Colon cancer, the second most common cause of cancer fatality in the U.S., is curable if detected at an early stage. Many tumor markers that appear promising for colon cancer diagnosis are carbohydrate antigens related to blood group substances. The major blood group antigens, ABO, undergo certain alterations associated with colonic neoplasia including: i) reappearance in the distal colon; ii) deletion in the proximal colon; and iii) incompatible expression of A or B antigens. We recently observed that most colon cancer tissues and almost one-third of adenomatous(premalignant)polyps demonstrated incompatibility of A or B antigen, whereas normal adult mucosa, fetal mucosa, and hyperplastic(non-premalignant) polyps never did. The overall purpose of this proposal is to investigate the biochemical basis for ABO incompatibility in colon cancer - a phenomenon which appears to be quite cancerspecific. To this end, we will first identify incompatible ABO expression in cancer tissues and established colon cancer cell lines. In addition, we will initiate new cell lines from tissues expressing incompatible ABO antigens to allow in vitro-in vivo comparisons. Next, from cell lines, we will isolate variant clones expressing incompatible A or B antigens, an clones expressing high andlow levels of compatible A or B antigens. In the selected clones and in tissues (both cancer and normal), the antigens responsible for blood group reactivity will be characterized by hemagglutination inhibition and western blots. Glycoproteins, glycolipids and oligosaccharides from these sources will be evaluated. The propoerties of the A- and B-glycosyltransferases of cancer cells and tissues will be assessed and compared to the serum A- and B- enzymes. Polyclonal antibodies will be raised against the serum A- and B- transferases to permit radioimmunoassay, immunoprecipitation, and immunohistochemical studies on the enzymes. Finally, clones expressing incompatible A or B antigens will be assessed for various biological parameters such as growth properties, tumorigenicity (in vitro, in vivo), invasive potential (in vitro) and metastatic potential in nude mice. These studes should help to elucidate the mechanism(s) of colon cancer cell expression of incompatible A and B antigens and might identify potentially useful tumor markers.
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