PTEN/AKTp53 signaling axis in tumor induced angiogenesis

描述（申请人提供）：目前成人和儿童恶性神经胶质性脑肿瘤的治疗效果较差。肿瘤抑制因子PTEN（一种双特异性蛋白磷酸酶，能使酸性肽和肌醇磷脂去磷酸化）的突变伴随着儿童和成人脑肿瘤从良性到恶性的发展。脑肿瘤的进展，特别是侵袭性和恶性脑肿瘤，与增殖增强和血管生成的诱导有关。我们的初步数据支持PTEN通过调节血管生成反应来调节脑肿瘤进展的假设。用PTEN cDNA稳定重组的U87MG胶质瘤细胞在裸鼠原位脑瘤模型中生长。我们观察到野生型PTEN的引入导致体内肿瘤生长下降，并延长了这些细胞植入小鼠的存活时间。这些变化与pten重组肿瘤内AKT磷酸化降低和血管生成活性降低相关，这是通过微血管密度和血小板反应蛋白1表达增加来确定的。在PTEN的G129E突变形式重组的肿瘤中，脂质磷酸酶活性被削弱，而这些影响未被观察到。这些数据支持我们的假设，并表明，除了PTEN对增殖和细胞存活的影响外，PTEN的缺失还通过调节磷酸肌醇依赖信号调节肿瘤诱导的血管生成和胶质瘤向恶性表型的进展。基于我们的初步数据，我们建议评估PTEN和PI-3激酶在脑肿瘤进展中的作用，因为它与血管生成反应有关，并确定PI-3激酶抑制剂是否可以阻断脑肿瘤生长、血管生成反应和促进生存。这些实验将提供重要的临床前数据，支持PI-3激酶抑制剂的开发，用于治疗与PI-3激酶/AKT信号轴失调相关的恶性胶质肿瘤。

DESCRIPTION (provided by applicant): Currently the treatment outcome of malignant glial brain tumors in adult and pediatric patients is poor. Mutations of the tumor suppressor, PTEN, a dual specificity protein phosphatase which dephosphorylates acidic peptides and inositol phospholipids, accompany progression of pediatric and adult brain tumors from benign to the most malignant forms. Brain tumor progression, particularly in aggressive and malignant brain tumors, is associated with augmented proliferation and the induction of angiogenesis. Our preliminary data support the hypothesis that PTEN regulates brain tumor progression by modulating the angiogenic response. U87MG glioma cells stably reconstituted with PTEN cDNA were tested for growth in a nude mouse orthotopic brain tumor model. We observed that the introduction of wild type PTEN resulted in decreased tumor growth in vivo and prolonged survival in mice implanted intracranially with these cells. These changes correlated with diminished phosphorylation of AKT within the PTEN-reconstituted tumor and diminished angiogenic activity, as determined by microvessel density and augmented thrombospondin 1 expression. These effects were not observed in tumors reconstituted with the G129E mutant form of PTEN in which lipid phosphatase activity is ablated. These data support our hypothesis and indicate that, in addition to the reported effects of PTEN on proliferation and cell survival, loss of PTEN regulates tumor-induced angiogenesis and the progression of gliomas to a malignant phenotype via the regulation of phosphoinositide-dependent signals. Based on our preliminary data we propose to evaluate the role of PTEN and PI-3 kinase in brain tumor progression as it relates to the angiogenic response and to determine if PI-3 kinase inhibitors can block brain tumor growth, the angiogenic response and promote survival. These experiments will provide important preclinical data to support the development of PI-3 kinase inhibitors for the treatment of malignant glial tumors associated with a deregulated PI-3 kinase/AKT signaling axis.