SFB / Transregio 23
"Vascular Differentiation and Remodeling"

Mannheim - Heidelberg - Frankfurt

Prof. Dr. Stefan W. Schneider Universitätsmedizin Mannheim Klinik für Dermatologie Sektion Experimentelle Dermatologie Theodor-Kutzer-Ufer 1-3 D-68167 Mannheim Phone: 0049 (0) 621 383 1643 Lab Homepage
	Stefan.Schneider(at)umm.de
A9: Mechanism controlling the transition from quiescent to activated endothelium by exocytosis of Weibel-Palade bodies triggered by tumor cells
Tumor cell spreading is accompanied by an intravascular pro-coagulatory activity as well as by inflammatory conditions. A key pro-coagulatory protein that is emerging as having a pivotal role in both the inflammatory and the metastatic process is von Willebrand factor (VWF). Under physiological conditions VWF is a large multimeric glycoprotein recognized for playing a major role in haemostasis. Its adhesive domains are the major ligands for the platelet adhesion receptor, glycoprotein Ib alpha (GPIb alpha), mediating the initial step in thrombus formation. VWF is synthesized by megakaryocytes and endothelial cells (EC) and thus present in platelets, EC, subendothelium and plasma. Furthermore, EC activation results in prompt exocytosis of its storage compartment Weibel-Palade body (WPB) and release of VWF to the luminal endothelial cell membrane and therefore exposure to the blood flow. This dipolar (basally and luminally)- released molecule forms ultra-large VWF fibers (ULVWF) immobilized at the luminal membrane ready to bind platelets. We hypothesize that intravascular tumor cells are able to induce WPB exocytosis and a prompt luminal ULVWF secretion that plays a major role in tumor cell adhesion, tumor-endothelial interaction and EC remodelling. In the last years we studied tumor-induced VWF release, the structure-function relationship of VWF and its impact on cell adhesion. We found that tumor-derived factors produced in vitro by malignant cells instantaneously trigger the release of ULVWF fibers at the luminal EC membrane. These VWF fibers bind circulating tumor cells and platelets under high shear flow leading to cell arrest and pro-thrombotic conditions. Therefore, in the upcoming 4-years we will focus our studies on the regulation of ULVWF release, in particular 1) tumor-induced EC activation accompanied by WPB exocytosis, 2) regulation of the VWF degrading enzyme ADAMTS13, 3) the impact of VWF upon tumor spreading via the lymphatic vessel system, and 4) validation of our in vitro results in animal models.