Role of Thromboxane in Prostate Cancer Progression

描述（由申请人提供）：血栓素（TX）合成酶将环加氧酶产物前列腺素HZ代谢为血栓素A2 (TXA.2)，血栓素A2可导致血管收缩、血小板活化和聚集。我们已经证明TX合成酶的表达在前列腺癌的进展过程中受到刺激，并且这种酶参与控制肿瘤细胞的运动。我们假设刺激TX合酶的表达是前列腺癌发生的一个组成部分，TX合酶使前列腺癌细胞具有更强的活动性和侵袭性，同时也增强了对宿主组织（如止血系统，特别是血小板）的破坏能力，以促进肿瘤的进展和转移。这三个具体目标提供了一个路线图，以确定在前列腺癌的发生和发展过程中何时以及如何刺激TX合酶，TX合酶和TXA2发挥什么作用，以及止血系统是否通过血栓信号环阻碍前列腺肿瘤的进展和转移。在第一个具体目标中，我们将使用前列腺癌的TRAMP小鼠模型来定义前列腺癌发生和发展过程中TX合成酶的表达模式。在具体的目的2中，我们将表征TXA.2受体在前列腺癌细胞中的表达，并进一步研究TXA2控制细胞骨架和运动的信号通路。在第三个特定目标中，我们将在肿瘤细胞中过表达或敲除TX合成酶的表达，并在体外研究细胞表型的变化、与血小板的相互作用以及体内肿瘤的形成、进展和转移。我们相信这些研究将为前列腺癌的发生和发展过程提供重要的见解，也为我们提供了一条令人兴奋的干预途径。

DESCRIPTION (provided by applicant): Thromboxane (TX) synthase metabolizes the cyclooxygenase product, prostanglandin HZ, into thromboxane A2 (TXA.2), which can cause vessel constriction, platelet activation, and aggregation. We have demonstrated that TX synthase expression is stimulated during prostate cancer progression and that this enzyme is involved in controlling tumor cell motility. We hypothesize that the stimulation of TX synthase expression is an integral part of prostate carcinogenesis and TX synthase confers upon prostate cancer cells with increased motility and invasiveness, and also with increased capability to elaborate host tissues such as the hemostatic system, especially platelets, to facilitate tumor progression and metastasis. The three specific aims present a road map to define when and how TX synthase is stimulated during prostate cancer initiation and progression, what role TX synthase and TXA2 play, and whether or not the hemostatic system is impeded to facilitate prostate tumor progression and metastasis through thrombane signaling loop. In the first specific aim, we will define the pattern of TX synthase expression during prostate cancer initiation and progression using TRAMP mouse model for prostate cancer. In the specific aim 2, we will characterize TXA.2 receptors expressed in prostate cancer cells and further study the signaling pathway involved for TXA2 to control cytoskeleton and motility. In the third specific aim, we will over express or knock out TX synthase expression in tumor cells and examine the resultant changes in cell phenotypes in vitro, interaction with platelets, and tumor formation, progression, and metastasis in vivo. We believe the proposed studies will provide significant insights into the process of prostate cancer initiation and progression and also afford us an exciting avenue for intervention previously unexplored.