CRYPT CELL ANTIGENS AS MARKERS FOR COLON CANCER

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Current research in our laboratory has identified a group of 7 monoclonal antibodies, produced against brush border membrane components of fetal and newborn rat intestinal cells, and the human colon tumor cell line CaCo-2, which define oncofetal antigens expressed by fetal intestinal cells, adult crypt small intestinal cells, and human and rat colonic adenocarcinomas. The antigens recognized by these antibodies, called "Crypt Cell" antigens, have been identified as high molecular weight glycoproteins. The long term objectives of the proposed research are: 1) To further define the structure of these crypt cell antigens expressed by human colon tumor cells and dimethyl hydrazine (DMH)-induced rat colonic tumors; 2) To correlate, in the rat model system, expression of the "Crypt Cell" antigens with different stages of carcinogenesis and histological features of the tumors; 3) To evaluate their expression in various normal and diseased human tissues. Most studies described in this proposal will be centered on the use of monoclonal antibodies and lectins as tools to identify specific antigens in cells and tissues by immunofluorescence staining, and to purify the "Crypt Cell" antigens by affinity chromatography. The purified antigens will be compared by slab gel electrophoresis, Western blotting and peptide mapping. Partial amino acid sequences will be determined, and the structure of the glycosidic chains associated with the antigens produced by CaCo-2 cells will be investigated. The ability of our 7 monoclonal antibodies to recognize carbohydrate groups associated with the antigens will be determined. Samples of colon cancer obtained from surgical specimens, and of adjacent and distal grossly normal mucosa will be used to correlate the distribution of the antigens to the various histological features of the primary tumors. We will also use specimens from patients suffering from Familial Polyposis and volunteer relatives at risk of the same disease. These studies may lead to the development of a test which would permit clinicians to predict who to the relatives at risk will eventually develop the phenotypic manifestation of the disease, and to aid in the follow- up of patients with recurrent formation of adenomatous polyps in the colon, as they belong to the "high risk" group prone to develop colon carcinoma. Overall, the proposed studies should provide valuable information regarding the potential role of the "Crypt Cell" antigens in colon carcinogenesis, and their use as histological and clinical markers of colon cancer.