GLYCOTRANSFERASES AND COLORECTAL CANCER METASTASIS

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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.