MUCIN GLYCOPROTEINS IN COLON CANCER METASTASIS

描述：(改编自研究人员的摘要)结直肠 与癌症相关的死亡率与肿瘤的范围密切相关 确诊时的细胞侵袭和转移。而粘液性疾病的患者 结肠癌的预后似乎很差，目前还不知道是哪种 结肠癌粘蛋白中的结构对生物学行为最重要 这些细胞的行为，或者转移的许多步骤中的哪一步 级联依赖于分泌物或细胞表面的特定变化 糖蛋白。我们的长期目标是进一步阐明 结肠癌细胞表面及分泌糖蛋白的影响 它们的转移能力。据认为，唾液粘蛋白是 高转移性结肠癌细胞优先分泌 能力，唾液酸化的碳水化合物结构在功能上 粘蛋白分子在转移中的重要部分。更改后的 转移性结肠癌细胞的唾液酸化导致细胞-细胞和细胞- 底物相互作用决定了这些细胞的能力 转移瘤。提案的目的是确定两国关系 结肠癌细胞产生唾液粘蛋白与转移的关系 能力，以确定无粘蛋白的类型和数量如何影响 转移能力，并确定其功能意义 在转移的各个阶段的粘蛋白。 PI开发的动物模型已被用于选择人的结肠 自发转移能力不同的癌细胞 从盲肠到肝脏，并在脾门脉后定植肝脏 注射。这些细胞和手术标本中的粘蛋白将被 与唾液酸化碳水化合物有关的提纯和特征 结构。相反，产生细胞的转移能力 唾液酸化抗原表达不同的粘蛋白将是 在体内转移模型中进行了测试。唾液酸链的哪个键 在转移中哪些结构在功能上是重要的 地址。人类粘蛋白由七种或七种以上不同的粘蛋白编码 基因，其中至少有两个在结肠中表达。这个 无粘蛋白类型与结肠癌转移的关系 进行评估，包括特异性抑制粘蛋白基因的效果 在实验性转移瘤中的表达。结肠癌粘蛋白和粘蛋白 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 将对结合蛋白进行评估，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，最终可能会 有可能识别预后不良的患者，并设计出特定的 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.