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)

Cancer-related changes in the serum seromucoid fraction are well known. Last year Woodman published an interesting carbocyanine dye binding method for determination of serum carbohydrate polyanions in sera of normal, traumatized, and tumor-bearing mice. The usefulness of this method for clinical practice has been investigated in this study. Carbocyanine dye-binding polyanion (CPA) and the sialidase-sensitive fraction of this polyanion (SPA) have been determined in sera of 705 human subjects including healthy normal individuals and patients suffering from a broad spectrum of malignant and nonmalignant disease states. Overall, in malignant diseases the CPA and SPA values, in mg pectin equivalents per liter (mean +/-2 S.D.) (292 +/- 111 and 135 +/- 68, respectively) were significantly higher than in the serum from normal controls (166 +/- 33; 74 +/- 18) and patients hospitalized with a variety of nonmalignant disease (195 +/- 56; 92 +/- 36). The highest CPA and SPA values were found in gynecological (331 +/- 117; 149 +/- 69), bronchial (294 +/- 72; 137 +/- 51), and gastrointestinal cancers (316 +/- 111; 154 +/- 69). Elevated CPA values were found in 59.9% and elevated SPA values in 52.8% of patients suffering from malignant diseases. Successfully, radically treated cancer patients with no detectable residues or metastases for at least 1 year had values (186 +/- 39; 76 +/-24) almost within the normal ranges (93 to 250 mg pectin equivalents per liter for CPA and 35 to 120 mg pectin equivalents per liter for SPA).
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PMID:Determination of carbocyanine dye-binding polyanions in malignant and nonmalignant disease states. 127 85

Reliable discriminatory tests to predict metastatic disease would clearly facilitate the management of cancer in the elderly. We have recently identified a 90-110-kilodalton (kDa) cell surface glycoprotein that is differentially expressed in benign and malignant murine adrenal carcinoma cells. In view of the proteins highly glycosylated nature, we have tested its ability to bind to a panel of agarose-bound lectins. Wheat germ agglutinin (WGA), a lectin specific for terminal sialic acid and N-acetylglucosamine (G1cNAc), had a strong affinity for the metastasis-related protein but failed to detect such a glycoprotein in nonmetastatic cells. Treatment of cells with sialidase to remove terminal sialic acids did not affect the affinity of the protein for the lectin, indicating the presence of terminal G1cNAc. We show by in situ that this metastatic binding protein (MBP) is regionally concentrated on the surface of invasive cells but absent in cells unable to invade. We postulate that MBP plays an active role in cell migration through interactions with beta-1,4 galactosytransferase and basement membrane glycoproteines.
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PMID:A murine model for evaluating metastatic potential: characterization of a 90-110-kDa metastasis-binding protein. 142 83

Human lung adenocarcinoma sub-cell lines HAL-8, HAL-24 and HAL-33, showing different lung colonization potential (LCP), were established from human lung adenocarcinoma cell line KUM-LK-2 using repeated cloning with limiting dilution technique. Cell lines HAL-8 and -33 were characterized by high and low LCP, respectively, while HAL-24 did not give rise to lung colonies. The cell surface protein and carbohydrate profiles were determined by cell surface labeling (with lactoperoxidase-dependent 125I-iodination and galactose oxidase-NaB3H4, respectively) followed by SDS-gel electrophoresis. Various carbohydrate epitopes expressed at the cell surface were analysed by cytofluorometry using various monoclonal antibodies (MAbs) directed to Le(x), sialosyl-Le(x), sialosyl dimeric Le(x), T, Tn and sialosyl-Tn structures, which are often reported as being highly expressed in a variety of human cancers, particularly adenocarcinoma. Expression of sialosyl dimeric Le(x) (defined by MAb FH6) was high on HAL-8, moderate on HAL-33, and relatively low on HAL-24. In contrast, each of the three lines showed essentially equal expression (as determined by MAb reactivity) of sialosyl-Tn (defined by MAb TKH2), Le(x) (defined by MAb SH1), and Tn (defined by MAb 1E3). The cell lines showed extremely weak expression of T (defined by MAb HH8). LCP of HAL-8 and -33 was completely inhibited by sialidase treatment of cells. It is suggested that higher expression of sialosyl dimeric Le(x) (defined by MAb FH6) in HAL-8 cells may play an important role in higher potential of blood-borne lung colonization.
Clin Exp Metastasis
PMID:Human lung adenocarcinoma cell lines with different lung colonization potential (LCP), and a correlation between expression of sialosyl dimeric Le(x) (defined by MAb FH6) and LCP. 167 53

Colorectal primary carcinomas and metastases from 20 Dukes' stage C or D patients were examined for the immunohistochemical localization and contents of various fucosylated N-acetyl-lactosamine oligomers by specific monoclonal antibodies (MAbs). MAbs used were SH1, specific for Lewis X antigen; FH4, specific for dimeric Lewis X antigen; FH6, specific for sialyl-dimeric Lewis X antigen; and KH1, specific for Lewis Y-Lewis X antigen. The distribution of the carbohydrate antigens identified by these MAbs was heterogeneous within the primary tumor as well as within the metastatic lesion. Examinations of serial sections indicated that areas within an individual tumor which were stained with one MAb were not always reactive with the other MAbs, although these four MAbs identify closely related structures. The degree of MAb reactivity with carcinoma sections was classified by percentage positive carcinoma cells, and primary tumors and metastases from the same patients were compared. An equivalent or higher proportion of carcinoma cells in the metastatic lesions were reactive with MAb FH6 than in the primary colon carcinomas, but each correlation was not seen with the other MAbs. Electrophoretic separation of tumor tissue extracts followed by staining with these MAbs revealed that a component having an approximate molecular weight of 1,000,000 is the major site for the binding of MAbs, FH6, FH4, and KH1. The electrophoretic mobility of the antigenic molecule on polyacrylamide gels as shown by direct MAb bindings was slightly different from that of a major sialomucin revealed by wheat germ agglutinin in the same tissues. MAb FH6 binding to a high molecular weight component was eliminated by prior treatment of the glycoprotein with mild acid or sialidase to remove sialic acid. Simultaneously, binding of MAb SH2, specific for dimeric Lex antigen, to this component increased. An extract was prepared from a liver metastasis, and high molecular weight components were isolated by gel filtration and then fractionated by DEAE-cellulose ion exchange chromatography. A fraction eluted from DEAE-cellulose between 0.10-0.25 M sodium chloride contained most of the MAb FH6 reactivity, as shown by antibody affinity chromatography. These results support a hypothesis that high molecular weight glycoproteins produced by colorectal carcinoma tissues are heterogeneous with regard to their carbohydrate chains and their antigenic structures may change during tumor progression.
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PMID:Sialyl-dimeric Lewis-X antigen expressed on mucin-like glycoproteins in colorectal cancer metastases. 197 61

Gastric and intestinal phenotypic expression in 37 surgically obtained primary signet ring cell carcinomas, five of their metastases to lymph nodes, and three signet ring cell carcinomas transplanted into nude mice were determined by biochemical, mucin, histochemical, and ultrastructural studies. Crude extracts of cancer tissues were used for measurements of pepsinogen isozymes, sucrase, aminopeptidase (microsomal), and alkaline phosphatase. Histochemical staining of mucin by paradoxical concanavalin A, the galactose oxidase-Schiff sequence and sialidase-galactose oxidase-Schiff, and the periodate-borohydride technique/potassium hydroxide/periodic acid-Schiff procedure was performed. The procedures allowed clear definition of pyloric gland, surface mucous, small and large intestinal goblet, and intestinal absorptive cell types. Of 40 specimens examined, 19 consisted entirely of gastric-type cells, and three entirely of intestinal-type cells. The others consisted of mixtures of gastric and intestinal-type cells. The observed high incidence of intestinal-type cells in signet ring cell carcinomas suggested that intestinal-type cells develop independently from intestinal metaplasia within signet ring cell carcinomas (diffuse-type gastric cancers), which probably originate from nonmetaplastic gastric mucosa.
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PMID:Gastric and intestinal phenotypic expressions of human signet ring cell carcinomas revealed by their biochemistry, mucin histochemistry, and ultrastructure. 301

Numerous investigations suggest that cell surface glycoconjugates, and in particular sialic acids, are directly involved in determining the metastatic phenotype. To further evaluate this hypothesis, we have used a variety of techniques to probe the cell surfaces of several metastatic variants of the murine B16 melanoma that were selected for experimental lung-colonizing ability (Fidler, I. (1973) Nature 242, 148-149) or for their ability to spontaneously metastasize from the site of a subcutaneous injection (Stackpole, C. W., Alterman, A. L., and Fornabaio, D. M. (1985) Invasion & Metastasis 5, 125-142). Using a highly sensitive high performance liquid chromatography sialic acid assay in conjunction with Vibrio cholerae sialidase, we find that none of these metastatic variants differ significantly in their overall levels of cell surface sialic acid. Using highly purified, linkage-specific sialyltransferases, in conjunction with specific glycosidases, to probe the cell surface saccharide topography of specific penultimate oligosaccharides, we also find no significant differences between the efficient lung-colonizing variant, B16-F10 and the poorly-colonizing B16-F1 or B16-Flr variants. In contrast, the spontaneously metastatic variants examined contain substantially different levels of specific penultimate sialylation sites. The tumorigenic but nonmetastatic B16-LM3/G3.26 variant contains 4-fold more penultimate Gal beta 1-3GalNAc sialylation sites than the tumorigenic and highly metastatic B16-LM3/G3.12 variant when CMP[3H]NeuAc and the alpha 2-3Gal beta 1-3GalNAc sialyltransferase are used to probe the melanoma cell surfaces. Several prominent glycoconjugates of apparent Mr 43,000, 40,000, and 30,000 are especially evident upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the nonmetastatic cells. The nonmetastatic variant also contains 2-fold more Gal beta 1-4GlcNAc sialylation sites than the metastatic variant when the alpha 2-6Gal beta 1-4GlcNAc sialyltransferase is used as a cell surface probe. In this case, glycoconjugates of apparent Mr 74,000, 45,000, and 43,000 are more prominently observed on the cell surfaces of the nonmetastatic variant. These data indicate that the differences in lung-colonizing abilities of B16 melanoma metastatic variants do not correlate with the numbers or sialylation states of specific penultimate oligosaccharide structures on their surfaces. However, the relative levels of specific penultimate saccharide structures do correlate with the ability of the cells to undergo spontaneous metastasis from a subcutaneous tumor.
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PMID:Cell surface sialylation and tumor metastasis. Metastatic potential of B16 melanoma variants correlates with their relative numbers of specific penultimate oligosaccharide structures. 337 1

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 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

In the experimental metastasis assay certain animals, from groups of similarly treated animals, develop more lung metastases than expected from random chance alone. This clustering of metastases is characterized by a power function relationship, sigma(2) = amu(b), between the variance, sigma(2), and mean, mu, of the numbers of lung metastases per animal (a and b are constants). To determine whether this clustering could be an artifact of experimental metastasis, whether it could be influenced by different experimental conditions, and to attempt to clarify its cause, 22 published data sets from experimental metastasis utilizing 2,145 mice, as well as 8 data sets from spontaneous metastasis utilizing 1,020 mice were analyzed. In these experiments cell cloning, cell-cell fusion, treatment with a protein kinase C inhibitor, treatment with cell adhesion compounds, and transfection with either the ras oncogene, the sialidase gene, or the urokinase sense and antisense genes were used to influence metastasis. They employed 14 different cell lines and 6 different strains of inbred mice. Clustering of metastasis was evident in animals from the spontaneous metastasis assays as well as from the experimental metastasis assays. It was apparent whether mice were injected with tumor cells derived from clones or from cell lines. Clustering was demonstrated within each data set, regardless of the experimental conditions employed. A single variance to mean power function (with a = 2.2 and b = 1.51) characterized the clustering in the 30 data sets. The regional distribution of blood flow through lungs and other organs is nonuniform, exhibiting a fractal symmetry on change of scale. This symmetry implies that the variance of a region's blood flow is related to its mean by the same power function as was observed with metastasis. Indeed, measurements of blood flow from isolated canine lungs yield b = 1.56, similar to the corresponding figure from murine lung metastasis. These findings lend support to the hypothesis that the observed clustering of metastases is a consequence of fractal variations in lung blood flow.
Invasion Metastasis
PMID:Clustering of murine lung metastases reflects fractal nonuniformity in regional lung blood flow. 1072 73

Patients with metastatic cancer commonly have increased serum galectin-3 concentrations, but it is not known whether this has any functional implications for cancer progression. We report that MUC1, a large transmembrane mucin protein that is overexpressed and aberrantly glycosylated in epithelial cancer, is a natural ligand for galectin-3. Recombinant galectin-3 at concentrations (0.2-1.0 microg/ml) similar to those found in the sera of patients with metastatic cancer increased adhesion of MUC1-expressing human breast (ZR-75-1) and colon (HT29-5F7) cancer cells to human umbilical vein endothelial cells (HUVEC) by 111% (111 +/- 21%, mean +/- S.D.) and 93% (93 +/- 17%), respectively. Recombinant galectin-3 also increased adhesion to HUVEC of MUC1 transfected HCA1.7+ human breast epithelial cells that express MUC1 bearing the oncofetal Thomsen-Friedenreich antigen (Galbeta1,3 GalNAc-alpha (TF)) but did not affect adhesion of MUC1-negative HCA1.7-cells. MUC1-transfected, Ras-transformed, canine kidney epithelial-like (MDE9.2+) cells, bearing MUC1 that predominantly carries sialyl-TF, only demonstrated an adhesive response to galectin-3 after sialidase pretreatment. Furthermore, galectin-3-mediated adhesion of HCA1.7+ to HUVEC was reduced by O-glycanase pretreatment of the cells to remove TF. Recombinant galectin-3 caused focal disappearance of cell surface MUC1 in HCA1.7+ cells, suggesting clustering of MUC1. Co-incubation with antibodies against E-Selectin or CD44H, but not integrin-beta1, ICAM-1 or VCAM-1, largely abolished the epithelial cell adhesion to HUVEC induced by galectin-3. Thus, galectin-3, by interacting with cancer-associated MUC1 via TF, promotes cancer cell adhesion to endothelium by revealing epithelial adhesion molecules that are otherwise concealed by MUC1. This suggests a critical role for circulating galectin-3 in cancer metastasis and highlights the functional importance of altered cell surface glycosylation in cancer progression.
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PMID:Galectin-3 interaction with Thomsen-Friedenreich disaccharide on cancer-associated MUC1 causes increased cancer cell endothelial adhesion. 1709 May 43


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