PATHOBIOLOGY OF COLON CANCER MUCIN

结肠癌粘蛋白的病理学

• 批准号: 3197229
• 负责人: STEVEN H. ITZKOWITZ
• 金额: $ 15.6万
• 依托单位: MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 1993-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3197229
• 关键词: O glycosidase; adult human (21+); antibody dependent killer cell; antigen presentation; athymic mouse; biomarker; carbohydrate sequence; cell mediated lymphocytolysis test; chemical fingerprinting; clone cells; colon neoplasms; colorectal neoplasms; enzyme linked immunosorbent assay; galactosyltransferases; glycoprotein structure; glycosyltransferase; human subject; human tissue; humoral immunity; immunocytochemistry; laboratory mouse; metastasis; monoclonal antibody; mucins; natural killer cells; neoplasm /cancer invasiveness; oncoproteins; pancreas neoplasms; prognosis; protein structure; sialate; stomach neoplasms; tumor antigens; western blottings

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.

结直肠癌是与癌症相关死亡率的第二大原因 在美国。结肠上皮的主要分泌产物是粘液， 其主要成分是粘蛋白。 粘蛋白是大糖蛋白 由蛋白质骨架上的碳水化合物侧链组成。 以前的 研究揭示了碳水化合物部分之间的差异 正常和癌性结肠粘蛋白。 但是，尚不知道是否 结肠癌产生的异常粘蛋白有助于生物学 肿瘤的行为。 一些临床研究表明，高度粘液结肠癌是 与预后不良有关。 实验研究发现 结肠癌细胞的转移潜力与它们的能力有关 在细胞表面产生粘蛋白和较高水平的唾液酸。 最近，首席研究人员的研究表明 特定硫化粘蛋白抗原sialosyl-tn的表达是一种 结肠癌预后不良的独立变量。 该提案的总体目的是专注于Sialosyl-TN抗原 是癌症的标志物，以进一步阐明癌症的机制 相关的粘蛋白寡糖合成并表征了影响 关于生物学和免疫识别结肠癌的粘蛋白抗原 细胞。 临床研究将检查其他糖粘粘蛋白是否 抗原也是结肠癌的预后因素 表达在胃和胰腺癌中是预后的，以及是否存在 Sialosyl-TN粘蛋白脱落到癌症患者或细胞培养的血清中 癌细胞系的培养基。 两个关键问题将在基本层面解决：（1）为什么有些 结肠癌sialosyl-tn（ - ）？ 抗原（+）和抗原（ - ）细胞系和 组织将在生化上检查粘蛋白的差异 寡糖和肽，生物合成（糖基转移酶）和 降解（糖苷酶）酶活性，前体的可用性 物质和抗原掩蔽。 （2）sialosyl-TN表型会影响 结肠癌细胞的生物学行为或免疫识别？ 将比较Sialosyl-TN（+）和（ - ）细胞的生长差异 性质，肿瘤性，侵入性和转移潜力。 血清 将分析正常人和结肠癌患者的患者 存在抗硫糖基-TN抗体。 其他实验将确定 抗体依赖性还是天然的结肠癌靶标的裂解是 杀伤细胞机制是唾液基-TN依赖性的。