Overexpression of the p53-inducible brain-specific angiogenesis inhibitor 1 suppresses efficiently tumour angiogenesis

The brain-specific angiogenesis inhibitor I 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 I 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 I may act as a mediator in the local angiogenesis balance. We herein demonstrate that brain-specific angiogenesis inhibitor I over-expression suppresses tumour angiogenesis, delaying significantly the human tumour growth in immunodeficient mice. The inhibitory effect of brain-specific angiogenesis inhibitor I was documented using our intravital microscopy system, strongly implicating brain-specific angiogenesis inhibitor I as a mediator in the control of tumour angiogenesis. In contrast, in vitro tumour cell proliferation was not inhibited by brain-specific angiogenesis inhibitor I 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 I-overexpressing tumours. At messenger level, moderate changes could be detected, involving the down-regulation of vascular endothelial growth factor and collagenase-I expression. Furthermore, brain-specific angiogenesis inhibitor I 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 I should be considered for gene therapy and development of efficient drugs based on endogenous antiangiogenic molecules.