The long term objective of this study is to understand the role of osteopontin (OPN) and its cell surface receptors in tumor metastasis. The central hypothesis is that OPN promotes metastasis by binding to the alphavbeta3 integrin, or to CD44, on the tumor cell surface. It is suggested that the three molecules may bind together in a ternary complex on the tumor cell surface and generate a unique set of intracellular signals that promote cell migration and/or survival. One series of experiments will focus on understanding the pro-metastatic effect of osteopontin in an experimental mode of metastasis. Experiments will be conducted to identify which receptor for osteopontin mediates the pro-metastatic effect. Because OPN is known to be highly sensitive to cleavage by thrombin, and is likely to be cleaved by this protease in vivo, experiments will also seek to determine if proteolytic cleavage of OPN has and effect on metastasis. To complement the experimental model of metastasis, studies are planned in an orthotopic model of breast cancer. These experiments will also focus on OPN and its two cell surface receptors. Imunohistochemical analyses will determine if the expression of OPN or either of its receptors correlates with metastasis. Then, antisense approaches will be used to ablate the synthesis of each protein, and the effects of these alterations on metastatic spread will be examined. A third goal is to understand how OPN interacts with the tumor cell surface. Experiments will be conducted to determine whether the alphavbeta3 integrin or CD44 mediates the majority of OPN binding to the tumor cell surface. Experiments will also be conducted to determine if the two receptors cooperate in binding to OPN. A fourth line of study will examine the structure-function relationships of the interaction between OPN and CD44. The kinetics of their binding will be measured, and the domain within OPN that binds to CD44 will be identified. Results from these analyses will greatly augment the interpretation of results obtained from the experiments on tumor metastasis.
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