semaphorins and hepatocyte growth factor (HGF).18 This will result in competition between those ligands for the binding site, because some of them are competitive binders. Neuropilins which bind VEGF are co-opted and form heteromers with VEGFRs, plexins and c-met, the receptor of HGF. In addition to their function on endothelial cells, HGF and semaphorins play a role in cancer growth and spread.19,20 This leads to the present picture, that neuropilins modulate the VEGF signaling in endothelial cells. A bypassing of the kinase activity of VEGFRs in endothelial cells via interaction of VEGF with neuropilin has not been demonstrated unequivocally up till now. Even the activation of VEGFR-2 by phosphorylation through semaphorin 6d and plexin-A1, which is described to occur in the absence of VEGF21 should be blocked by VEGFR kinase inhibitors. However, VEGF may exert an action on tumor cells competing with sema 3a for the binding to neuropilins, and thus may modulate the migratory response of tumor cells as it was shown for MDA-MB-231 cells.22

3. Further Angiogenesis-Related Signaling

PDGFR kinases located mainly on stromal cells are additional important players. They are stimulated by PDGFs secreted by endothelial cells.23 Also EphB4 receptor kinase shows endothelial specificity but not a completely defined function.24 EphB4 and its ligand ephrinB2 appear to play a role in the demarcation of boundaries between cells with differential fate.25 In recent years, several new factors and their role in angiogenesis, especially in the guidance of newly developing vessel sprouts have been found. Amongst them are notch and jagged,26 wnt and frizzled,27 slit and robo,28,29 netrin and Unc5B,30 and the BMP/TGFβ family with their corresponding receptors.31,32 From those factors new anti-angiogenic targets will arise, which may capitalize on kinase inhibition.

4. Need for Selectivity of Anti-Angiogenic Kinase Inhibitors

Kinase inhibitors in clinical development as anti-angiogenic agents target VEGFRs with first priority. However, the extent to which the VEGFR inhibitors affect other cellular kinases as well is variable. One