Crosstalk between tumor cells and endothelial cells via the tetraspanin D6.1A

• Antragstellerin: Professorin Dr. Margot Zöller
• Fachliche Zuordnung: Pathologie
• Förderung: Förderung von 2006 bis 2010
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 21952065

Rapidly growing tumors essentially depend on angiogenesis, which is initiated by the dominance of proangiogenic factors, called the angiogenic switch. We recently identified the tetraspanin D6.1A as a most potent angiogenesis inductor. In vivo, over-expression of the tetraspanin D6.1A on a rat pancreatic adenocarcinoma line (AS-D6.1A) is accompanied by disseminated intravascular coagulation and excessive vessel formation, which extends to tumor-free adjacent organs and is completely inhibited by a D6.1A-specific antibody. ASD6.1A cells and supernatant thereof also induce endothelial cell growth and branching in vitro. ASD6.1A- induced angiogenesis is not solely due to the secretion of angiogenic factors by the tumor itself. Instead, D6.1A-induced angiogenesis is accompanied by strong D6.1A, VEGF and VEGFR expression in newly formed capillaries, thus creating an angiogenic loop. To clarify the underlying mechanism, we will focus on two questions: 1. What are the selective features of the tetraspanin D6.1A, that provoke angiogenesis? The question will be answered by a comparison with related tetraspanins, that do not support angiogenesis. 2. How does D6.1A or associated molecules induce the angiogenic switch in the tumor environment? First evidences point towards an exosome-mediated intercellular communication. The finding that the tetraspanin D6.1A initiates the angiogenic switch at a systemic level is of major clinical importance and demands for clarifying the underlying mechanism. Because D6.1A is highly expressed in proliferating endothelial cells and angiogenesis is completely suppressed by a D6.1A-specific antibody, the option of an effective and selective therapeutic drug needs to be substantiated.

• DFG-Verfahren: Schwerpunktprogramme
• Teilprojekt zu: SPP 1190: The tumor - vessel interface