PI3K Pathway in Prostate Tumorigenesis and Angiogenesis

越来越多的证据表明，PI3K和PTEN信号的解除调控在人类前列腺中很重要 癌症。然而，PI3K诱导和PTEN抑制前列腺癌生长的机制尚不清楚 为人所知。这项建议的长期目标是了解前列腺癌的分子机制。 PI3K和PTEN通路失控导致的肿瘤发生以及PI3K与肿瘤发生的关系 以及体内肿瘤血管生成的PTEN下游信号转导元件。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癌发生的靶点和介体。具体目标1旨在确定 PI3K和PTEN效应分子调控前列腺癌发生的机制和新功能 我们已建立的肿瘤模型。本研究旨在研究PI3K和PTEN在前列腺癌生长中的作用。 检测血管生成在PI3K诱导的肿瘤生长中的作用，寻找PI3K效应分子的新功能 参与前列腺癌的生长和血管生成。《特殊目标2》旨在描述PI3K 下游信号分子传递PI3K信号诱导前列腺癌生长和 血管生成。我们将确定AKT是否传递了来自解除管制的致癌信号 PI3K和PTEN信号转导，以及AKT是否进而激活p70S6K1和MDM2诱导前列腺癌 体内肿瘤血管生成。由于我们发现PI3K和AKT上调培养的前列腺中的MDM2 癌细胞的初步研究，MDM2在PI3K和AKT诱导的前列腺肿瘤形成中的研究 血管生成将有助于我们理解MDM2表达在传递PI3K和PI3K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 前列腺癌的发生和血管生成，揭示PI3K信号调节前列腺的机制 肿瘤的发生，并通过靶向帮助建立合理的前列腺癌治疗策略 未来特定的信号分子。

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.