Migration of human prostate tumor cells to bone is a metastatic process that occurs preferentially to prostate tumor metastasis to other distant sites. Recent findings suggest that human prostate tumor cells exhibit augmented adhesive capabilities to human bone marrow endothelium (BMEC) compared with cell adhesion to vascular endothelium in other tissues. Human prostate tumor cell adhesion molecules that initiate intravascular binding to human BMEC under blood flow (shear stress) prior to emigration into bone marrow are unknown. The selectins are a class of cell adhesion molecules that mediate cell adhesion interactions under shear stress, and since endothelial (E)-selectin is constitutively expressed on human BMEC, we hypothesize that E-selectin ligand(s) on human prostate tumor cells help initiate adhesion to BMEC and cause preferential cell lodgement in the bone marrow. We have obtained preliminary evidence showing that a human prostate tumor cell line derived from bone metastases expresses the leukocyte E-selectin ligand, cutaneous lymphocyte-associated antigen (CLA). Surprisingly, CLA expressed on bone-metastatic prostate tumor cells appears to be functionally and structurally identical to CLA on leukocytes. Since CLA expression is critical for leukocyte entry into bone, we hypothesize that CLA also plays an important role in migration of aggressive human prostate tumor cells to bone. The objectives of this proposal are to establish whether CLA is the principal E-selectin ligand on human bone-metastatic prostate tumor cells, to investigate whether 4-F-GIcNAc, a novel inhibitor of CLA synthesis, will prevent human prostate tumor cell binding to BMEC E-selectin and interfere with human prostate tumor metastasis to bone. Accordingly, we will utilize parallel-plate flow chamber methodology to compare and contrast candidate E-selectin ligand(s), including CLA, expressed by human bone-metastatic prostate tumor cells and analyze the effects of 4-F-GIcNAc on prostate tumor cell adhesion to human BMEC under shear stress conditions. Furthermore, we will employ a mouse model of spontaneous human prostate tumor metastasis to investigate in vivo efficacy of 4-F-GIcNAc in preventing bone metastasis. These studies will help reveal the importance of E-selectin ligand(s), namely CLA, in mediating the migration of human prostate tumor cells to bone and stimulate the development of novel anti-metastatic therapeutics, such 4-F-GIcNAc.
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