Much of the mortality associated with cancer results from uncontrolled metastasis of the primary tumor. Metastasis is a poorly-understood process, for which there are few effective treatments. It is well-accepted that tumor cell association with the extracellular matrix comprises an important factor in metastasis, and in turn, this interaction is regulated by cell adhesion receptors such as integrins. Work from our laboratory has identified a novel mechanism for regulation of the beta l subfamily of integrin receptors. In particular, we have found that beta l integrin function is modulated by the acquisition of alpha 2-6 sialic acids, a sugar structure added by ST6Gal I, a sialyl transferase which has long been implicated in the progression/metastasis of colon carcinoma. Our work suggests that ST6Gal I, and accordingly, integrin alpha 2-6 sialylation, are upregulated in tumor cell lines that have oncogenic ras, as well as in human colon tumors. In vitro studies further suggest that integrin sialylation has a marked on the adhesion, migration and invasiveness of colon tumor cells. To better understand the contribution of sialylation to integrin structure/function, as well as the potential role of integrin sialylation in tumor cell metastasis, we have proposed the following aims:
Specific Aim 1 : Influence of site-specific glycosylation on integrin conformation and function. As part of this aim, we will characterize the conformation and function of integrins that have each of the individual N- glycosylation sites ablated.
Specific Aim 2 : Effects of integrin sialylation on galectin-3-regulated cell behaviors. We will examine the role of integrin sialylation in regulating gal-3 - induced cellular responses including adhesion, migration, invasion and apoptosis.
Specific Aim 3 : Modulation of metastasis-related cell behaviors by ras-directed differential sialylation. These studies aim to determine whether integrin sialylation serves as a downstream effector of ras in mediating behaviors such as anchorage-independent growth and invasion.
Specific Aim 4 : Role of integrin sialylation in promoting tumor growth and/or metastasis in nude mice. We will monitor tumorigenesis and metastasis of cells with variant levels of integrin sialylation. ? ? ? ?
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