Search

Vascular endothelial growth factor (VEGF) is a key growth factor driving angiogenesis (i.e. the formation of new blood vessels) in health and disease. Pharmacological blockade of VEGF signaling to inhibit tumor angiogenesis is clinically approved but the survival benefit is limited as patients invariably acquire resistance. This is partially mediated by the intrinsic flexibility of tumor cells to adapt to VEGF-blockade. However, it has become clear that tumor stromal cells also contribute to the resistance. Originally, VEGF was thought to specifically target endothelial cells (ECs) but it is now clear that many stromal cells also respond to VEGF signaling, making anti-VEGF therapy more complex than initially anticipated. A more comprehensive understanding of the complex responses of stromal cells to VEGF-blockade might inform the design of improved anti-angiogenic agents., (Copyright © 2014. Published by Elsevier Ltd.)

The role of transforming growth factor beta (TGFbeta) in tumor promotion and in angiogenesis is context-dependent. While TGFbeta prevents tumor growth and angiogenesis in early phases of tumor development, evidence is accumulating about its pro-angiogenic and tumor promotion activities in late-stages of tumor progression. Here we have studied, in an experimental context previously reported to disclose the pro-angiogenic effects of TGFbeta, the blocking activity of TGFbeta antagonist peptides. In agreement with previous results, we have observed that TGFbeta exerts a powerful pro-angiogenic activity on human normal dermal microvascular endothelial cells (MVEC), by promoting invasion and capillary morphogenesis in Matrigel. No apoptotic activity of TGFbeta was observed. By RT-PCR we have shown that TGFbeta up-regulates expression not only of plasminogen activator inhibitor type-1 (PAI-1), but also of the urokinase-type plasminogen activator receptor (uPAR), whose inhibition by specific antibodies blunted the TGFbeta angiogenic response in vitro. The SMAD2/3 and FAK signaling pathways were activated by TGFbeta in MVEC, as an early and late response, respectively. The use of two different TGFbeta1 antagonist peptides, derived from TGFbeta type III receptor sequence and 15-mer phage display technology, inhibited the signaling and pro-angiogenic response in vitro, as well as uPAR and PAI-1 up-regulation of MVEC following TGFbeta challenge. The anti-angiogenic properties of both inhibitors were evident also in the in vivo TGFbeta Matrigel Sponge Assay. These results may be relevant to develop a potentially fruitful strategy for the therapy of late-stage-associated tumor angiogenesis.