rate compared to either treatment alone. Swainsonine alone did not inhibit tumor cell growth in vitro; however, the drug enhanced the antiproliferative effect of interferon. The survival time of mice bearing established MDAY-D2 metastases was extended by treating the animals with swainsonine and polyinosinic:polycytidylic acid; however, the number of long-term survival was unchanged. Swainsonine-treated tumor cells appeared to be compromised in two ways: reduced organ colonization potential; and drug-treated MDAY-D2 cells were more sensitive to the antiproliferative effects of interferon in vitro and in vivo.
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PMID:Effects of swainsonine and polyinosinic:polycytidylic acid on murine tumor cell growth and metastasis. 309 60

Radiation is curative in many types of localized cancer, whereas chemotherapy is rarely curative in either localized or widespread cancer. For this reason, chemotherapy should never be employed in any situation where it might hinder or prevent the administration of a potentially curative dose of radiation. However, in Burkitt's tumor in Africa, where a multicentric origin seems to be much more probable, cyclophosphamide, 40 mg/kg intravenously repeated every 3 to 4 weeks, has occasionally been curative. In the treatment of Wilms' tumor, surgery, radiation and chemotherapy are essential for optimal results. In acute leukemia, chemotherapy with the conventional agents, as well as newer drugs such as cytosine arabinoside and L-asparaginase, is the treatment of choice, with radiation being useful mainly in treatment of localized disease in the bones or in the central nervous system. The great interest in L-asparaginase at the present time lies in the fact that certain neoplastic cells have a specific nutritional requirement for the amino acid L-asparagine, whereas no normal cells appear to have this requirement. In many cases of advanced neoplastic disease, the partnership of radiation therapy to reduce large bulky lesions composed to a large extent of nonproliferating cells, followed by chemotherapy to destroy the few surviving and now perhaps proliferating cells remaining in the original mass or in metastases, would seem to offer the greatest promise of theoretical and practical benefit.
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PMID:Chemotherapy and radiotherapy--competitors or partners? 437 33

Cystosarcoma phyllodes (CSP) is a rare breast neoplasm composed of stromal and epithelial elements. It usually runs a benign course but it may metastasize. In a 31-year-old patient with recurring CSP, a mesenchymal tumor in the leg developed. The question arose whether the latter tumor could be a metastasis from the CSP, which would have major treatment consequences. The problem was addressed using molecular methods, i.e., comparison of the pattern of polymorphic repeat markers on chromosome 17p as well as single strand conformation polymorphism analysis and sequencing of exons 5 to 8 of the TP53 gene in both tumor and normal tissue. An identical pattern of loss of heterozygosity in both breast tumors was demonstrated, but a different pattern was shown in the tumor in the leg. This led to the conclusion that the latter tumor had to be a new primary tumor. A mutation in codon 162 of the TP53 gene was found in the tumor tissue as well as in the normal tissue of this patient. This germ line mutation leads to the replacement of isoleucine by asparagine and most likely has functional consequences. In all four examined tumors of this patient, the normal TP53 allele was lost. This is strong evidence that this germ line TP53 mutation causes the genesis of these two rare primary mesenchymal tumors in this young patient. The current study exemplifies the power of molecular diagnostic methods in investigating the specific clinical problem of clonal relation between two separate tumors. The germ line mutation found in codon 162 of the TP53 gene and the association with cystosarcoma phyllodes have not been described previously.
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PMID:Molecular assessment of clonality leads to the identification of a new germ line TP53 mutation associated with malignant cystosarcoma phyllodes and soft tissue sarcoma. 1020 67

Invasion of tumor cells into the extracellular matrix is an essential step in the formation of metastases in renal cancer. Cell adhesion molecules such as beta(1)-integrins, which bind to the RGD sequence (arginine-glycine-asparagine) and CD44 are involved in this process. We examined the invasion of a renal carcinoma cell line (CCF-RC1) into the extracellular matrix compounds fibronectin, collagen IV and laminin and the effect of TGFbeta and IFNgamma on this process. The inhibitory effect of an antibody against the beta(1)-subunit of integrins (CD29), as well as a pentapeptide including the RGD sequence, was also evaluated. A micro-chemotaxis chamber, including a polycarbonate membrane with a pore diameter of 8 microm, was used for quantification of cell migration. The addition of the extracellular matrix compounds fibronectin, laminin and collagen IV resulted in a 5-10-fold increase in invasion. This increased invasion depends strongly on the presence of beta(1)-integrins, shown by the use of an antibody against CD29 or a RGD including peptide which inhibit the cell migration by approximately 88%. CD44 is less involved in collagen IV dependent migration and almost no influence of CD44 was observed on a fibronectin and laminin dependent migration. TNFalpha and IFNgamma did not significantly influence the expression of CD29 or CD44, and no alteration in tumor cell migration was observed. These results show that the invasion of renal cancer cells is differentially regulated by compounds of the extracellular matrix, whereby fibronectin seems to be the most critical factor. The molecular interactions in this process are strongly dependent on beta(1)-integrins and the corresponding amino acid sequence RGD.
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PMID:Differential inhibition of renal cancer cell invasion mediated by fibronectin, collagen IV and laminin. 1082 36

Several gene mutations responsible for human cancer initiation have been discovered, whereas only a few have been identified in association with the progression to metastasis. In this study, we screened a large panel of human sporadic cancers, metastases, and tumor cell lines for mutations in the tyrosine kinase domain of the MET receptor, crucially involved in invasive cell growth and motility during embryogenesis. MET activating mutations have been described previously in hereditary papillary renal cell carcinoma and in a few sporadic tumors. Summarizing results of this and our previous studies, we did not detect mutations in the MET kinase domain from 153 sporadic human cancers and 25 cancer cell lines, whereas we found somatic MET mutations in 10 of 46 lymph nodal and 2 of 14 pulmonary metastases. We identified four MET mutations in metastases. Two were known as MET germ-line mutations (H1112R and Y1248C), which predispose to hereditary renal cell carcinoma. One of the two novel mutations (N1118Y) changed an asparagine in the region of the glycine-rich ATP binding site, which is highly conserved in all of the kinases. The other (Y1253D) changed a critical tyrosine, known to regulate MET kinase activity, to a negatively charged residue. The MET receptors carrying either the N1118Y or the Y1253D mutation were constitutively active and conferred a motile-invasive phenotype on transduced carcinoma cells. The latter phenotype was additionally stimulated by the MET receptor ligand scatter factor/hepatocyte growth factor. These data suggest that MET might be one of the long sought oncogenes controlling progression of primary cancers to metastasis.
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PMID:Novel somatic mutations of the MET oncogene in human carcinoma metastases activating cell motility and invasion. 1246 Sep 23

Three human Escherichia coli heat-stable peptide (STh) analogues, each containing a DOTA chelating group, were synthesized by SPPS and oxidative refolding and compared in in vitro and in vivo systems. One analogue, DOTA-F19-STh(1-19), contains an N-terminal DOTA group attached via an amide bond linkage to an STh moiety which is essentially wild-type except for a Tyr to Phe alteration at position 19 of the molecule. A second analogue, DOTA-R1,4,F19-STh(1-19), differs from the first in that asparagine residues in positions 1 and 4 have been altered to arginine residues in order to examine the effect of positively charged groups in the linker domain. A third analogue, DOTA-11AUN-F19-STh(1-19), differs from the first in that it incorporates an 11-aminoundecanoic acid spacer group between the DOTA group and the first asparagine residue. In vitro competitive binding assays utilizing T-84 human colon cancer cells demonstrated that significant alterations to the N-terminal region of the STh molecule were well tolerated and did not significantly affect binding affinity of STh for the guanylyl cyclase C (GC-C) receptor. Internalization and efflux studies of the indium-labeled species demonstrated that inclusion of positive charge in the linker moiety inhibits internalization of the compound within tumor cells. The characteristics of the three analogues were compared in an in vivo model utilizing T-84 human colon cancer cell xenografts in SCID mice. Clearance of all analogues was rapid, primarily via renal excretion into the urine, with >89% ID excreted into the urine at 1 h pi for all analogues. The 111In-DOTA-R1,4,F19-STh(1-19) and 111In-DOTA-11AUN-F19-STh(1-19) analogues both had longer residence times in the blood than did the 111In-DOTA-F19-STh(1-19) analogue, probably accounting for increased %ID/g values for tumors and nontarget tissues at 1 h pi. At 4 h pi, significant differences between analogues were only seen with respect to metabolic routes of excretion, indicating that increased blood residence time did not result in increased tumor residualization. Reduction of hepatic uptake of these compounds, however, could have significance in the development of agents for the imaging of hepatic metastases. The ability to manipulate in vivo pharmacodynamics and tumor uptake of radiolabeled STh peptides through modification of linker moieties is under continuing investigation in order to produce optimal imaging and therapeutic radiopharmaceuticals.
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PMID:In vitro and in vivo comparison of human Escherichia coli heat-stable peptide analogues incorporating the 111In-DOTA group and distinct linker moieties. 1526 76

N-acetylglucosaminyltransferase V (Mgat5 or GnT-V) is an enzyme that catalyzes beta1-6 branching of N-acetylglucosamine on asparagine (N)-linked oligosaccharides (N-glycan) of cell proteins. The levels of Mgat5 glycan products commonly are increased in malignancies. Although Mgat5 is known to be important in tumor metastases, the effects of Mgat5 on host immune responses are not fully defined. In this study, a Mgat5 specific-short hairpin RNA (shRNA) vector was transfected into murine mammary adenocarcinoma MA782 cells to assess the effects of Mgat5 on tumor cell growth, T cells, and macrophages following inoculation of mice with shRNA-transfected cancer cells. The results showed that blocking expression of Mgat5-modified glycans in MA782 cells significantly suppressed tumor progression both in vivo and in vitro, strongly stimulated Th1 cytokine production, and enhanced opsonophagocytic capability of macrophages in vivo. Importantly, reduction of complex N-glycans on MA782 tumor cells by Mgat5-shRNA resulted in significantly increased proliferation and CD45 surface expression of CD4+ T cells. Our data suggest Mgat5-shRNA could serve as a useful tool to treat breast cancer as well as a powerful tool for the functional investigation of N-glycans and glycoprotein synthesis. Our data suggest that knockdown of Mgat5 inhibits breast cancer cells' growth with activation of CD4+ T cells and macrophages.
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PMID:Knockdown of Mgat5 inhibits breast cancer cell growth with activation of CD4+ T cells and macrophages. 1829 39


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