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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA042981-01
Application #
3184792
Study Section
Pathology B Study Section (PTHB)
Project Start
1986-09-01
Project End
1989-08-31
Budget Start
1986-09-01
Budget End
1987-08-31
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Itzkowitz, S H (1992) Blood group-related carbohydrate antigen expression in malignant and premalignant colonic neoplasms. J Cell Biochem Suppl 16G:97-101
Itzkowitz, S; Kjeldsen, T; Friera, A et al. (1991) Expression of Tn, sialosyl Tn, and T antigens in human pancreas. Gastroenterology 100:1691-700
Itzkowitz, S H; Dahiya, R; Byrd, J C et al. (1990) Blood group antigen synthesis and degradation in normal and cancerous colonic tissues. Gastroenterology 99:431-42
Itzkowitz, S H; Bloom, E J; Kokal, W A et al. (1990) Sialosyl-Tn. A novel mucin antigen associated with prognosis in colorectal cancer patients. Cancer 66:1960-6
Yan, P S; Ho, S B; Itzkowitz, S H et al. (1990) Expression of native and deglycosylated colon cancer mucin antigens in normal and malignant epithelial tissues. Lab Invest 63:698-706
Thor, A; Itzkowitz, S H; Schlom, J et al. (1989) Tumor-associated glycoprotein (TAG-72) expression in ulcerative colitis. Int J Cancer 43:810-5
Dahiya, R; Itzkowitz, S H; Byrd, J C et al. (1989) ABH blood group antigen expression, synthesis, and degradation in human colonic adenocarcinoma cell lines. Cancer Res 49:4550-6
Itzkowitz, S H; Yuan, M; Montgomery, C K et al. (1989) Expression of Tn, sialosyl-Tn, and T antigens in human colon cancer. Cancer Res 49:197-204
Ho, S B; Itzkowitz, S H; Friera, A M et al. (1989) Cell lineage markers in premalignant and malignant colonic mucosa. Gastroenterology 97:392-404
Byrd, J C; Lamport, D T; Siddiqui, B et al. (1989) Deglycosylation of mucin from LS174T colon cancer cells by hydrogen fluoride treatment. Biochem J 261:617-25

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