TGFβ1 antagonistic peptides inhibit TGFβ1-dependent angiogenesis

Simona Serratì, Francesca Margheri, Marco Pucci, Anna Rita Cantelmo, Rosaria Cammarota, Javier Dotor, Francisco Borràs-Cuesta, Gabriella Fibbi, Adriana Albini, Mario Del Rosso

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)813-825
Number of pages13
JournalBiochemical Pharmacology
Volume77
Issue number5
DOIs
Publication statusPublished - Mar 1 2009

Fingerprint

Transforming Growth Factor beta
Peptides
Tumors
Endothelial cells
Urokinase Plasminogen Activator Receptors
Neoplasms
Endothelial Cells
Plasminogen Activator Inhibitor 1
Up-Regulation
Bacteriophages
Porifera
Morphogenesis
Human Activities
Assays
Display devices
Technology
Polymerase Chain Reaction
Skin
Antibodies

Keywords

  • Angiogenesis
  • PAI-1
  • SMAD
  • TGFβ
  • uPAR

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this

Serratì, S., Margheri, F., Pucci, M., Cantelmo, A. R., Cammarota, R., Dotor, J., ... Del Rosso, M. (2009). TGFβ1 antagonistic peptides inhibit TGFβ1-dependent angiogenesis. Biochemical Pharmacology, 77(5), 813-825. https://doi.org/10.1016/j.bcp.2008.10.036

TGFβ1 antagonistic peptides inhibit TGFβ1-dependent angiogenesis. / Serratì, Simona; Margheri, Francesca; Pucci, Marco; Cantelmo, Anna Rita; Cammarota, Rosaria; Dotor, Javier; Borràs-Cuesta, Francisco; Fibbi, Gabriella; Albini, Adriana; Del Rosso, Mario.

In: Biochemical Pharmacology, Vol. 77, No. 5, 01.03.2009, p. 813-825.

Research output: Contribution to journalArticle

Serratì, S, Margheri, F, Pucci, M, Cantelmo, AR, Cammarota, R, Dotor, J, Borràs-Cuesta, F, Fibbi, G, Albini, A & Del Rosso, M 2009, 'TGFβ1 antagonistic peptides inhibit TGFβ1-dependent angiogenesis', Biochemical Pharmacology, vol. 77, no. 5, pp. 813-825. https://doi.org/10.1016/j.bcp.2008.10.036
Serratì S, Margheri F, Pucci M, Cantelmo AR, Cammarota R, Dotor J et al. TGFβ1 antagonistic peptides inhibit TGFβ1-dependent angiogenesis. Biochemical Pharmacology. 2009 Mar 1;77(5):813-825. https://doi.org/10.1016/j.bcp.2008.10.036
Serratì, Simona ; Margheri, Francesca ; Pucci, Marco ; Cantelmo, Anna Rita ; Cammarota, Rosaria ; Dotor, Javier ; Borràs-Cuesta, Francisco ; Fibbi, Gabriella ; Albini, Adriana ; Del Rosso, Mario. / TGFβ1 antagonistic peptides inhibit TGFβ1-dependent angiogenesis. In: Biochemical Pharmacology. 2009 ; Vol. 77, No. 5. pp. 813-825.
@article{bf91780f878145a081370dea7475c57b,
title = "TGFβ1 antagonistic peptides inhibit TGFβ1-dependent angiogenesis",
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.",
keywords = "Angiogenesis, PAI-1, SMAD, TGFβ, uPAR",
author = "Simona Serrat{\`i} and Francesca Margheri and Marco Pucci and Cantelmo, {Anna Rita} and Rosaria Cammarota and Javier Dotor and Francisco Borr{\`a}s-Cuesta and Gabriella Fibbi and Adriana Albini and {Del Rosso}, Mario",
year = "2009",
month = "3",
day = "1",
doi = "10.1016/j.bcp.2008.10.036",
language = "English",
volume = "77",
pages = "813--825",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "5",

}

TY - JOUR

T1 - TGFβ1 antagonistic peptides inhibit TGFβ1-dependent angiogenesis

AU - Serratì, Simona

AU - Margheri, Francesca

AU - Pucci, Marco

AU - Cantelmo, Anna Rita

AU - Cammarota, Rosaria

AU - Dotor, Javier

AU - Borràs-Cuesta, Francisco

AU - Fibbi, Gabriella

AU - Albini, Adriana

AU - Del Rosso, Mario

PY - 2009/3/1

Y1 - 2009/3/1

N2 - 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.

AB - 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.

KW - Angiogenesis

KW - PAI-1

KW - SMAD

KW - TGFβ

KW - uPAR

UR - http://www.scopus.com/inward/record.url?scp=59949099664&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=59949099664&partnerID=8YFLogxK

U2 - 10.1016/j.bcp.2008.10.036

DO - 10.1016/j.bcp.2008.10.036

M3 - Article

C2 - 19041849

AN - SCOPUS:59949099664

VL - 77

SP - 813

EP - 825

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 5

ER -