The aim of this project is to study carbohydrate structures in mucins and relate these to states of differentiation and malignant transformation in colonic epithelium. One arm of the study is designed to detect and develop markers of cellular differentiation, malignancy, and premalignant colonic tissues. A second arm is designed to study the structural and enzymatic basis of the heterogeneity of colonic mucins. Differentiation-dependent changes have been found in the normal colon; transformation-associated changes have been found in cancer and """"""""transitional mucosa."""""""" Identification of modifications in mucin structure has been found in a variety of premalignant epithelia, including adenomatous polyps, rectal biopsies from patients with chronic ulcerative colitis, and colons from mice treated with a chemical carcinogen. Preliminary evidence suggests that cancer-associated alterations in colonic mucins may be due to incomplete glycosylation of the oligosaccharide chains. In the past year, progress has been made in two areas. First, large quantities of mucin may be obtained through the generation of xenografts in nude mice from cultured human cancer cells. Intracellular mucin-type glycoconjugates may be identified in cultured cells, and secreted mucin has been identified and isolated from the xenografts. This will allow us to pursue a biochemical analysis of the immunochemical determinants of cancer-associated mucin. Two methods have been developed to quantitate the binding of lectins to isolated mucins. Second, colons from several species of marmosets (new world monkeys) have been examined and found to have carbohydrate structures similar to those in humans. In captivity, the cotton-top tamarin (Saginus oedipus oedipus) develops an illness similar to ulcerative colitis in humans, and colonic carcinoma complicates the illness in 25 to 50% of the animals. The cancer-associated mucin determinant was found in the colons of a large percentage of this and two other species of tamarins that develop colitis in captivity, and significantly larger amounts were found in the species in which cancer develops and in those colons in which a cancer was also present. (1)
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| Carethers, J M; Hawn, M T; Chauhan, D P et al. (1996) Competency in mismatch repair prohibits clonal expansion of cancer cells treated with N-methyl-N'-nitro-N-nitrosoguanidine. J Clin Invest 98:199-206 |
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| Shimamoto, C; Deshmukh, G D; Rigot, W L et al. (1989) Analysis of cancer-associated colonic mucin by ion-exchange chromatography: evidence for a mucin species of lower molecular charge and weight in cancer. Biochim Biophys Acta 991:284-95 |
