TGFbeta1 antagonistic peptides inhibit TGFbeta1-dependent angiogenesis
| Autor: | Gabriella Fibbi, Rosaria Cammarota, Adriana Albini, Mario Del Rosso, Javier Dotor, Francisco Borrás-Cuesta, Anna Rita Cantelmo, Francesca Margheri, Marco Pucci, Simona Serratì |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
medicine.medical_specialty
Angiogenesis Blotting Western Biochemistry Transforming Growth Factor beta1 Internal medicine medicine Humans Cell Proliferation DNA Primers Pharmacology Matrigel biology Base Sequence Neovascularization Pathologic Reverse Transcriptase Polymerase Chain Reaction Transforming growth factor beta Immunohistochemistry Capillaries Urokinase receptor Endocrinology Tumor progression Cancer research biology.protein Tumor promotion Peptides Plasminogen activator Transforming growth factor |
| Zdroj: | Biochemical pharmacology. 77(5) |
| ISSN: | 1873-2968 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect