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Article Dans Une Revue Frontiers in Cell and Developmental Biology Année : 2021

Targeting the Urotensin II/UT G Protein-Coupled Receptor to Counteract Angiogenesis and Mesenchymal Hypoxia/Necrosis in Glioblastoma

Vadim Le Joncour
  • Fonction : Auteur
Pierre-Olivier Guichet
Kleouforo-Paul Dembélé
  • Fonction : Auteur
Alexandre Mutel
  • Fonction : Auteur
Daniele Campisi
  • Fonction : Auteur
Nicolas Perzo
  • Fonction : Auteur
Laurence Desrues
  • Fonction : Auteur
Pierre-Olivier Couraud
  • Fonction : Auteur
Jérôme Honnorat
François-Xavier Ferracci
  • Fonction : Auteur
Florent Marguet
  • Fonction : Auteur
Annie Laquerrière
  • Fonction : Auteur
Olivier Langlois
  • Fonction : Auteur
Fabrice Morin
  • Fonction : Auteur
Pierrick Gandolfo
  • Fonction : Auteur
Hélène Castel
  • Fonction : Auteur

Résumé

Glioblastomas (GBMs) are the most common primary brain tumors characterized by strong invasiveness and angiogenesis. GBM cells and microenvironment secrete angiogenic factors and also express chemoattractant G protein-coupled receptors (GPCRs) to their advantage. We investigated the role of the vasoactive peptide urotensin II (UII) and its receptor UT on GBM angiogenesis and tested potential ligand/therapeutic options based on this system. On glioma patient samples, the expression of UII and UT increased with the grade with marked expression in the vascular and peri-necrotic mesenchymal hypoxic areas being correlated with vascular density. In vitro human UII stimulated human endothelial HUV-EC-C and hCMEC/D3 cell motility and tubulogenesis. In mouse-transplanted Matrigel sponges, mouse (mUII) and human UII markedly stimulated invasion by macrophages, endothelial, and smooth muscle cells. In U87 GBM xenografts expressing UII and UT in the glial and vascular compartments, UII accelerated tumor development, favored hypoxia and necrosis associated with increased proliferation (Ki67), and induced metalloproteinase (MMP)-2 and -9 expression in Nude mice. UII also promoted a “tortuous” vascular collagen-IV expressing network and integrin expression mainly in the vascular compartment. GBM angiogenesis and integrin αvβ3 were confirmed by in vivo 99m Tc-RGD tracer imaging and tumoral capture in the non-necrotic area of U87 xenografts in Nude mice. Peptide analogs of UII and UT antagonist were also tested as potential tumor repressor. Urotensin II-related peptide URP inhibited angiogenesis in vitro and failed to attract vascular and inflammatory components in Matrigel in vivo . Interestingly, the UT antagonist/biased ligand urantide and the non-peptide UT antagonist palosuran prevented UII-induced tubulogenesis in vitro and significantly delayed tumor growth in vivo. Urantide drastically prevented endogenous and UII-induced GBM angiogenesis, MMP, and integrin activations, associated with GBM tumoral growth. These findings show that UII induces GBM aggressiveness with necrosis and angiogenesis through integrin activation, a mesenchymal behavior that can be targeted by UT biased ligands/antagonists.

Dates et versions

hal-03222754 , version 1 (10-05-2021)

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Vadim Le Joncour, Pierre-Olivier Guichet, Kleouforo-Paul Dembélé, Alexandre Mutel, Daniele Campisi, et al.. Targeting the Urotensin II/UT G Protein-Coupled Receptor to Counteract Angiogenesis and Mesenchymal Hypoxia/Necrosis in Glioblastoma. Frontiers in Cell and Developmental Biology, 2021, 9, pp.652544. ⟨10.3389/fcell.2021.652544⟩. ⟨hal-03222754⟩
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