PI3K Pathway in Prostate Tumorigenesis and Angiogenesis

越来越多的证据表明PI3K和PTEN信号的失调在人前列腺中是重要的， 癌的然而，PI3K诱导的和PTEN抑制的前列腺肿瘤生长的机制并不清楚。 知道的这项提案的长期目标是了解前列腺增生的分子机制， 肿瘤发生由于PI3K和PTEN通路的失调，并阐明PI3K的连接， 和PTEN下游信号成分对体内肿瘤血管生成的影响。我们假设PI3K 通过在发展中的肿瘤中诱导血管生成和通过激活 未开发的诱导前列腺肿瘤发生的靶点和介质。具体目标1旨在确定 PI3K和PTEN效应子调节前列腺肿瘤发生的机制和新功能， 我们建立的肿瘤模型。本研究旨在研究PI3K和PTEN在前列腺肿瘤生长中的作用， 测试血管生成在PI3K诱导的肿瘤生长中的作用，并寻找PI3K效应物的新功能 参与前列腺肿瘤生长和血管生成。特定目标2旨在表征PI3K 下游信号传导分子，其传递PI3K信号以诱导前列腺肿瘤生长， 血管生成我们将确定AKT是否传递了来自细胞凋亡失调的致癌信号。 PI3K和PTEN信号传导，以及AKT是否反过来激活p70S6K1和MDM 2诱导前列腺增生 体内肿瘤血管生成。由于我们发现MDM2在体外培养的前列腺中被PI3K和AKT上调， 癌细胞在我们的初步研究中，MDM2在PI3K和AKT诱导的前列腺肿瘤发生中的研究 和血管生成将有助于我们理解MDM2表达在传递PI3K和PI3K中的新机制。 AKT信号诱导肿瘤血管生成。这项工作将确定PI3K效应器的新功能， 前列腺肿瘤发生和血管生成，揭示PI3K信号转导在调节前列腺 肿瘤发生，并帮助建立合理的治疗策略，为人类前列腺癌的靶向 特定的信号分子

Accumulating evidence shows that deregulation of PI3K and PTEN signaling is important in human prostate cancers. However, the mechanisms of PI3K-induced and PTEN-inhibited prostate tumor growth are not known. The long-term objectives of this proposal are to understand the molecular mechanisms of prostate tumorigenesis due to deregulation of the PI3K and PTEN pathway, and to elucidate the connection of PI3K and PTEN downstream signaling components to tumor angiogenesis in vivo. We hypothesize that PI3K regulates prostate tumorigenesis by inducing angiogenesis in the developing tumor and by activating unexploited targets and mediators for inducing prostate tumorigenesis. Specific Aim 1 is designed to identify the mechanisms and new functions of PI3K and PTEN effectors that regulate prostate tumorigenesis using our established tumor models. This aim will study the effects of PI3K and PTEN in prostate tumor growth, test the role of angiogenesis in PI3K-induced tumor growth, and search for novel functions of PI3K effectors involved in prostate tumor growth and angiogenesis. Specific Aim 2 is designed to characterize PI3K downstream signaling molecules to transmit PI3K signals for inducing prostate tumor growth and angiogenesis. We will determine whether AKT transmits the oncogenic signals from the deregulation of PI3K and PTEN signaling, and whether AKT in turn activates p70S6K1 and MDM2 in inducing prostate tumor angiogenesis in vivo. Since we found that MDM2 is upregulated by PI3K and AKT in cultured prostate cancer cells in our preliminary study, the study of MDM2 in PI3K- and AKT-induced prostate tumorigenesis and angiogenesis will help us to understand novel mechanisms of MDM2 expression in transmiting PI3K and AKT signals for inducing the tumor angiogenesis. This work will identify new functions of PI3K effectors in prostate tumorigenesis and angiogenesis, reveal mechanisms of PI3K signaling in regulating prostate tumorigenesis, and help to establish rational therapeutic strategies for human prostate cancer by targeting specific signaling molecules in the future.