The role of transforming growth factor beta (TGFb) in tumor promotion and in angiogenesis is context-dependent. While TGFb 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 TGFb, the blocking activity of TGFb antagonist peptides. In agreement with previous results, we have observed that TGFb 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 TGFb was observed. By RT-PCR we have shown that TGFb 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 TGFb angiogenic response in vitro. The SMAD2/3 and FAK signaling pathways were activated by TGFb in MVEC, as an early and late response, respectively. The use of two different TGFb1 antagonist peptides, derived from TGFb 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 TGFb challenge. The anti-angiogenic properties of both inhibitors were evident also in the in vivo TGFb Matrigel Sponge Assay. These results may be relevant to develop a potentially fruitful strategy for the therapy of late-stage-associated tumor angiogenesis.
|Titolo:||TGFb1 antagonistic peptides inhibit TGFb1-dependent angiogenesis|
|Parole Chiave:||tgf ; angiogenesis ; tumour|
|Data di pubblicazione:||1-mar-2009|
|Digital Object Identifier (DOI):||10.1016/j.bcp.2008.10.036|
|Appare nelle tipologie:||01 - Articolo su periodico|