Colorectal cancer is the second most common epithelial cancer in North America with an estimated annual mortality of 55,000 in the United States. The majority of colon cancer-related deaths are due to metastasis, a complex multi-step process by which tumor cells escape the primary tumor and establish secondary foci at distant sites. Mucins, the major secreted glycoproteins of the colon and galectin-3 an endogenous mucin binding protein play an important role in colon cancer metastasis. Direct evidence in support of a particular function(s) for mucin and galectin-3 are now emerging through identification of interacting ligands and structural motifs. Mucins are encoded by at least 9 genes and while a role for the MUC2 gene in mucinous carcinomas has been established, it remains to be determined which structural domains of MUC2 and other mucins are necessary to promote metastasis of colon cancer cells. Galectin-3 also consists of distinct structural domains. The protein may be localized in the nucleus, cytoplasm, on the cell surface or be secreted by colon cancer cells, and may therefore act in several ways to promote metastasis. The long-term objective of this proposal is to determine how the cell surface and secreted glycoproteins of colon cancer cells influence their metastatic capacity. Based on progress during the current funding period efforts will continue which are designed to elucidate the structure-function relationships between colon cancer mucins, mucin-binding proteins and metastasis. We hypothesize that specific structural domains of mucin apoproteins and glaectin-3 are necessary for their metastasis-enhancing effects, and that these molecules interact to promote tumor spread during defined stages of colon cancer metastasis. To accomplish these goals the following specific aims are proposed 1) Determine which structural domains of mucins are necessary for promoting the metastasis of colon cancer cells 2) Determine whether MUC2 and galectin-3 interact to affect the metastatic potential of colon cancer cells 3) Determine at which stages of liver colonization MUC2 and galectin-3 act to augment the metastatic potential of mucinous colon cancer cells. Further understanding of the roles of mucins and galectin-3 in colon cancer metastasis may make it possible to design specific diagnostic and therapeutic strategies to alter the course of metastatic disease.
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