Exploiting pleiotropic activities of semaphorins as multi-target therapies for cancer

Abstract

Semaphorins (SEMAs) are a superfamily of secreted or membrane‐associated glycoproteins implicated in the control of axonal wiring and involved in angiogenesis and cancer progression. Class‐3 SEMAs are the only secreted vertebrate SEMAs and several of them are regulated by protease‐mediated cleavage (Capparuccia & Tamagnone, 2009). Their high‐affinity receptors, Plexins and co‐receptor Neuropilins, are expressed in a wide variety of cell types including endothelial and tumour cells. Plexins show an intrinsic R‐Ras GAP activity, but interestingly also form complexes with additional transmembrane molecules, including certain receptor tyrosine kinases (RTKs) such as c‐Met, ErbB2 and vascular endothelial growth factor receptor 2 (VEGFR2), that are transactivated by Plexins and initiate critical signalling pathways. These functional interactions with transactivated kinase receptors are key to define the cellular activities of SEMAs and convert the SEMAs into pleiotropic molecules. Thus, SEMAs can positively or negatively modulate many intrinsic properties of tumour cells, such as proliferation, cell survival, alteration in cell adhesion and tumour invasiveness, but also modulate several stromal components including endothelial cell migration and survival (Capparuccia & Tamagnone, 2009; Serini et al, 2009)...