GLYCOTRANSFERASES AND COLORECTAL CANCER METASTASIS

肝脏是最常见的远处转移部位， 结直肠癌 植入机制和 肿瘤细胞在肝脏中的存活涉及一系列复杂的 分子反应，我们对此知之甚少。 我们已经证明 从人结肠直肠癌产生肝转移的能力 裸鼠模型中的细胞系与1）细胞的存在有关 表面唾液酸，2）α 2，6唾液酸转移酶活性，和3） 唾液酸掺入的抑制剂将抑制肝转移 阵 我们的假设是肿瘤细胞释放唾液酸化的 可溶性产物（例如，CEA）激活枯否细胞。 的 产生的细胞因子激活窦状隙内皮细胞， 粘附分子如E-选择素。 这些激活的内皮细胞 细胞，然后增加保留的肿瘤细胞在肝脏内， 增强与含唾液酸的结构的结合， 唾液酸化的刘易斯抗原。 我们研究这一假设的具体目的 是：1. 为了研究α 2，6和α 2，3的作用， 唾液酸转移酶在确定转移潜能中的应用 通过构建低转移的转染子的癌细胞系 人结直肠癌细胞系MIP-101和克隆A以及 检查它们在转移试验中的性质。2.识别 来自转染子的肿瘤细胞表面唾液酸化分子， 参与粘附的转移性结肠直肠癌细胞系 至肝内皮，以及3.研究新的类似物， 作为CMP-唾液酸的唾液酸转移酶的抑制剂的CMP-唾液酸 酸转运蛋白作为转移的潜在抑制剂。

The liver is the most common site for distant metastasis from colorectal carcinomas. The mechanisms for implantation and survival of tumor cells in the liver involve a complex set of molecular reactions that are poorly understood. We have shown that the ability to produce liver metastases from human colorectal cancer cell lines in nude mouse models is related to the presence of 1) Cell surface sialic acids, 2) alpha2,6 sialyltransferase activity, and 3) that inhibitors of sialic acid incorporation will inhibit hepatic metastasis formation. Our hypothesis is that tumor cells release sialylated soluble products (e.g., CEA) that activate Kupffer cells. The cytokines produced activate sinusoidal endothelial cells to up-regulate adhesion molecules such as E-selection. These activated endothelial cells then increase the retention of tumors cells within the liver by augmenting binding to sialic acid containing structures such as the sialylated Lewis antigens. Our specific aims to study this hypothesis are: 1. To examine the role of the alpha2,6 and alpha2,3 sialyltransferases in determining metastatic potential I colorectal cancer cell lines by constructing transfectants of the low metastatic human colorectal cancer cell lines MIP-101 and Clone A and examining their properties in assays for metastases. 2. To identify the tumor cell surface sialylated molecules from the tansfectants and metastatic colorectal cancer cell lines that are involved in adherence to the hepatic endothelium, and 3. To examine novel analogues of CMP-sialic acid as inhibitors of the sialyltransferases of CMP-sialic acid transport proteins as potential suppressors of metastasis.