PTEN/AKTp53 signaling axis in tumor induced angiogenesis

描述(申请人提供)：目前，成人和儿童恶性胶质脑瘤的治疗效果很差。肿瘤抑制基因PTEN是一种双特异性蛋白磷酸酶，可使酸性多肽和肌醇磷脂去磷酸化，其突变伴随着儿童和成人脑肿瘤从良性向最恶性的发展。脑肿瘤的进展，特别是在侵袭性和恶性的脑肿瘤中，与增强的增殖和诱导血管生成有关。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基因稳定重组的U87 MG胶质瘤细胞在裸鼠原位脑肿瘤模型上进行生长实验。我们观察到，野生型PTEN的引入导致体内肿瘤生长减少，并延长了植入这些细胞的小鼠的生存时间。这些变化与PTEN重组肿瘤内AKT的磷酸化减少和血管生成活性降低有关，这是由微血管密度和增强的血栓反应蛋白1表达确定的。这些效应在用PTEN的G129E突变形式重组的肿瘤中没有观察到，在这些突变形式中，脂磷酸酶活性被去除。这些数据支持我们的假设，并表明，除了已报道的PTEN对细胞增殖和存活的影响外，PTEN的缺失还通过调节磷脂酰肌醇依赖的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。根据我们的初步数据，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瘤的生长、血管生成反应和提高生存率。这些实验将提供重要的临床前数据，以支持PI-3激酶抑制剂的开发，用于治疗与PI-3激酶/AKT信号轴失控相关的恶性胶质瘤。

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.