Mucin Glycoproteins in Colon Cancer Metastasis

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DESCRIPTION (provided by applicant): Colorectal cancer is the second most common cause of cancer-related death in the United States. Colorectal cancer-related mortality is due in large part to metastasis, a complex multistage 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 have each been associated with the metastatic potential of human colon cancer cells. Direct evidence in support of particular functions for mucin and galectin-3 are now emerging through identification of interacting ligands and structural motifs. While a role for mucins encoded by the MUC2 mucin gene in metastasis has been established, it remains to be determined which structural domains of MUC2 are necessary to promote metastasis of colon cancer cells. Galectin-3 also consists of distinct structural domains which contribute to its pleiotropic functions. The protein may be localized in the nucleus, cytoplasm, cell surface or be secreted and may therefore act in several ways to promote metastasis. Recent work from our laboratory has demonstrated that galectin-3 modulates MUC2 expression in colon cancer cells at the level of transcription, and that phosphorylation of the protein may be necessary for this function. 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, and how galecin-3 and MUC2 interact to promote metastasis. We hypothesize that specific structural domains of mucin apoproteins and galectin-3 are necessary for their metastasis-enhancing effects and that these molecules interact to promote tumor spread during metastasis. This knowledge may lead to the development of targeted therapies which interfere with metastasis. To accomplish these goals the following specific aims are proposed 1) "Determine the role of secreted mucins and mucin isoforms in colon cancer metastasis" This aim will examine which MUC2 structural domains and associated carbohydrate structures are responsible for metastasis. 2) "Determine biological significance of the interactions between galectin-3 and its carbohydrate ligands". This aim seeks to identify carbohydrate structures, including mucin- related structures which can be used as reagents to interfere with metastasis. 3) Determine the functional mechanism(s) by which galectin-3 modifies expression of MUC2 in colon cancer cells.