title: Characterization of gastrin-induced proangiogenic effects in vivo in orthotopic U373 experimental human glioblastomas and in vitro in human umbilical vein endothelial cells.
abstract: OBJECTIVE
  This study aims to investigate the role of gastrin-17 (G17) on angiogenesis features in gliomas both in vitro and in vivo.
  
  
  METHODS
  The influences of G17 and G17 receptor antagonists were characterized in vitro in terms of angiogenesis on human umbilical vein endothelial cell (HUVEC) tubulogenesis processes on Matrigel and in vivo with respect to U373 orthotopic glioma xenografts. The influence of phosphatidylinositol 3'-kinase, protein kinase C, and nuclear factor-kappaB inhibitors was characterized in vitro on G17-mediated HUVEC tubulogenesis. G17-mediated release of interleukin (IL)-8 from HUVECs and G17-induced modifications in nuclear factor-kappaB DNA binding activity were characterized by means of specific enzyme-linked immunosorbent assays. The influence of G17 on E- and P-selectin expression was determined by means of computer-assisted microscopy, whereas the influence of E- and P-selectin on HUVEC migration was approached by means of antisense oligonucleotides. The chemotactic influence of G17 and IL-8 on HUVEC migration was characterized by means of computer-assisted videomicroscopy with Dunn chambers.
  
  
  RESULTS
  Messenger RNAs for cholecystokinin (CCK)A, CCKB, and CCKC receptors were present in HUVECs and microvessels dissected from a human glioblastoma. Whereas G17 significantly increased the levels of angiogenesis in vivo in the U373 experimental glioma model and in vitro in the HUVECs, the CCKB receptor antagonist L365,260 significantly counteracted the G17-mediated proangiogenic effects. G17 chemoattracted HUVECs, whereas IL-8 failed to do so. IL-8 receptor alpha (CXCR1) and IL-8 receptor beta (CXCR2) mRNAs were not detected in these endothelial cells. Gastrin significantly (but only transiently) decreased the level of expression of E-selectin, but not P-selectin, whereas IL-8 increased the expression of E-selectin. Specific antisense oligonucleotides against E- and P-selectin significantly decreased HUVEC tubulogenesis processes in vitro on Matrigel.
  
  
  CONCLUSIONS
  The present study shows that gastrin has marked proangiogenic effects in vivo on experimental gliomas and in vitro on HUVECs. This effect depends in part on the level of E-selectin activation, but not on IL-8 expression/release by HUVECs.
authors.affiliation: Department of Neurosurgery, Erasmus University Hospital.
authors.forename: Florence
authors.initials: F
authors.lastname: Lefranc
authors.forename: Tatjana
authors.initials: T
authors.lastname: Mijatovic
authors.forename: Véronique
authors.initials: V
authors.lastname: Mathieu
authors.forename: Sandrine
authors.initials: S
authors.lastname: Rorive
authors.forename: Christine
authors.initials: C
authors.lastname: Decaestecker
authors.forename: Olivier
authors.initials: O
authors.lastname: Debeir
authors.forename: Jacques
authors.initials: J
authors.lastname: Brotchi
authors.forename: Philippe
authors.initials: P
authors.lastname: Van Ham
authors.forename: Isabelle
authors.initials: I
authors.lastname: Salmon
authors.forename: Robert
authors.initials: R
authors.lastname: Kiss
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D001932:Brain Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005755:Gastrins / Q000494:pharmacology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D016209:Interleukin-8 / Q000378:metabolism; D007797:Laminin / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D019007:P-Selectin / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011509:Proteoglycans / Q000737:chemistry; D051381:Rats; D011923:Rats, Nude; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors / Q000378:metabolism; D023062:Receptors, Interleukin-8A / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000473:pathology; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D001570:Benzodiazepinones; D003094:Collagen; D004338:Drug Combinations; D019040:E-Selectin; D005755:Gastrins; D016209:Interleukin-8; D007797:Laminin; D016328:NF-kappa B; D019007:P-Selectin; D010671:Phenylurea Compounds; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D011509:Proteoglycans; D011949:Receptors, Cholecystokinin; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; C059485:matrigel; C058121:L 365260; C013550:gastrin 17