Endothelial cells are induced to proliferate under the influence of factors released from tumor cells. This project seeks to identify aspects of the response to these factors on the part of endothelial cells and to use this information as a basis for developing novel cancer treatments which influence endothelial cell function. Using cultures of primary human umbilical vein endothelial cells, specific goals for this project include a definition of cell surface determinants specific for the proliferating endothelial cell, as these molecules could be developed as targets for the delivery of selectively toxic molecules; a distinction and in tissue sections from human tumors and in tissue culture between endothelial cell activation markers, such as the recently described edg1 gene, (which appear after stimulation of differentiated endothelial cells by agents such as tumor necrosis factor, interleukin-1, or tumor promoting phorbol esters) and endothelial cell proliferation markers, including antigens recognized by the EN2/3 and 70-1 antibodies; examination of endothelial cell response pathways which might mediate anti-tumor activity, including the nitric oxide generating system and elaboration of pro-coagulant activities including von Willebrand's Factor; examination of the role played by endothelial cells in the elaboration of toxicities observed by various biological response modifiers including cytokine-induced destabilization of cellular junctions and alteration of endothelial cell resistance in response to cytokines and toxins.
