Bone-Homing Molecules on Human Prostate Tumor Cells

Brigham And Women'S Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): Migration of human prostate tumor cells to bone is a metastatic process that occurs preferentially to metastases formation at 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 interactions with BMEC under blood flow (shear stress) prior to emigration into bone marrow are unknown. The selectins are class of cell adhesion molecules that mediate interactions under shear flow conditions and since endothelial (E)-selectin is constitutively expressed on human BMEC, we hypothesize that E-selectin ligands on human prostate tumor cells are critically important to the formation of bone metastases. Thus, the proposed studies described herein address the identification and characterization of E-selectin ligands expressed on human prostate tumor cells derived from bone metastases utilizing an innovative technology developed by our laboratory for identifying adhesion molecules functioning under physiologic blood flow conditions. We have preliminary evidence showing that a human bone-metastatic prostate tumor cell line expresses a known leukocyte E-selectin ligand, but there is no definitive evidence on its function on these cells as well as its expression on other prostate tumor cell lines derived from bone or other potential sites of metastasis. The objectives of proposed studies are 1.) to establish whether E-selectin ligand activity on human prostate tumor cells directly correlates with bone metastases formation, 2.) to identify and characterize the structural biochemistry of E-selectin ligand(s) on human bone-metastatic prostate tumor cells and, more importantly, 3.) to increase our knowledge of the cell adhesion repertoire on human prostate tumor cells that may promote migration to bone. To obtain these objectives, numerous cell adhesion assays performed under physiologic shear flow conditions, including the novel "blot rolling" assay, will be employed to investigate the identity and structural biochemistry of E-selectin ligand(s) on human prostate tumor cells derived from bone metastasis. Molecular analysis of identified E-selectin ligand(s) will provide rationale for the development of anti-metastatic therapeutics against these new targets.