MUCIN GLYCOPROTEINS IN COLON CANCER METASTASIS

描述：（改编自研究者摘要）结直肠 与癌症相关的死亡率与肿瘤的程度最密切相关 细胞浸润和转移。而粘液性 结肠癌似乎预后不良，目前尚不清楚哪种情况。 结肠癌粘蛋白中的结构对生物学活性最重要。 这些细胞的行为，或者转移过程中的哪些步骤， 级联依赖于分泌或细胞表面的特定改变 糖蛋白长期目标是进一步阐明 结肠癌细胞的细胞表面和分泌的糖蛋白影响 转移能力。有人提出，唾液粘蛋白是 优先由具有高转移性的结肠癌细胞分泌 能力，并且唾液酸化的碳水化合物结构在功能上是 转移中粘蛋白分子的重要部分。改变 转移性结肠癌细胞的唾液酸化导致细胞-细胞和细胞- 基质相互作用决定了这些细胞的能力， 转移该提案的目的是确定 结肠癌细胞产生唾液粘蛋白与转移性 能力，以确定apomucin的类型和数量如何影响 转移能力，并确定功能意义 粘蛋白在转移的各个阶段。 PI开发的动物模型已用于选择人类结肠 自发转移能力不同的癌细胞 从盲肠到肝脏，并在脾门静脉后定植于肝脏 注射将从这些细胞和手术标本中提取粘蛋白， 关于唾液酸化碳水化合物的纯化和表征 结构.相反，产生癌细胞的转移能力 在唾液酸化抗原的表达方面不同的粘蛋白将被 在转移的体内模型中测试。唾液酸键和 哪些结构在转移中具有重要的功能， 已解决。人类粘蛋白由七种或更多不同的粘蛋白编码 基因，其中至少两个在结肠中表达。的 脱粘蛋白类型与结肠癌转移的关系将 评估，包括粘蛋白基因的特异性抑制作用 实验转移的表达。结肠癌粘蛋白和 相关的碳水化合物结构影响肿瘤细胞与 基底膜、内皮结构和内源性碳水化合物 将评估结合蛋白以阐明粘蛋白在 转移的各个阶段。 随着对这些关系的进一步了解， 可以识别预后不良的患者，并设计特定的 针对转移性疾病的治疗。

DESCRIPTION: (adapted from the investigator's abstract) Colorectal cancer-related mortality is most strongly related to the extent of tumor cell invasion and metastasis at diagnosis. While patients with mucinous colon cancer appear to have a poor prognosis, it is not yet known which structures in colon cancer mucin are most important to the biological behavior of these cells, or which of the many steps in the metastasis cascade depend on specific alterations in secreted or cell-surface glycoproteins. The long term objective is to further elucidate how the cell surface and secreted glycoproteins of colon cancer cells influence their metastatic capacity. It is proposed that sialomucins are preferentially secreted by colon cancer cells with high metastatic ability, and that sialylated carbohydrate structures are functionally important portions of the mucin molecule in metastasis. Altered sialylation of metastatic colon cancer cells leads to cell-cell and cell- substratum interactions which determine the ability of these cells to metastasize. The aims of the proposal are to determine the relationship between production of sialomucin by colon cancer cells and metastatic capacity, to determine how the type and amount of apomucin affects metastatic capacity, and to determine the functional significance of mucins in individual stages of metastasis. Animal models developed by the PI have been used to select human colon cancer cells which differ in their capacity to spontaneously metastasize from cecum to liver, and to colonize the liver after splenic-portal injection. Mucins from these cells and from surgical specimens will be purified and characterized with relation to sialylated carbohydrate structures. Conversely, the metastatic ability of cells which produce mucins that vary in their expression of sialylated antigens will be tested in in vivo models of metastasis. Which sialic acid linkage and which structures are functionally important in metastasis will be addressed. Human mucins are encoded by seven or more distinct mucin genes, at least two of which are expressed in the colon. The relationship between type of apomucin and colon cancer metastasis will be assessed, including the effect of specific inhibition of mucin gene expression on experimental metastasis. How colon cancer mucins and associated carbohydrate structures affect tumor cell interactions with basement membranes, endothelial structures and endogenous carbohydrate binding proteins will be evaluated to clarify the role of mucin in individual stages of metastasis. With further understanding of these relationships, it may eventually be possible to identify patients with a poor prognosis and design specific therapies targeted against metastatic disease.