Role of Thromboxane in Prostate Cancer Progression

描述(由申请人提供)：血栓烷(TX)合成酶将环氧合酶产物前列腺素HZ代谢成血栓烷A2(TXA.2)，可导致血管收缩、血小板激活和聚集。我们已经证明TX合成酶的表达在前列腺癌进展过程中被刺激，并且该酶参与控制肿瘤细胞的运动。我们假设Tx合酶表达的刺激是前列腺癌发生过程中不可或缺的一部分，Tx合酶赋予前列腺癌细胞更高的活力和侵袭力，并增强了对宿主组织(如止血系统，特别是血小板)的精细加工能力，以促进肿瘤的进展和转移。这三个特定的目标提供了一个路线图，以确定前列腺癌发生和发展过程中Tx合酶何时以及如何被激活，Tx合酶和TXA2发挥什么作用，以及止血系统是否受到阻碍，通过凝血酶信号环促进前列腺癌的进展和转移。在第一个特定目标中，我们将使用TRAMP小鼠前列腺癌模型来确定TX合成酶在前列腺癌发生和发展过程中的表达模式。在特定的目标2中，我们将对前列腺癌细胞中表达的TXA.2受体进行表征，并进一步研究TXA2参与调控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，并在体外检测由此产生的细胞表型的变化，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，拟议的研究将为前列腺癌的发生和发展过程提供重要的见解，并为我们提供一种以前从未探索过的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.