TGFβ1 antagonistic peptides inhibit TGFβ1-dependent angiogenesis

The role of transforming growth factor beta (TGF beta) in tumor promotion and in angiogenesis is context-dependent. While TGF beta 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 TGF beta, the blocking activity of TGF beta antagonist peptides. In agreement with previous results, we have observed that TGF beta 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 TGF beta was observed, By RT-PCR we have shown that TGF beta 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 TGF beta angiogenic response in vitro. The SMAD2/3 and FAK signaling pathways were activated by TGF beta in MVEC, as an early and late response, respectively. The use of two different TGF beta 1 antagonist peptides, derived from TGF beta 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 TGF beta challenge. The anti-angiogenic properties of both inhibitors were evident also in the in vivo TGF beta Matrigel Sponge Assay. These results may be relevant to develop a potentially fruitful strategy for the therapy of late-stage-associated tumor angiogenesis, (C) 2008 Elsevier Inc. All rights reserved.