TGFβ1 antagonistic peptides inhibit TGFβ1-dependent angiogenesis


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Abstract

The role of transforming growth factor beta (TGFβ) in tumor promotion and in angiogenesis is context-dependent. While TGFβ 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 TGFβ, the blocking activity of TGFβ antagonist peptides. In agreement with previous results, we have observed that TGFβ 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 TGFβ was observed. By RT-PCR we have shown that TGFβ 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 TGFβ angiogenic response in vitro. The SMAD2/3 and FAK signaling pathways were activated by TGFβ in MVEC, as an early and late response, respectively. The use of two different TGFβ1 antagonist peptides, derived from TGFβ 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 TGFβ challenge. The anti-angiogenic properties of both inhibitors were evident also in the in vivo TGFβ Matrigel Sponge Assay. These results may be relevant to develop a potentially fruitful strategy for the therapy of late-stage-associated tumor angiogenesis.

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