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

Abstract

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.

Vasculostatin, a proteolytic fragment of Brain Angiogenesis Inhibitor 1, is an antiangiogenic and antitumorigenic factor

“…Similarly, pulmonary pancreatic and gastric cancers show less BAI1 expression than their normal tissue counterparts, suggesting that tumor formation selects for lack of BAI1 expression (Hatanaka et al, 2000;Lee et al, 2001;Duda et al, 2002). This is supported by the preliminary finding that transient BAI1 expression by adenovirus gene therapy reduces pancreatic tumor growth (Duda et al, 2002). Taken together, these findings support the hypothesis that BAI1 function may impede tumor development through an antiangiogenic mechanism.…”

“…TSRs are present in over 70 human proteins and some of them confer antiangiogenic properties to their parent proteins (de Fraipont et al, 2001). Isolated peptides containing three of the five 50 amino acid TSRs of BAI1 were shown to have an antiangiogenic function in a rat corneal model Duda et al, 2002). This interesting preliminary finding suggested putative antiangiogenic function for BAI1 but did not provide a mechanism by which it might occur.…”

The cell-adhesion G protein-coupled receptor BAI3 is a high-affinity receptor for C1q-like proteins

“…RNA quantification and in situ hybridization have indicated that in adult mice, BAI proteins are expressed primarily in the brain, with low-level expression in other tissues (12)(13)(14)(15). The BAI1 gene, originally identified in a screen for p53-inducible genes, is thought to inhibit neovascularization, a process required for tumor growth (10,13,(16)(17)(18)(19). Human BAI1 expression is down-regulated in glioblastoma and is inversely correlated with neovascularization in colorectal and lung cancers, consistent with an antiangiogenesis function (20)(21)(22).…”

Oncolytic replication-competent adenovirus suppresses tumor angiogenesis through preserved E1A region

“…The picture of the skin of the back was taken using a NICON F3 for the analysis of tumor angiogenesis. Subcutaneous tumors were histologically studied by hematoxylin-eosin staining or immunostaining with rat anti-mouse PECAM-1 (CD 31) antibody (BD pharmingen, San Diego, CA) for detection of endothelial cells in tumor tissue, as described, 40,41 and E1A antibody and hexon antibody for the detection of Adv. Capillaries (diametero10 mm) of tissue sections were counted in 400 high fields per section using a microscope.…”

“…40 Subsequently, aliquots of 10 ml from the amplification reactions were electrophoresed on 2% agarose (FMC BioProducts, Rokland, ME) Tris-acetate EDTA gels and autoradiographed. 40 Subcutaneous tumor model AsPC-1 cells infected with AxCA-lacZ, AxE1A dB, or dl 1101 were collected and injected into the flank of severe combined immunodeficient mice (6-8 W male, Fox Chase C.B-17/Icr-severe-combined immunodeficient (SCID) Jcl). Subcutaneous tumors and skin of the back were harvested 7 days after inoculation.…”