PTEN decreases in vivo vascularization of experimental gliomas in spite of proangiogenic stimuli.
Approximately 30-40% of malignant glial tumors exhibit mutations in the tumor suppressor gene, PTEN/MMAC. Additionally, these tumors are associated with (a) mutations in epidermal growth factor receptor (EGFR), leading to a pro-oncogenic constitutive activation, as well as amplification of its gene, and/or (b) mutations in p53, disrupting normal cellular homeostatic processes. Whereas PTEN/MMAC has been shown to possess antiangiogenic action, constitutively active EGFR or p53 gene defects have been associated with proangiogenic action. In this article, we asked if PTEN/MMAC gene transfer into human glioma cells that possess inactivating mutations of the PTEN/MMAC gene but also express either constitutively active EGFR (U87DeltaEGFR cells) or possess an inactivating mutation of p53 (U251 cells) still display inhibited angiogenesis in orthotopic and ectopic models of gliomas. Human glioma xenografts treated with PTEN/MMAC gene transfer exhibited significantly decreased vascularity both in an orthotopic and in an ectopic model. Taken in combination, these results provide strong evidence of PTEN/MMAC's role in regulating glioma angiogenesis even in the presence of strong proangiogenic signals provided by constitutive EGFR activation or p53 inactivation.
Molecular Neuro-Oncology Laboratories, Neurosurgery Service, Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129, USA.
Tatsuya
T
Abe
Kinya
K
Terada
Hiroaki
H
Wakimoto
Ryo
R
Inoue
Edyta
E
Tyminski
Robert
R
Bookstein
James P
JP
Basilion
E Antonio
EA
Chiocca
D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000628:therapy; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D005910:Glioma / Q000098:blood supply* / Q000235:genetics / Q000628:therapy; D006801:Humans; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D011923:Rats, Nude; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D066246:ErbB Receptors; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human