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

• Published in: British journal of cancer 2002-02, Vol.86 (3), p.490-496
• Main Authors: Duda, D G, Sunamura, M, Lozonschi, L, Yokoyama, T, Yatsuoka, T, Motoi, F, Horii, A, Tani, K, Asano, S, Nakamura, Y, Matsuno, S
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - blood supply; Adenocarcinoma - pathology; Angiogenesis; Angiogenesis Inhibitors; Angiogenic Proteins; Animals; Biomedical and Life Sciences; Biomedicine; Brain research; Cancer Research; Cell Division - drug effects; Drug Resistance; Epidemiology; Experimental Therapeutics; Genes, p53; Humans; Hypotheses; Medical research; Mice; Mice, SCID; Molecular Medicine; Neovascularization, Pathologic - prevention & control; Oncology; Pancreatic Neoplasms - blood supply; Pancreatic Neoplasms - pathology; Proteins - genetics; Reverse Transcriptase Polymerase Chain Reaction; Transfection; Transplantation, Heterologous; Tumor Cells, Cultured; Tumors; Vascular endothelial growth factor
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6600067

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.