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--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

Blood group-related oligosaccharides have been isolated from a limited number of carcinomas. The carcinoma-associated oligosaccharides show chain elongation, for example due to repeating Gal 1,4 GlcNAc 1,3 sequences, or a higher degree of branching, which permit increased sialylation and fucosylation. Abnormal carbohydrate structures have been demonstrated on tumor cell membranes by immunological techniques, which suggests deletion of ABH, accumulation of 'crypt' antigens such as I and T antigens, and abnormal expression of Lewis antigens. Changes in carcinoma-associated oligosaccharides can result from altered biosynthetic processing in the Golgi apparatus or the occurrence of abnormal tumor glycosyltransferase isoenzymes. Structural alterations of oligosaccharides on the tumor cell membrane are related to the regulation of tumor growth, cell-cell interaction, cell differentiation, and metastasis. Glycoproteins secreted by tumor cells into the circulation evoke cellular and humoral immunity and cause immune suppression by binding to cytotoxic T lymphocytes and lymphocyte subsets. The relationship of oligosaccharide structures to biologic function awaits elucidation.
Cancer Metastasis Rev 1987
PMID:The structural relationship of blood group-related oligosaccharides in human carcinoma to biological function: a perspective. 332 32

Researchers have endeavored to define surface alterations associated with neoplasia for at least 25 years. In comparisons of normal tissues with animal and human tumors, cultured cells before and after transformation with oncogenic agents, tumorigenic and nontumorigenic transformed cells, metastatic and nonmetastatic tumor cells, high- and low-metastatic variants, and tumor cells before and after induction of differentiation to a less malignant phenotype, a consistent finding has been some form of alteration in surface carbohydrate structures. These changes in glycolipids, glycoproteins and glycosaminoglycans are reviewed, and their structures are illustrated. Both nucleotide sugar biosynthesis and glycosyltransferase changes have been associated with these alterations. In some cases, alterations in transformed cells were related to growth, rather than transformation. In others, the altered glycoconjugates are truly tumor-associated. There is evidence that cell surface glycoconjugates may function in growth control. Altered carbohydrate structures could also serve as receptors for growth promoting factors and be directly responsible for altered growth control. Recent studies with monoclonal antibodies indicate that the vast majority of antibodies recognizing tumor-associated antigens are detecting altered carbohydrate structures. Mechanisms by which the immune system can recognize these carbohydrate structures are considered, and immune recognition of tumor-associated carbohydrate structural alterations is explored. A number of these hypotheses relating to alterations in glycosylation, growth control, and tumor immunity deserve further investigation.
Cancer Metastasis Rev 1985
PMID:Carbohydrate structure in tumor immunity. 393 11

The ability of retinoids to prevent or alter the course of experimental tumorigenesis is well established. We have extended these observations to include effects on establishment of tumors and tumor metastases. A diet containing excess retinyl acetate fed to rats prior to injection of a metastatic line of transplantable hepatoma, prevented establishment of secondary tumor foci while 75% of the animals fed adequate retinyl acetate showed pulmonary metastases. Metastatic ability may be related to the ability to bind fibronectins, proteins that link cells to an underlying stroma. Findings suggest involvement of higher gangliosides in the attachment of cells to a fibronectin-collagen complex. Prior to metastasis, hepatoma lines become depleted in the putative fibronectin receptor gangliosides as an end result of a complex cascade of altered glycosyltransferase activities. After metastasis, fibronectin receptors are apparently restored in those secondary tumor foci that become established. Analyses suggest that excess vitamin A may prevent the reappearance of fibronectin receptor gangliosides so that secondary tumor foci do not establish.
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PMID:Glycosylation reactions and tumor establishment: modulation by vitamin A. 694 82

The expression of carbohydrate antigens has been shown by retrospective immunohistochemical analysis to correlate to the progression and metastases of human cancers. However, the mechanisms of these changes of carbohydrate expression and the role of carbohydrates in the malignant behavior of tumor cells are not well known. In this article, we introduce methods to experimentally modify carbohydrate expression in tumor cells and to assess the involvement of these carbohydrate antigens in the malignant behavior of tumor cells. Modifications of the biosynthesis of O- and N-linked carbohydrates, and glycolipids are achieved by treating cultured tumor cells with culture media containing Benzyl-alpha-GalNAc, swainsonine, or D-PDMP, respectively. Enzymatic digestion of cell surface carbohydrates with sialidase, endo-beta-galactosidase or other glycosidases can also be performed. These cells can be used for short term experiments such as adhesion assays. However, modified carbohydrates may be recovered during in vitro and in vivo assays. By transfection of glycosyltransferase cDNA, or selection of tumor cells by binding lectins or antibodies, stable carbohydrate variant cells can be obtained which are suitable for long term experiments such as the experimental formation of metastases in vivo. The biological function of tumor cell surface carbohydrates may be diverse. These molecules are thought to influence adhesion interaction between tumor cells and the endothelial cells of target organs. However, carbohydrate recognition molecules, or lectins, are expressed on a variety of cells in the vascular system and in the immune system. Therefore, it is essential to design appropriate experimental models to study the biological significance of carbohydrate-lectin interactions in cancer progression and metastatic dissemination. Adhesion assays of tumor cells to selectin-transfected CHO cells were performed. Taking molecules other than selectins into consideration, adhesion assays using frozen tissue sections were also performed.
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PMID:[Tumor metastases and adhesion molecules carbohydrates and lectins]. 1041 Jan 58

Thomsen-Friedenreich (TF)-related blood group antigens, such as TF, Tn, and their sialylated variants, belong to a family of tumor-associated carbohydrates. The aim of the present study was to examine tumor-associated alterations of glycosyltransferases involved in the biosynthesis of the TF glycotope in colorectal carcinomas. To this end, glycosyltransferase expression was examined in 40 cases of colorectal carcinoma specimens classified according to the WHO/Union International Contre Cancer guidelines and in "normal" mucosa of the same patients. Occurrence of TF glycotope was examined by immunohistochemistry with the monoclonal antibody A78-G/A7. Expression of sialyltransferases CMP-sialic acid:Galbeta1,3GalNAc-R alpha3-sialyltransferase I and II (ST3Gal-I and ST3Gal-II) and CMP-sialic acid:Galbeta1,3GalNAc-R alpha6-sialyltransferase (ST6GalNAc-II) and of core 2 beta1,6-N-acetylglucosaminyltransferase was determined by reverse transcription-PCR in the same cryostat sections used for immunohistochemistry. Additionally, alpha2,3-sialyltransferase enzyme activity was studied in each of these tissues. The TF glycotope was detected in 7% of the normal mucosa, but in 57% of the carcinoma samples. Expression of alpha2,3-sialyltransferases ST3Gal-I, ST3Gal-II, and enzyme activity of alpha2,3-sialyltransferase was significantly increased (P < 0.001) in carcinoma specimens compared with normal mucosa. ST3Gal-I mRNA expression was significantly increased (P = 0.05) in cases showing invasion of lymph vessels. Expression of ST6GalNAc-II was significantly increased (P = 0.04) in cases with metastases to lymph nodes along the vascular trunk. Moreover, ST6GalNAc-II expression provides an prognostic factor for patient survival (log rank, P = 0.02). In an attempt to study the functional relevance of the glycosyltransferases for TF biosynthesis, SW480 colorectal cells were transfected with each of the enzymes, and cell surface expression of the TF glycotope was examined by flow cytometry. The presence of TF was not altered by transfection of the cells with either sialyltransferase ST3Gal-I or ST3Gal-II. However, successful transfection with core 2 beta1,6-N-acetylglucosaminyltransferase led to reduced expression of TF. In contrast, increased cell surface expression of TF was found after ST6GalNAc-II transfection. Thus, expression of TF on the cell surface of SW480 colorectal carcinoma cells depends on the ratio of core 2 beta1,6-N-acetylglucosaminyltransferase and ST6GalNAc-II. Earlier immunohistological studies demonstrated that TF is a prognostic factor for patient survival. Our results suggest that sialyltransferase ST6GalNAc-II is of crucial relevance for the prognostic significance of TF.
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PMID:Overexpression of sialyltransferase CMP-sialic acid:Galbeta1,3GalNAc-R alpha6-Sialyltransferase is related to poor patient survival in human colorectal carcinomas. 1138 97

Aberrant glycosylation of membrane components due to specific alterations of glycosyltransferase activity is a common feature of carcinoma cells and is usually associated with invasion and metastasis. In a prospective study, the enzyme activity of the sialyltransferases ST6GAL-I and ST3GAL-III was studied in gastric cancer and normal mucosa in 55 patients by a radiometric assay. Cellular localization of sialyltransferase ST6GAL-I mRNA expression was studied by in situ hybridization. Sialyltransferase ST6GAL-I mRNA expression was mainly localized to epithelial cells. ST6GAL-I enzyme activity was enhanced within the tumor tissue. Significant correlations were found between the presence of signet ring cells and enhanced ST6GAL-I activity in the tumor tissue (p = 0.047) or in the mucosa (p = 0.024), and between signet ring cells and ST3GAL-III activity in the mucosa (p < 0.001). Multivariate Cox analysis demonstrated that only lymph node metastases (p = 0.044) had a significant influence on tumor-related survival. ST3GAL-III and ST6GAL-I activity showed no independent prognostic relevance in multivariate analysis, but high levels of ST3GAL-III and ST6GAL-I in the tumor tissue correlated with secondary local tumor recurrence (p = 0.005; p = 0.012). Interestingly, also the nonmalignant and uninvolved mucosa of tumor patients was altered on the molecular level and in some cases showed enhanced sialyltransferase levels indicative of the alteration of glycosylation very early during tumorigenesis.
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PMID:Clinical relevance of sialyltransferases ST6GAL-I and ST3GAL-III in gastric cancer. 1293 Oct 20

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

Although the control of bone metastasis has been the focus of intensive investigation, relatively little is known about the molecular mechanisms that regulate or predict the process, even though widespread skeletal dissemination is an important step in the progression of many tumors. As a result, understanding the complex interactions contributing to the metastatic behavior of tumor cells is essential for the development of effective therapies. Using a state-of-the-art combination of gene expression profiling and functional annotation of human tumor cells, and surface-enhanced laser desorption/ionization time-of-flight mass spectrometry of patient serum, we have shown that changes in tumor biochemistry correlate with disease progression and help to define the aggressive tumor phenotype. Based on these approaches, it is apparent that the metastatic phenotype of tumor cells is extremely complex. The identification of the phenotype of tumor cells has benefited greatly from the application of gene expression profiling (microarray analysis). This technology has been used by many investigators to identify changes in gene expression and cytokine and growth factor elaboration (such as interleukin 8). The tumor phenotype(s) presumably also include changes in the cell surface carbohydrate profile (via altered glycosyltransferase expression) and heparan sulfate expression (via increased heparanase activity), to name but a few. These specific alterations in gene expression, identified by functional annotation of accumulated microarray data, have been validated using a variety of approaches. Collectively, the data described here suggest that each of these activities is associated with distinct aspects of the aggressive tumor cell phenotype. Collectively, the data suggest that multiple factors constitute the complex phenotype of metastatic tumor cells. In particular, the differences observed in gene expression profiles and serum protein biomarkers play a critical role in defining the mechanisms responsible for bone-specific colonization and growth of tumors in bone. Future studies will identify the mechanisms that participate in the formation of secondary tumor growths of cancers in bone.
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PMID:Genomics and proteomics of bone cancer. 1706 4

Glycoconjugates on cell surfaces are known to have important physiological and biological functions. The oligosaccharide components of the cell surface glycoconjugates are recognized as important mediators of cellular interaction and interaction of cells with ligands such as hormones and growth factors (1,2). In normal tissues, such molecules (receptors) form part of the transmembrane structures linking extracellular signals with intracellular transducers of the received information (3) Disruption of these receptors results in loss of transmembrane communication and hence cellular dysfunction Oligosaccharide domains of cellular glycoprotems and glycohpids are synthesized by a series of hierarchically organized glycosyltransferase enzymes within the Golgi apparatus. Structural modifications to oligosaccharide domains of these glycoconjugates occur during ontogeny and oncogenests (4,5). It is increasingly recognized that these modified oligosaccharide domains (antigens) on cancer cells may represent the accumulation of precursor chains with absence of more complex structures because of decreased activity of synthesizing enzymes for terminal components of the carbohydrate chains. In addition, neosynthesis of new saccharide structures may occur because of enhanced synthesis of new components, often because of aberrant fucosylation or sialylation or a combination of both It has been postulated that altered glycoconjugates interact in vivo with lectins associated with the membrane of corresponding cells, as is thought to be the case in the interaction between tumor cells and endothelium in the course of seeding of metastases (6). Increasing awareness of the major significance of cell surface glycoconjugates has led to a rapid expansion in techniques for their analysis.
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PMID:Application of sequential smith degradation to lectin blots. 2137 56


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