Selectin-mediated cell adhesion has been implicated in the metastasis of colorectal carcinoma (CRC), and the carbohydrate ligand components sialyl Lewis x (sLex) and sialyl Lewis a (sLea) on tumor cells have long been considered markers for development and progression of human carcinoma. Recent data showing important roles for inflammation in CRC pathogenesis point to selectin ligands as potential translational targets. Although corresponding glycosyltransferase expression is complex in malignant cells and tumor specimens, sLex and sLea synthesis appears to be largely controlled by the human alpha(1,3)fucosyltransferase gene families. Two of these genes are highly expressed in CRC: FUT3 and FUT6. Our group has shown that inhibition of sLex/sLea expression in CRC cells by antisense FUT3 sequences results in markedly reduced CRC metastases in nu/nu mice. Furthermore, antisense inhibition of FUT6-- which is often co-expressed with FUT3 in CRC and is inducible with inflammatory cytokines-- results in decreased carcinoma proliferation invitro and in vivo. Mutations in FUT3 and FUT6 have been described in diverse human populations, but no information has been available to determine the effect(s), if any, of these null phenotypes on development and/or progression of CRC. Similarly, expression at the transcript level has been limited by lack of adequate human data sets and samples. Over the past several years at UNC, SPORE investigators have helped assemble large CRC patient data sets with appropriate specimens. We propose to: 1. Identify FUT3 and/or FUT6 mutations associated with polyp and/or CRC development and examine potential interactions with use of non-steroidal anti-inflammatory drugs (NSAIDs) and other clinical variables; 2. Examine FUT transcript levels in polyps and CRC lesions at various stages of progression; and 3. Combine FUT antisense oligodeoxynucleotides with NSAIDs for experimental therapy of CRC in vitro and in nu/nu mice models. Our long term goal is extend the pre-clinical use of these agents to appropriate patient populations as our understanding of selectin ligand function grows.
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