New target for tumor therapy - Nature letter: When drugs could permanently disrupt the pathological formation of blood vessels
6th May 2010
As from a specific size, solid tumors form a capillary network of blood vessels that grows along with them. One therapy approach is to suppress growth of blood vessels to starve the tumor. Drugs so far used in the clinic block the vessel growth factor VEGF (Vascular Endothelial Growth Factor). However, there is growing evidence that tumors can avoid or become resistant to this blockade. Little is known about how this takes place since the sprouting of blood vessels (angiogenesis) is not understood in detail yet. Prof. Amparo Acker-Palmer from the Cluster of Excellence Macromolecular complexes of the Goethe-University and her husband, Prof. Till Acker from the University of Giessen, now unraveled another signaling pathway in angiogenesis. As they report in the current issue of the journal "Nature", these findings could reveal new targets for cancer therapy.
Notably, molecules that also arrange networks of neurons play a central role in this process. The neurobiologist Acker-Palmer has already intensively studied these so-called Ephrin-B2 receptors in conjunction with learning processes in the brain. For her work she was recently awarded with the Paul-Ehrlich price for young researchers. Now the scientist discovered that these receptors are present in the membrane of endothelial tip cells and are critical for angiogenesis. Ephrin-B2 not only transduces signals to neighboring cells by activating forward direction, but also reverse to the inside of the cell that expresses this ligands. Amparo Acker-Palmer and the neuropathologist Till Acker now deciphered a so far unknown signaling pathway downstream of ephrinb2 that regulates the internalization and activation of VEGFR2.
"As it turned out, the intracellular pathway that controls the internalization of the growth factor receptor constitutes an important mechanism required for angiogenesis", Acker-Palmer explains the impact of her work. As a proof the two researchers blocked the cytoplasmic end of the ephrin-B2 ligand which transduces signals into the cell. In these animals, vessel sprouting was suppressed.
Apparently Ephrin-B2 regulates not only the growth factor receptor VEGFR2, which was so far suppressed by pharmaceuticals, but also another family member VEGFR3, as Ralf Adams and his colleagues of the Max-Planck-Institute for Molecular Biomedicine in Münster report in the same issue of Nature. "Ephrin-B2 thus is a crucial target for the development of pharmacological treatments that can prevent undesired blood vessel growth", Till Acker explains.
Full reference: Suphansa Sawamiphak, Sascha Seidel, Clara L. Essmann, George A. Wilkinson, Mara E. Pitulescu, Till Acker & Amparo Acker-Palmer. 2010. Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis. Nature. Online publication ahead of print 6 May 2010. doi:10.1038/nature08995. Link to full paper
Information: Prof. Amparo Acker-Palmer, Institute für Cell biology und Neuroscience, Frankfurt Institute for Molecular life Sciences, Campus Riedberg, Tel: (069) 798-29645; acker-palmer(at)bio.uni-frankfurt.de; Homepage of Amparo Acker-Palmer;