Effects of Tumor Suppressor Gene (p53) on Brain Tumor Angiogenesis and Expression of Angiogenic Modulators

• Published in: Anticancer research Vol. 24; no. 1; pp. 1 - 10
• Main Authors: Tse, Victor, Yung, Yun, Santarelli, Justin G, Juan, David, Hsiao, Michael, Haas, Martin, Harsh, 4th, Griffith, Silverberg, Gerald
• Format: Journal Article
• Language: English
• Published: Attiki International Institute of Anticancer Research 01.01.2004
• Subjects: Angiogenic Proteins - biosynthesis; Angiopoietin-1 - biosynthesis; Angiopoietin-2 - biosynthesis; Animals; Biological and medical sciences; Brain Neoplasms - blood supply; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Cell Line, Tumor; DNA, Complementary - genetics; Genes, p53 - physiology; Glioblastoma - blood supply; Glioblastoma - genetics; Glioblastoma - metabolism; Humans; Immunohistochemistry; Medical sciences; Neoplasm Transplantation; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neurology; Rats; Rats, Sprague-Dawley; Receptor, TIE-2 - biosynthesis; Reverse Transcriptase Polymerase Chain Reaction; Transfection; Tumor Suppressor Protein p53 - biosynthesis; Tumor Suppressor Protein p53 - genetics; Tumors of the nervous system. Phacomatoses; Vascular Endothelial Growth Factor A - biosynthesis; Nervous system diseases; Modulator; Angiopoietin; Central nervous system; Encephalon; Angiogenesis; Retrovirus; Vascular endothelium growth factor; TP53 Gene; Treatment; Glioma; Central nervous system disease; Tumor; Neovascularization; Gene therapy; Tumor suppressor gene
• ISSN: 0250-7005; 1791-7530

Background: p53 retarded tumor growth by several known mechanisms, including suppression of cell proliferation and inhibition of tumor angiogenesis. Vascular endothelial growth factors (VEGF) and angiopoietins (Ang-1, Ang-2) are major angiogeneic modulators. The current study examined the effect of p53 on the expression of these factors in conjunction with tumor growth and vascular formation. Materials and Methods: Growth characteristics of rat glioma cells (RT-2) infected with retrovirus (MSCV) encoding a full-length human wild-type p53 gene were examined by clonogenic assay. Expression of the transgene in vitro was verified by RT-PCR and immunoprecipitation. Tumor morphology, vascular architecture and the expression of VEGF, Ang-1, Ang-2 and Tie-2 were examined by immunohistochemistry and semiquantitative RT-PCR. Results: p53-infected cells showed retardation in growth and colony formation. In vivo, expression of the transgene resulted in prolonged survival and reduction of tumor volume (62%) and reduced the expression of VEGF (57.8%) and Tie-2 (15.4%) but not Ang-1 and Ang-2. The tumor exhibited increased necrosis (38%), hemorrhage and abnormal vascular architecture. Conclusion: p53 causes tumor regression by suppressing tumor proliferation and indirectly induces involution of tumor vessels by fostering unopposed activity of Ang-2 in an environment of diminishing VEGF.