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

Autor:	Le Joncour V; UNIROUEN, INSERM U1239, DC2N, Institute for Research and Innovation in Biomedicine (IRIB), Normandie Rouen Université, Rouen, France., Guichet PO; UNIROUEN, INSERM U1239, DC2N, Institute for Research and Innovation in Biomedicine (IRIB), Normandie Rouen Université, Rouen, France., Dembélé KP; UNIROUEN, INSERM U1239, DC2N, Institute for Research and Innovation in Biomedicine (IRIB), Normandie Rouen Université, Rouen, France., Mutel A; UNIROUEN, INSERM U1239, DC2N, Institute for Research and Innovation in Biomedicine (IRIB), Normandie Rouen Université, Rouen, France., Campisi D; UNIROUEN, INSERM U1239, DC2N, Institute for Research and Innovation in Biomedicine (IRIB), Normandie Rouen Université, Rouen, France., Perzo N; UNIROUEN, INSERM U1239, DC2N, Institute for Research and Innovation in Biomedicine (IRIB), Normandie Rouen Université, Rouen, France., Desrues L; UNIROUEN, INSERM U1239, DC2N, Institute for Research and Innovation in Biomedicine (IRIB), Normandie Rouen Université, Rouen, France., Modzelewski R; EA 4108, Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), University of Rouen, Mont-Saint-Aignan, France., Couraud PO; Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR 8104, Paris, France., Honnorat J; Neuro-Oncology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France.; Institute NeuroMyoGéne, INSERM U1217/CNRS UMR 5310, Lyon, France.; University Claude Bernard Lyon 1, Université de Lyon, Lyon, France., Ferracci FX; UNIROUEN, INSERM U1239, DC2N, Institute for Research and Innovation in Biomedicine (IRIB), Normandie Rouen Université, Rouen, France.; Neurosurgery Service, Rouen CHU Hospital, Rouen, France., Marguet F; Anathomocytopathology Service, Rouen CHU Hospital, Rouen, France., Laquerrière A; Anathomocytopathology Service, Rouen CHU Hospital, Rouen, France., Vera P; EA 4108, Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), University of Rouen, Mont-Saint-Aignan, France., Bohn P; EA 4108, Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), University of Rouen, Mont-Saint-Aignan, France., Langlois O; UNIROUEN, INSERM U1239, DC2N, Institute for Research and Innovation in Biomedicine (IRIB), Normandie Rouen Université, Rouen, France.; Neurosurgery Service, Rouen CHU Hospital, Rouen, France., Morin F; UNIROUEN, INSERM U1239, DC2N, Institute for Research and Innovation in Biomedicine (IRIB), Normandie Rouen Université, Rouen, France., Gandolfo P; UNIROUEN, INSERM U1239, DC2N, Institute for Research and Innovation in Biomedicine (IRIB), Normandie Rouen Université, Rouen, France., Castel H; UNIROUEN, INSERM U1239, DC2N, Institute for Research and Innovation in Biomedicine (IRIB), Normandie Rouen Université, Rouen, France.
Jazyk:	angličtina
Zdroj:	Frontiers in cell and developmental biology [Front Cell Dev Biol] 2021 Apr 14; Vol. 9, pp. 652544. Date of Electronic Publication: 2021 Apr 14 (Print Publication: 2021).
DOI:	10.3389/fcell.2021.652544
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Le Joncour, Guichet, Dembélé, Mutel, Campisi, Perzo, Desrues, Modzelewski, Couraud, Honnorat, Ferracci, Marguet, Laquerrière, Vera, Bohn, Langlois, Morin, Gandolfo and Castel.)
Databáze:	MEDLINE
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