Overexpression of the p53-inducible brain-specific angiogenesis inhibitor 1 suppresses efficiently tumour angiogenesis.
The brain-specific angiogenesis inhibitor 1 gene has been isolated in an attempt to find fragments with p53 "functional" binding sites. As reported herein and by others, brain-specific angiogenesis inhibitor 1 expression is present in some normal tissues, but is reduced or lost in tumour tissues. Such data and its particular structure prompted the hypothesis that brain-specific angiogenesis inhibitor 1 may act as a mediator in the local angiogenesis balance. We herein demonstrate that brain-specific angiogenesis inhibitor 1 over-expression suppresses tumour angiogenesis, delaying significantly the human tumour growth in immunodeficient mice. The inhibitory effect of brain-specific angiogenesis inhibitor 1 was documented using our intravital microscopy system, strongly implicating brain-specific angiogenesis inhibitor 1 as a mediator in the control of tumour angiogenesis. In contrast, in vitro tumour cell proliferation was not inhibited by brain-specific angiogenesis inhibitor 1 transfection, whereas some level of cytotoxicity was assessed for endothelial cells. Immunohistochemical analysis of tumour samples confirmed a reduction in the microvessel density index in brain-specific angiogenesis inhibitor 1-overexpressing tumours. At messenger level, moderate changes could be detected, involving the down-regulation of vascular endothelial growth factor and collagenase-1 expression. Furthermore, brain-specific angiogenesis inhibitor 1 expression that was lost in a selection of human cancer cell lines could be restored by wild-type p53 adenoviral transfection. Brain-specific angiogenesis inhibitor 1 should be considered for gene therapy and development of efficient drugs based on endogenous antiangiogenic molecules.
Duda
D G
DG
First Department of Surgery, Tohoku University Medical School, 1-1 Seiryomachi, Aoba-ku, 980-8574 Sendai, Japan.
Sunamura
M
M
Lozonschi
L
L
Yokoyama
T
T
Yatsuoka
T
T
Motoi
F
F
Horii
A
A
Tani
K
K
Asano
S
S
Nakamura
Y
Y
Matsuno
S
S
D000230:Adenocarcinoma / Q000098:blood supply / Q000473:pathology*; D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D016158:Genes, p53; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000473:pathology*; D011506:Proteins / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
C468226:ADGRB1 protein, human; D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D011506:Proteins; D043562:Receptors, G-Protein-Coupled