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)

Oncogenic transformation is often accompanied by alterations of glycosylation on a tumor cell's surface, which may contribute to uncontrolled cell growth. The sialoglycans and degree of sialylation on the cell surface are of increasing interest because of their possible role in metastasis and tissue invasion. Since primary tumors and metastases may differ in the degree of sialylation, we examined the expression of sialic acid as a terminal constituent of lactosaminyl glycans on the cell surfaces of 30 cervical lymph-node metastases and 30 squamous-cell carcinomas of the oropharynx and oral cavity. Cell-surface sialylation was determined by a new histobiochemical assay on cryostat sections and was based on the enzymatic introduction of a fluorescence-labelled sialic acid into lactosaminyl type (Gal-beta 1-4 GlcNAc) oligosaccharide chains of cell-surface-expressed glycoproteins. To this end, tissues were incubated in the presence of 5-acetamido-9-deoxy-9-fluoresceinyl-thioureido neuraminic acid (CMP-9-fluoresceinyl-NeuAc) and alpha-2,6-sialyltransferase. In order to compare the degree of sialylation with the potential total amount of sialylation sites, pretreatment with sialidase for desialylation was required. We observed a significantly higher amount of lactosaminyl-type binding sites for sialic acid on metastases compared to the primary tumors (P = 0.001), indicating a lower degree of sialylation in metastases. In primary tumors no correlation was seen between the amount of binding sites and tumor localization, TNM stage or histologic grading. Pretreatment of specimens with sialidase demonstrated a significant degree of sialylation on both primary tumors and lymph-node metastases, but no difference between primary tumors and metastases. When tumor stroma of primary tumors and metastases was compared, tumor cells showed a higher degree of free binding sites for sialic acid, but a low degree of sialylation. Our results suggest that differences in the degree of sialylation of glycoconjugates on a tumor cell's surface may play an important role in the process of cell metastasis. Our histobiochemical method turned out to be very reliable, effective and readily performed.
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PMID:A new histobiochemical method to analyze sialylation on cell-surface glycoproteins of head and neck squamous-cell carcinomas. 943 13

The level of sulfo-Lea (SO3-3Gal beta 1-3(Fuc alpha 1-4)GlcNAc) epitope recognized by monoclonal antibody (mAb) 91.9H in hepatic metastasis of colon carcinoma is known to be lower than at the primary sites. We examined 19 human colon carcinoma cell lines for their production of this epitope. Sixteen cell lines were found to produce high M(r) components that metabolically incorporated [35S]sulfate and were resistant to heparitinase I and chondroitinase ABC, and 8 of them were reactive with mAb 91.9H as shown by western blotting analysis. These were all of the 4 cell lines derived from well differentiated primary tumors (HCCP-2998, LS174T, GEO, and CBS), 2 of 10 cell lines (DLD-1 and HCT116) from moderately to poorly differentiated primary tumors, and 2 of 5 cell lines (SW480 and HCC-M1544) from metastases. Incubation of LS174T cells with benzyl-N-acetyl-alpha-D-galactosaminide abrogated the incorporation of [35S]sulfate and the reactivity of mAb 91.9H with high M(r) components in the cell lysates. Sodium chlorate, which inhibits the formation of 3'-phosphoadenosine 5'-phosphosulfate, also inhibited the [35S]sulfate incorporation and reactivity with mAb 91.9H. These treatments did not change the incorporation of [14C]threonine into high M(r) components. These results indicated that sulfo-Lea epitopes were expressed on O-linked carbohydrate chains in sulfomucins. Immunohistochemical studies of tumor tissues in nude mice indicated that sulfo-Lea was expressed at the site of orthotopic transplantation in the cecum. The expression appeared to be suppressed in liver metastatic foci in nude mice.
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PMID:Expression of mucin-associated sulfo-Lea carbohydrate epitopes on human colon carcinoma cells. 1008 87

We have determined the crystal structure of a novel regulatory protein (MGP-40) from the mammary gland. This protein is implicated as a protective signaling factor that determines which cells are to survive the drastic tissue remodeling that occurs during involution. It has been indicated that certain cancers could surreptitiously utilize the proposed normal protective signaling by proteins of this family to extend their own survival and thereby allow them to invade the organ and metastasize. In view of this, MGP-40 could form an important target for rational structure-based drug design against breast cancer. It is a single chain, glycosylated protein with a molecular mass of 40 kDa. It was isolated from goat dry secretions and has been cloned and sequenced. It was crystallized by microdialysis from 20 mg ml(-1) solution in 0.1 m Tris-HCl, pH 8.0, and equilibrated against the same solution containing 19% ethanol. Its x-ray structure has been determined by molecular replacement and refined to a 2.9 A resolution. The protein adopts a beta/alpha domain structure with a triose-phosphate isomerase barrel conformation in the core and a small alpha+beta folding domain. A single glycosylation site containing two N-acetylglucosamine units has been observed in the structure. Compared with chitinases and chitinase-like proteins the most important mutation in this protein pertains to a change from Glu to Leu at position 119, which is part of the so-called active site sequence in the form of Asp(115), Leu(119), and Asp(186) and in this case resulting in the loss of chitinase activity. The orientations of two Trp residues Trp(78) and Trp(331) in the beta barrel reduces the free space, drastically impairing the binding of saccharides/polysaccharides. However, the site and mode of binding of this protein to cell surface receptors are not yet known.
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PMID:Crystal structure of a novel regulatory 40-kDa mammary gland protein (MGP-40) secreted during involution. 1252 29

We studied adhesive properties and physiological activity in vivo of cells from Lewis lung carcinoma and its metastases. These cells differed in tumorogenic activity and metastatic potential in the syngeneic system. In vivo non-metastasizing cells are characterized by a lower content of surface lectins to tetrasaccharides SiaLex [Neu5Aca2-3Galb1-4(Fuca1-3) GlcNAcb] and SiaLea [Neu5Aca2-3Galb1-3(Fuca1-4)GlcNAcb] and trisaccharide HSO3Lex [HSO32-3Galb1-4(Fuca1-3)GlcNAcb] compared to cells forming metastases in the syngeneic system. Metastatic cells with low tumorogenic activity weakly expressed lectins to disaccharide ligands 6-SiaLac [Neu5Aca2-6Galb1-4Glc], 6-HSO3LacNAc, and A-di [GalNAca 1-3Galb] and trisaccharides H-type 1 [Fuca1-2Galb1-3GlcNAc and Lex [Fuca1-3(Galb 1-4)GlcNAc] compared to cells that initiated tumor formation in the syngeneic system (similarly to transplanted tumors). We hypothesized that cell receptors to these carbohydrate determinates are involved in the development and growth of primary tumors, while lectins to SiaLex, SiaLea, and HSO3Lex play a role in the progress of tumor process and metastasizing.
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PMID:Phenotypic characteristics of lewis lung carcinoma cells. 1253 66

The mechanisms that guide organ-specific metastases are not fully established. The aberrant expression of carbohydrates may play a fundamental role in defining the molecular mechanisms for metastases to distant organs and facilitate positive interactions within the target organ. The purpose of the present study was to determine the glycomic profile of a variant of the MDA-MB-231 breast cancer cell line that colonizes the bone and to ascribe mechanistic functions mediated by carbohydrates that might correlate with clinical bone metastases. The carbohydrate expression profiles of osteolytic MDA-MET breast cancer cells and non-osteolytic parental MDA-MB-231 cells were determined. MDA-MET cells were derived from MDA-MB-231 cells by in vivo selection of metastatic bone lesions following intracardiac inoculation. The two related breast cancer cell lines expressed distinct carbohydrate profiles; MDA-MET cells displayed an increased expression of alpha (2,6) linked sialic acid, N-beta1-6 GlcNAc, and sialylated Lewis-A antigen, and decreased expression of Galbeta1,3GalNAc as detected using a combination of lectins and anti-carbohydrate antibodies. Microarray analysis demonstrated an increased expression of glycosyltransferase genes, correlative for the distinct glycomic phenotype. The altered glycomic phenotypes of MDA-MET cells include effects on the differential binding to bone marrow endothelial cells, enhanced ECM binding and an increase in invasive potential. These data suggest that the glycomic phenotype of MDA-MET cells is associated with a select set of accumulated functions that collectively impact on the bone metastases and bone colonization capacity of breast cancer cells.
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PMID:Characterization of the glycosylation profile of the human breast cancer cell line, MDA-231, and a bone colonizing variant. 1659 33

N-Acetylglucosaminyltransferase-V (GnT-V) has been reported to be up-regulated in invasive/metastatic cancer cells, but a comprehensive understanding of how the transferase correlates with the invasive/metastatic potential is not currently available. Through a glycomics approach, we identified 30 proteins, including tissue inhibitor of metalloproteinase-1 (TIMP-1), as a target protein for GnT-V in human colon cancer cell WiDr. TIMP-1 was aberrantly glycosylated as characterized by the addition of beta1,6-N-acetylglucosamine, polylactosaminylation, and sialylation in GnT-V-overexpressing WiDr cells. Compared with normal TIMP-1, the aberrantly glycosylated TIMP-1 showed the weaker inhibition on both matrix metalloproteinase (MMP)-2 and MMP-9, and this aberrancy was closely associated with cancer cell invasion and metastasis in vivo as well as in vitro. Integrated data, both of TIMP-1 expression level and aberrant glycosylation, could provide important information to aid to improve the clinical outcome of colon cancer patients.
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PMID:Functional proteomics study reveals that N-Acetylglucosaminyltransferase V reinforces the invasive/metastatic potential of colon cancer through aberrant glycosylation on tissue inhibitor of metalloproteinase-1. 1787 70

Distinguishing cutaneous metastasis of gastric cancer from primary sweat gland carcinoma can be problematic in some cases, especially with a single lesion. Previously we showed that a monoclonal antibody HIK1083 directed to alpha1,4-GlcNAc-capped O-glycans expressed in gastric gland mucin reacts to gastric cancer cells. By contrast, it was reported that immunohistochemistry for cytokeratin 20 (CK20) may be helpful in the differential diagnosis between cutaneous metastasis of gastric cancer and primary sweat gland carcinoma. Here, we immunohistochemically examined the expression of alpha1,4-GlcNAc-capped O-glycans and CK20 in 7 primary sweat gland carcinomas, 7 cutaneous metastases of gastric cancer, and 21 cutaneous metastases of other origin including breast, lung, colorectum, prostate, thyroid and pancreas using HIK1083 and CK20-specific Ks 20.8 antibodies and then assessed the usefulness of these antibodies in distinguishing cutaneous metastases of gastric cancer from primary sweat gland carcinoma and other cutaneous metastatic tumors. Both alpha1,4-GlcNAc-capped O-glycans and CK20 were positive in 5 of 7 cases of cutaneous metastases of gastric cancer, while neither alpha1,4-GlcNAc-capped O-glycans nor CK20 were detected in any of the primary sweat gland carcinomas. By contrast, alpha1,4-GlcNAc-capped O-glycans was not detected in any of the cutaneous metastases other than that of gastric cancer, whereas CK20 was detected in cutaneous metastases of colorectal cancer (2/2), breast cancer (2/13), and lung adenocarcinoma (1/3). These findings indicate that immunohistochemistry using HIK1083 antibody is superior to immunohistochemistry for CK20 in distinguishing cutaneous metastasis of gastric cancer from primary sweat gland carcinomas and other cutaneous metastases.
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PMID:Usefulness of monoclonal antibody HIK1083 specific for gastric O-glycan in differentiating cutaneous metastasis of gastric cancer from primary sweat gland carcinoma. 1789 Sep 13

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

Metastasis is a key aspect of tumor malignancy, and several malignant tumors show expression of various mature N-type glycans. In particular, beta1-6 branching N-acetylglucosamine (GlcNAc) is abundantly expressed as a part of high-mannose glycans in various highly metastatic cancers. Phaseolus vulgaris agglutinin-L(4) isolectin (L(4)-PHA), which adheres to beta1-6 GlcNAc specifically, has been used for in situ cancer diagnosis. Bionanocapsules (BNCs), hollow particles with a diameter of approximately 80 nm and composed of hepatitis B surface antigen (HBsAg) and a lipid bilayer, have been developed as human liver-specific nanocapsules for in vivo drug delivery system. In this study, we have generated L(4)-PHA-displaying BNCs (PHA-BNCs) and examined whether L(4)-PHA could retarget the BNCs to malignant tumors as a "biosensor" distinguishing tumor metastaticity. Fluorescence-labeled PHA-BNCs injected systemically into a mouse xenograft model were found to accumulate in beta1-6 GlcNAc-expressing malignant tumors. The PHA-BNCs were able to deliver DNA to the malignant cancer cells. These results open up the possibility of using L(4)-PHA lectin as a targeting molecule in a drug delivery system, and of using PHA-BNCs as a novel nanodevice for malignant tumor-specific bioimaging and drug delivery.
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PMID:In vivo delivery of bionanocapsules displaying Phaseolus vulgaris agglutinin-L4 isolectin to malignant tumors overexpressing N-acetylglucosaminyltransferase V. 1871 44

Variations in glycosylation levels or in the glycoprofile of a certain glycoprotein in tumor-related sera have been widely reported and can be used as a means of differentiation. However, quantitative mass analysis of glycoproteins is difficult because of their high structural complexity and low mass sensitivity of glycopeptides. Therefore, more powerful technologies are required for the discovery of these potential biomarkers. Tissue inhibitor of metalloproteinase 1 (TIMP1), a glycoprotein typically present at a low concentration in serum, is known to be aberrantly glycosylated in colorectal cancer cell lines as a result of the terminal addition of beta-1,6-N-acetylglucosamine (beta-1,6-GlcNAc) by N-acetylglucosaminyltransferase-V (GnT-V), which is reportedly up-regulated in invasive/metastatic cancer cells. In this report, a highly sensitive method is presented for the quantitative analysis of aberrant GlcNAcylated TIMP1 in the serum of colorectal cancer (CRC) patients. Glycoproteins having an N-linked glycan terminating with beta-1,6-GlcNAc were enriched by phytohemagglutinin-L(4) (L-PHA), a lectin that specifically recognizes the beta-1,6-GlcNAc moiety of N-linked glycan. The L-PHA-enriched glycoproteins were digested in solution with trypsin. With the use of a monoclonal anti-peptide TIMP1 antibody linked covalently to magnetic beads, a unique target peptide (antigen) of TIMP1 was immuno-enriched from the L-PHA-enriched tryptic digests and analyzed quantitatively by multiple reaction monitoring (MRM) mass analysis. The systematic coupling of L-PHA lectin enrichment followed by stable isotope standards and capture by anti-peptide antibodies (SISCAPA) with MRM mass analysis afforded quantitation of TIMP1 at attomolar (10(-18)) concentrations. An aberrantly GlcNAcylated substoichiometric TIMP1 isoform was quantified at approximately 0.8 ng/mL serum, using sample equivalent to only 1.7 microL of serum from a CRC patient. This approach provides a useful tool for the quantitation of a specific aberrant glycoform from human serum containing a variety of protein isoforms and may be helpful in studies of biological function as it pertains to protein glycan heterogeneity.
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PMID:Quantitative analysis of an aberrant glycoform of TIMP1 from colon cancer serum by L-PHA-enrichment and SISCAPA with MRM mass spectrometry. 1964 85


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