Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peanut lectin (PNA) has a specificity for the disaccharide beta-D-Gal-(1 leads to 3)-D-GalNac which is the purported antigenic determinant for the T blood group antigen (TAg). This TAg is considered the immediate precursor of the MN blood group substance. In normal colonic epithelium, PNA binds to the supranuclear (stalk) portion of epithelial cells. This corresponds to the detection of beta-DGal-(1 leads to 3)-D-GalNac in nascent oligosaccharide chains in the Golgi cisternae prior to addition of terminal sialic acid. Colonic carcinomas bind PNA in the "region" of the glycocalyx or in the apical portion of the cell, which represents incomplete glycoprotein synthesis. Eighty-two percent of tubular adenomas, 80% of villous adenomas, and 91% of adenomas with in situ cancer expressed PNA in a supranuclear distribution, reminiscent of normal colonic epithelium. This stalk distribution was seen in goblet cells. Twenty-five percent of tubular adenomas, 43% of villous adenomas and 60% of adenomas with in situ cancer (adenoma portion) expressed PNA in an apical cytoplasmic and/or glycocalyx pattern among nonmucinous columnar cells. In 80% of the cases, the in situ cancer itself expressed PNA in an apical cytoplasmic and/or glycocalyx pattern. Fetal and most colon cancer cells fail to produce mucin goblets and make incomplete glycoproteins. The cytologic localization of TAg by PNA corresponds to the cells' ability to produce mucin goblets. Most adenomas consist of goblet cells, localize TAg to the stalk, and probably make complete MN glycoprotein as does normal colonic epithelium. However, in adenomas, nonmucinous columnar cells localize TAg to the apical cytoplasm and/or glycocalyx region and represent incomplete blood group glycoprotein synthesis.
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PMID:Peanut lectin-binding sites in polyps of the colon and rectum. Adenomas, hyperplastic polyps, and adenomas with in situ carcinoma. 665 97

Altered expression of ABH blood group substances is a common feature of human colorectal carcinoma, yet it remains unclear how these structural changes influence the biological properties of tumor cells. Azoxymethane-induced rat colon tumors display many features of the human disease, thereby providing a potentially useful model to study the role of blood group substances in colon cancer progression. We have prepared monoclonal antibodies to a microsomal fraction isolated from an azoxymethane-induced rat colon tumor and selected an antibody that detects cancer-associated changes. Monoclonal antibody (mAb) 3A7 recognizes a determinant on type 2 chain blood group A (GalNAc alpha 1-3[Fuc alpha 1-2]Gal beta 1-4GlcNAc-R) and B (Gal alpha 1-3[Fuc alpha 1-2]Gal beta 1-4GlcNAc-R) oligosaccharides. Expression of the epitope detected by this antibody was developmentally regulated in rat colon, with maximal expression from day 4-21 after birth. Immunohistochemical staining and Western blotting analyses of azoxymethane-induced colon tumors revealed increased expression of the epitope in all of the 21 colonic tumors examined, including preneoplastic glands within transitional mucosa. Conventional and signet-ring adenocarcinomas that had invaded through the muscularis propria (Duke's B2) consistently showed the most intense staining with mAb 3A7, including regions depicting angioinvasion. Some of the lymph node metastases (Duke's C2) stained poorly with the antibody. The epitope was also expressed in blood group A positive human colon carcinoma cell lines, including HT29 and SW480 but not by SW620, a cell line derived from a lymph node metastasis isolated in vivo from the SW480 primary tumor, or in the blood group B cell line SW1417. The glycoproteins detected by mAb 3A7 in rat colon tumors and HT29 cells ranged in size between 50 and 200 kd, including a major species of 140 kd. Affinity chromatography of detergent lysates of normal rat colon on the blood group A specific lectin Dolichos biflorus (DBA)-agarose resulted in nearly quantitative binding of glycoprotein species detected by the antibody. By contrast, immunoreactive glycoproteins from rat colon tumors or HT29 cells bound poorly to DBA-agarose but were retained by another blood group A-binding lectin, Helix-pomatia (HPA)-agarose. These results indicate that colon carcinogenesis results in quantitative as well as qualitative changes in oligosaccharides detected by mAb 3A7 and suggest that the combined use of mAb 3A7 and blood group A-specific lectins may provide a useful tool for early detection of colon cancer.
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PMID:Monoclonal antibody recognizing a determinant on type 2 chain blood group A and B oligosaccharides detects oncodevelopmental changes in azoxymethane-induced rat colon tumors and human colon cancer cell lines. 753 50

Inositol hexaphosphate (InsP6 or phytic acid) has been shown to have antineoplastic action in in vivo models of colon carcinogenesis. We therefore investigated its effect on proliferation and differentiation of the human colon cancer cell line HT-29 in vitro. Proliferation was evaluated by neutral red incorporation assay, and differentiation was assessed by expression of the markers, cytokeratin, carcinoembryonic antigen (CEA) and beta-D-galactose-[1-->3]-N-acetyl-galactosamine (Gal-GalNAc). InsP6 in the culture media (0.66-10 mM) inhibited cell proliferation in a dose-dependent manner (P < 0.001), while inositol or inositol hexasulfate used as controls or media without InsP6 did not show any suppressive effect. The expression of the tumor marker, Gal-GalNac, was augmented (100.7% increase) by low dose (0.66 mM) of InsP6 but was subsequently suppressed with higher concentrations of InsP6. The expression of cytokeratin and CEA were both augmented by either InsP6 or inositol at all concentrations tested, although the degree of augmentation was milder with inositol than with InsP6. The combination of InsP6 and inositol (both 0.66 mm) resulted in augmentation (P < 0.001) of cytokeratin expression, while that of CEA remained unchanged. The inhibitory effect of InsP6 on cell proliferation was not altered by combination with additional inositol at any concentrations tested. Our results show that InsP6 inhibits cell proliferation and concomitantly increases differentiation and is therefore a candidate chemopreventive and chemotherapeutic agent for human large intestinal cancer.
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PMID:Growth inhibition and differentiation of HT-29 cells in vitro by inositol hexaphosphate (phytic acid). 769 27

Neoplastic transformation is commonly associated with altered glycosylation of proteins and lipids. To understand the basis for altered mucin glycosylation, we have examined the distribution of RER markers, a cis-Golgi resident protein, and the GalNAc alpha-O-Ser/Thr epitope (Tn) in human colon cancer cells and in normal colon. In cultured mucin-producing colon cancer cells, Gal-NAc alpha-O-Ser/Thr was found in mucin droplets and in RER cisternae. In addition, the Golgi apparatus was disorganized in a proportion of cells and a 130 kDa cis-Golgi resident protein was also abnormally redistributed to the RER. The distribution of the MUC2 intestinal apomucin, protein disulphide isomerase, Gal-NAc alpha-O-Ser/Thr, and the 130 kDa cis-Golgi resident protein was analysed in normal colon and in colon cancer tissues. In normal colon, MUC2 apomucin and protein disulphide isomerase were located in the RER, whereas the cis-Golgi resident protein and GalNAc alpha-O-Ser/Thr were detected only in the cis-Golgi compartment. In contrast, the two Golgi markers colocalized with the MUC2 apomucin and protein disulphide isomerase in the RER of colon cancer cells. On the basis of these results, we propose that in colon cancer cells a redistribution of molecules normally present in the Golgi apparatus takes place; this alteration may contribute to the abnormal glycosylation of proteins and lipids associated with neoplastic transformation.
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PMID:cis-Golgi resident proteins and O-glycans are abnormally compartmentalized in the RER of colon cancer cells. 769 49

Human colon cancer is associated with antigenic and structural changes in mucin-type carbohydrate chains (O-glycans). To elucidate the control of the biosynthesis of these O-glycans is colon cancer, we have studied glycosyltransferase and sulphotransferase activities involved in the assembly of elongated O-glycan structures. We analysed homogenates prepared from cancer tissue, adjacent normal and distal normal tissue from 20 patients. Several transferase activities showed pronounced changes in cancer tissue. The changes correlate with previous findings of a loss of O-glycans in cancer mucins, but did not always correlate with levels of Tn, sialyl-Tn, T and Lex antigens in homogenates or with the differentiation status and Duke's stages of the cancer tissue or the patient's blood type, sex and age. UDP-GlcNAc: Gal NAc-R beta 3-N-acetylglucosaminyltransferase (where GlcNAc is N-acetyl-D-glucosamine and GalNAc is N-acetyl-D-galactosamine) synthesizing O-glycan core 3, GlcNAc beta 1-3GalNAc-, CMP-sialic acid: GalNAc-peptide alpha 6-sialyltransferase synthesizing the sialyl-Tn antigen and sulphotransferase activities towards O-glycan core 1, Gal beta 1-3GalNAc-, were found to be decreased in cancer. UDP-GlcNAc: Gal beta 1-3GalNAc beta 6-N-acetylglucosaminyltransferase was also decreased in cancer concomitant with a loss of the ability to synthesize the I antigen and core 4, GlcNAc beta 1-6(GlcNAc beta 1-3) GalNAc-, CMP-sialic acid: Gal beta 1-3GalNAc-R alpha 3-sialyltransferase and GDP-fucose: Gal beta-R alpha 2-fucosyltransferase, synthesizing the blood group H determinant, were found to be 4- and 3- to 8-fold increased, respectively, in cancer compared to normal tissue. The data suggest that the biosynthesis of antigens and mucin-bound O-glycan structures in colon cancer is subject to complex control mechanisms.
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PMID:Alterations of O-glycan biosynthesis in human colon cancer tissues. 773 50

Increased binding of the lectin peanut agglutinin is a common feature in epithelial malignancy and hyperplasia. This may have considerable functional importance in the intestine by allowing interaction between the epithelium and mitogenic lectins of dietary or microbial origin. Peanut agglutinin binds the disaccharide Thomsen-Friedenreich (TF, T or core 1) blood group antigen, Gal beta (1-3) GalNAc alpha-, but is not totally specific for this site. Consequently, there has been controversy about the presence of this structure in colon cancer; studies with anti-TF monoclonal antibodies have failed to detect it. We have examined the presence of TF antigen in colonic mucus glycoprotein (mucin) using endo-alpha-N-acetylgalactosaminidase (O-Glycanase), which specifically catalyzes the hydrolysis of TF antigen from glycoconjugates. Samples of adenocarcinoma, inflammatory bowel disease (ulcerative colitis), and normal mucin were treated with O-glycanase, the liberated disaccharide was separated from the glycoprotein and analyzed using dual CarboPac PA-100 column high performance anion-exchange chromatography coupled with pulsed amperometric detection. O-Glycanase treatment released increased amounts of TF antigen from both colonic adenocarcinoma (8.0 +/- 3.9 ng/micrograms protein, n = 11; P < 0.0001 ANOVA) and ulcerative colitis mucin (3.3 +/- 0.3 ng/micrograms protein, n = 5; P = 0.04) compared with mucin samples from histologically normal mucosa distant from carcinoma (1.5 +/- 1.1 ng/micrograms protein, n = 9). However, after mild acid treatment to remove sialic acids and fucose, releasable TF antigen was increased in all nine of these histologically normal mucin samples (5.5 +/- 2.6 ng/micrograms protein, P < 0.0002). We conclude that TF antigen is an oncofetal antigen which is expressed in colon cancer, but is concealed by further glycosylation (sialylation and/or fucosylation) in the normal colonic mucosa.
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PMID:Direct demonstration of increased expression of Thomsen-Friedenreich (TF) antigen in colonic adenocarcinoma and ulcerative colitis mucin and its concealment in normal mucin. 786 Jul 40

Carbohydrate antigens can be designed by referring to previously defined carbohydrate structures. We have generated a novel monoclonal antibody (MAb) (F1 alpha-75) against an artificially designed antigen (F1 alpha), using organic-synthetic chemistry methods and hybridoma technology. F1 alpha (Gal beta 1-->4GlcNAc beta 1-->6GalNAc alpha 1-->Ser/Thr) belongs to core type 6 of O-linked glycans, which has not been previously reported in human cancers. To produce antibodies against F1 alpha, a glycolipid was synthesized which carries the carbohydrate portion of F1 alpha on a ceramide foundation (Gal beta 1-->4GlcNAc beta 1-->6GalNAc alpha 1-->Cer). The MAbs we obtained (F1 alpha-75, F1 alpha-87) specifically recognized F1 alpha and had only a very weak or no cross-reactivity with other glycolipids similar to F1 alpha. We investigated the expression of F1 alpha in human tissues, including 110 gastric cancers, 73 colon cancers and 42 pancreatic cancers. F1 alpha was found in human cancerous tissues but not in normal adult tissues. The rate of positive staining with F1 alpha-75 was 80.0% for gastric cancer, 52.4% for pancreatic cancer and 38.4% for colon cancer. F1 alpha-75 also reacted with the tissues neighboring gastric and pancreatic tumors but not intensely. Among fetal tissues, F1 alpha-75 reacted with the pyloric glands of the stomach, the centro-acinar cells of the pancreas, the convoluted tubules of the kidney and the terminal bronchioles of the lung.
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PMID:A new cancer-associated antigen defined by a monoclonal antibody against a synthetic carbohydrate chain. 805 Aug 16

Galactosyl beta-1,3-N-acetyl galactosamine (Gal beta-1,3-GalNAc) (Thomsen Friedenreich antigen), the Class I core sequence in O-linked oligosaccharide chains, behaves as an oncofetal antigen showing increased expression in many epithelial malignancies. Previous work has shown that peanut agglutinin (PNA), a lectin that binds Gal beta-1,3-GalNAc, stimulates proliferation in HT-29 (human colon cancer) cells and normal human colonic epithelium and this implies that cell surface glycoproteins which express Gal beta-1,3-GalNAc may play an important role in the regulation of epithelial cell proliferation. We have now studied the effect on epithelial cells of another dietary Gal beta-1,3-GalNAc-binding lectin, the edible mushroom Agaricus bisporus lectin (ABL). This differs from PNA in its ability to bind also to sialylated Gal beta-1,3-GalNAc. In contrast to PNA, ABL (25 micrograms/ml) inhibited incorporation of [3H]-thymidine into DNA of HT29 colon cancer cells by 87% (95% confidence limit, 85-89%), Caco-2 colon cancer cells by 16% (95% confidence limit, 12-20%), MCF-7 breast cancer cells by 50% (95% confidence limit, 47-52%), and Rama-27 rat mammary fibroblasts by 55% (95% confidence limit, 51-60%) when these cells were grown for 24 h in serum-free medium. When assessed by cell count, similar inhibition of proliferation of HT29 cells by ABL was found. In the presence of 2% fetal calf serum (which contains the ABL-binding glycoprotein fetuin), the inhibitory effect of ABL on cell proliferation was still demonstrable but at increased ABL concentration (60 micrograms/ml for 49% inhibition). Ten micrograms/ml ABL completely abolished the stimulatory effect on [3H]thymidine incorporation of epidermal growth factor (100 pg/ml) and PNA (25 micrograms/ml) and markedly inhibited the stimulatory effect of insulin (50 ng/ml). ABL (0.2 mg/ml) caused no cytotoxicity to HT29, MCF-7, and Rama-27 cells as measured by trypan blue exclusion, and inhibition of proliferation in HT29 cells caused by 50 micrograms/ml ABL was reversible after removal of the lectin. Binding studies with 125I-labeled ABL suggested a single class of binding site with an apparent Kd value of (4.12 +/- 0.29) x 10(-7) M with (3.6 +/- 0.3) x 10(7) binding sites/cell. A. bisporus lectin is a reversible noncytotoxic inhibitor of epithelial cell proliferation which deserves study as a potential agent for cancer therapy.
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PMID:Reversible inhibition of proliferation of epithelial cell lines by Agaricus bisporus (edible mushroom) lectin. 840 38

Comparative and correlative studies of the pathology and pathogenesis of colon cancer in animal models and human disease have resulted in conceptualization of 'field effect" theory and identification of markers that are expressed early during carcinogenesis. This assimilated body of knowledge has resulted in development of a simple rectal mucus test for colon cancer screening. The marker galactose-N acetylgalactosamine (Gal-GalNAC) is expressed in the rectal mucus of patients with colonic cancer or precancerous lesions and is detected by enzymatic oxidation (10 minutes) followed by color reaction (1 minute). The high sensitivity, specificity, positive predictive value and negative predictive value, as well as the cost-effectiveness of this test makes it a great tool in our strategies for early detection, hence control of colon cancer. Because of its high accuracy (as opposed to the fecal occult blood tests), it would reduce the number of unnecessary colonoscopies, thereby decreasing the total national health-care cost to the society. Similar expression of this marker in cancers of breast, lungs, prostate, pancreas, makes it a potentially useful general cancer screening test.
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PMID:A simple mucus test for cancer screening. 869 42

The disaccharide tumor marker Gal-GalNAc visualized by galactose oxidase-Schiff sequence is commonly present in cancer cells and in rectal mucous of patients with colon cancer. The expression of this marker on tissue sections taken during experimental colon carcinogenesis shows excellent correlation with human precancerous lesions and even higher percentage of colon cancers express this marker, whereas, no expression is seen in the normal human large intestine. Multifocal expression of the marker is seen throughout the entire colon of patients with precancer and cancer; these include dysplasia, dilated and distorted crypts, regenerative dysplasia and hyperplastic crypts, as well as the morphologically normal crypts remote from cancer. Nearly identical pattern of Gal-GalNAc expression throughout the entire colon also appear during rat colon carcinogenesis induced by azoxymethane including non-expression by the normal and regenerative epithelia during wound healing following mechanical injury. Thus, Gal-GalNAc detected by the simple technique of galactose oxidase-Schiff sequence, is a biomarker that appears during the very early stages of progression of carcinogenesis. The expression pattern supports the field effect theory of carcinogenesis and also explains the basis for mass screening for cancer and precancerous conditions. Chemoprevention strategy using Gal-GalNAc as an intermediate marker detected by accurate and cost-effective rectal mucus test may have great potential.
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PMID:Gal-GalNAc: a biomarker of colon carcinogenesis. 883 67


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