Survival, growth and spread of tumors depend upon an adequate blood supply ensured by neovascularization, cooption of existing vessels and stem cell differentiation into endothelial cells. Our laboratory is interested in studying tumor angiogenesis and in manipulating this process to reduce tumor growth. We have focused on three related areas. First, we have examined the processes by which adult stem cells differentiate into endothelial cells. Using umbilical cord blood, we have identified endothelial cell precursors from the pool of CD34-negative cells and studied their maturation in vitro into endothelial cells and migration in vivo to sites of tumor neovascularization. Extending these studies, we are currently evaluating ES cells requirements for differentiation into mature endothelial cells. Second, we have studied the role SDF-1 plays in angiogenesis. SDF-1 is a chemokine that mediates stem cell mobilization from the bone marrow to the peripheral blood. We characterized the mechanisms by which the molecule is cleaved in serum to generate an inactive chemokine. This inactivation has critical consequences in regulating systemic versus local chemokine function. Locally, SDF-1 plays a critical role in endothelial cell morphogenesis, an important step in the alignment of endothelial cells on extracellular matrix. Third, we have begun studies on the role of inflammation in the regulation of angiogenesis. In particular, we have focused on the role of mast cells in the regulation of angiogenesis in the context of plasma cell malignancies. We have discovered that mast cells promote plasmacytoma cell growth by secretion of angiopoitin-1, which amplifies angiogenesis induced by vascular endothelial growth factor. Fourth, we have continued working on inhibitors of angiogenesis. We have previously identified the N-domain of calreticulin, vasostatin, as an inhibitor of endothelial cell growth and angiogenesis, which has clear anti-tumor activities in vivo. We have now characterized an 18 amino acids fragment within vasostatin that retains all the anti-angiogeneic and anti-tumor activities. Using this tool in conjunction with the full-length molecule, we have identified the endothelial cell binding protein for vasostatin, and began characterization of how this protein functions as a signaling receptor.
