Colon cancer, the second most common cause of cancer fatality in the USA, 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, ABH, are normally expressed by epithelial cells of the proximal but not distal colon. In premalignant and malignant colonic tissues, the following cancer-associated alterations of ABH expression can occur: 1) reappearance in the distal colon; 2) deletion in the proximal colon; and 3) incompatible A or B antigen expression. We obtained evidence that the absence of ABH expression from normal distal colon is not a defect of impaired terminal glycosylation or enhanced ABH degradation. Therefore, antigen masking or altered precursor synthesis and availability may be responsible for distal ABH absence. Furthermore, several N-acetylgalactosaminyltransferase activities were discovered in colon cancers which might contribute to A-like (incompatible) antigen synthesis. The overall purpose of this proposal is to focus mainly on the blood group A antigen to further elucidate mechanisms of ABH structure, synthesis, and regulation. To this end we will further investigate the several structural variants of A antigen in cell lines and tissues. Using colonic tissues and cancer cell lines to be established from individuals of known secretor and Lewis status, we will investigate precursor biosynthesis and competition. Studies will also characterize the enzymatic activity and products of several A-like transferases detected in preliminary studies, and colonic tissues and cells will be surveyed for these enzyme activities. Further, in studies concerning the regulation and function of A antigens, attempts will be made to identify endogenous N-acetyl-galactosamine-specific lectins, and determine whether A antigen or other tumor-associated carbohydrate antigens are found on biologically important proteins such as growth factor receptors. Finally, using colon cancer cell lines with high and low A-transferase activities, we will test the effect of growth factors and putative differentiation agents on A antigen expression and synthesis. These studies should broaden our knowledge of colonocyte synthesis and regulation of the major blood group substances. The results obtained could provide important insight into the role of carbohydrate antigens on cancer cells.
Showing the most recent 10 out of 14 publications
