Colorectal cancer is the second leading cause of cancer-related mortality in the U.S.A. The chief secretory product of colonic epithelium is mucus, the main component of which is mucin. Mucins are large glycoproteins consisting of carbohydrate side chains on protein backbones. Previous studies have revealed differences between the carbohydrate portions of normal and cancerous colonic mucin. However, it is not known whether abnormal mucin produced by colon cancers contributes to the biological behavior of the tumor. Some clinical studies have suggested that highly mucinous colon cancers are associated with a poor prognosis. Experimental studies have found that metastatic potential of colon cancer cells is related to their ability to produce mucin and to higher levels of sialic acid on the cell surface. Recently, studies by the principal investigator demonstrated that expression of a particular sialylated mucin antigen, sialosyl-Tn, was an independent variable predicitive of poor prognosis in colon cancer. The overall purpose of this proposal is to focus on the sialosyl-Tn antigen is a marker of cancer mucin to further elucidate mechanisms of cancer- associated mucin oligosaccharide synthesis and characterize the influence of this mucin antigen on the biology and immune recognition of colon cancer cells. Clinical studies will examine whether other sialylated mucin antigens are also prognostic factors in colon cancer, whether sialosyl-Tn expression is prognostic in stomach and pancreatic cancers, and whether sialosyl-Tn mucin is shed into the serum of cancer patients or cell culture medium of cancer cell lines. Two key questions will be addressed at the basic level: (1) Why are some colon cancers sialosyl-Tn (-)? Antigen (+) and antigen (-) cell lines and tissues will be examined biochemically for differences in mucin oligosaccharides and peptides, biosynthetic (glycosyl-transferases) and degradative (glycosidase) enzyme activities, availability of precursor substances, and antigen masking. (2) Does sialosyl-Tn phenotype influence the biological behavior or immune recognition of colon cancer cells? Sialosyl-Tn (+) and (-) cells will be compared for differences in growth properties, tumorigenicity, invasiveness, and metastatic potential. Serum from normal individuals and colon cancer patients will be analyzed for the existence of anti-sialosyl-Tn antibodies. Other experiments will determine whether lysis of colon cancer targets by antibody-dependent or natural killer cell mechanisms is sialosyl-Tn dependent.
Showing the most recent 10 out of 26 publications
