Characterization of gastrin-induced proangiogenic effects in vivo in orthotopic U373 experimental human glioblastomas and in vitro in human umbilical vein endothelial cells.

Abstract

PURPOSE:

This study aims to investigate the role of gastrin-17 (G17) on angiogenesis features in gliomas both in vitro and in vivo.

EXPERIMENTAL DESIGN:

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: Florence Lefranc, Tatjana Mijatovic, Véronique Mathieu, Sandrine Rorive, Christine Decaestecker, Olivier Debeir, Jacques Brotchi, Philippe Van Ham, Isabelle Salmon, Robert Kiss
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 24 Pg. 8250-65 (Dec 15 2004) ISSN: 1078-0432 [Print] United States
• PMID: 15623601 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzodiazepinones
• Drug Combinations
• E-Selectin
• Gastrins
• Interleukin-8
• Laminin
• NF-kappa B
• P-Selectin
• Phenylurea Compounds
• Phosphoinositide-3 Kinase Inhibitors
• Proteoglycans
• Receptors, Cholecystokinin
• Receptors, Interleukin-8A
• Receptors, Interleukin-8B
• matrigel
• L 365260
• gastrin 17
• Collagen
• Protein Kinase C

Topics

• Animals
• Benzodiazepinones (pharmacology)
• Brain Neoplasms (blood supply, metabolism, pathology)
• Cell Movement (drug effects)
• Collagen (chemistry)
• Drug Combinations
• E-Selectin (metabolism)
• Endothelium, Vascular (drug effects, metabolism)
• Enzyme-Linked Immunosorbent Assay
• Female
• Gastrins (pharmacology)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Glioblastoma (blood supply, metabolism, pathology)
• Humans
• In Vitro Techniques
• Interleukin-8 (metabolism)
• Laminin (chemistry)
• Mice
• Mice, Nude
• NF-kappa B (antagonists & inhibitors, metabolism)
• Neovascularization, Pathologic (drug therapy)
• P-Selectin (metabolism)
• Phenylurea Compounds (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase C (antagonists & inhibitors, metabolism)
• Proteoglycans (chemistry)
• Rats
• Rats, Nude
• Receptors, Cholecystokinin (antagonists & inhibitors, metabolism)
• Receptors, Interleukin-8A (metabolism)
• Receptors, Interleukin-8B (metabolism)
• Transplantation, Heterologous
• Tumor Cells, Cultured (drug effects, pathology)
• Umbilical Veins (cytology)