Effects of tumor suppressor gene (p53) on brain tumor angiogenesis and expression of angiogenic modulators.
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.


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 semi-quantitative 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.


CONCLUSIONS
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.
Tse
Victor
V
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA. vkt@stanford.edu
Yung
Yun
Y
Santarelli
Justin G
JG
Juan
David
D
Hsiao
Michael
M
Haas
Martin
M
Harsh
Griffith
G
Silverberg
Gerald
G
D042501:Angiogenic Proteins / Q000096:biosynthesis*; D042683:Angiopoietin-1 / Q000096:biosynthesis; D042702:Angiopoietin-2 / Q000096:biosynthesis; D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000235:genetics; D016158:Genes, p53 / Q000502:physiology*; D005909:Glioblastoma / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D042787:Receptor, TIE-2 / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D042501:Angiogenic Proteins; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D018076:DNA, Complementary; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2