The Role of Thromboxane A2 (TP) Receptor Beta in Bladder Cancer

描述（由申请人提供）：在美国，膀胱癌是男性第四大常见癌症，女性第八大常见癌症。每年大约有6万人患上膀胱癌。不幸的是，即使在早期看似成功的治疗之后，复发、侵袭和转移也是膀胱癌的特征。旨在阐明其发展过程中涉及的因素的研究应有助于设计基于分子的诊断和治疗方法。我们的初步数据表明：(i)血栓素A2 (TP) β受体异构体在人类膀胱癌和细胞系中独特地过表达，并且过表达与患者预后较差相关；（ii） TP β，而不是TP α，受体的表达增加了体外的恶性表型，并在体内产生永生化膀胱上皮细胞的恶性转化；（iii） TP受体拮抗剂在体内抑制膀胱癌细胞的生长、迁移和侵袭，抑制肿瘤生长；（iv）与对照组相比，膀胱癌患者尿TXB2和TP β受体蛋白显著增加，支持潜在的诊断和预后效用。根据前期研究和已发表的文献，我们推测TP β受体的表达增加及其信号通路的激活在膀胱癌细胞的生长和转移中起关键作用。为了确定TP β受体信号传导的致癌潜力，我们提出以下具体目标：1 .确定与TP β受体亚型偶联的信号通路的近端介质（G蛋白依赖和独立），这些信号通路负责膀胱癌细胞的迁移、侵袭和增殖；2. 确定TP β调控下游效应因子（肿瘤抑制因子PTEN和促血管生成多营养因子）诱导恶性表型的机制；确定TXAS、TP β受体、尿TXB2、尿TP β受体及下游效应物的组织表达在人膀胱癌进展中是否具有预后意义。建议的研究利用分子和细胞技术的结合，适当的小鼠模型和临床研究。这些方法提供了TP β受体信号可能的肿瘤相关功能的全面分析，并可能为膀胱癌和其他癌症找到新的治疗靶点。

DESCRIPTION (provided by applicant): In the US, bladder cancer is the fourth most common cancer in men and the eighth most common cancer in women. Approximately 60,000 people develop bladder cancer each year. Unfortunately, recurrence, invasion, and metastasis, even after a seemingly successful treatment at a very early stage, are characteristic of bladder cancer. Studies directed towards elucidation of the factors involved in its progression should facilitate the design of molecularly based diagnostic and therapeutic approaches. Our preliminary data demonstrate that: (i) the thromboxane A2 (TP) beta receptor isoform uniquely is over-expressed in human bladder cancer and cell lines and over-expression is correlated with a poorer prognosis in patients; (ii) TP beta, but not TP alpha, receptor expression increases malignant phenotypes in vitro and produces a malignant transformation of immortalized bladder epithelial cells in vivo; (iii) TP receptor antagonists reduce bladder cancer cell growth, migration and invasion and inhibit tumor growth in vivo; and (iv) urinary TXB2 and TP beta receptor protein are significantly greater in bladder cancer patients compared to controls, supporting potential diagnostic and prognostic utility. Based upon our preliminary studies and published literature, we hypothesize that the increased expression of TP beta receptor and activation of its signaling pathways play a critical role in bladder cancer cell growth and metastases. To define the oncogenic potential of TP beta receptor signaling, we propose the following specific aims: 1: Determine the proximal mediators (G protein dependent and independent) of the signaling pathways coupled to the TP beta receptor isoform responsible for bladder cancer cell migration, invasion, and proliferation; 2. Determine the mechanism of the regulation by TP beta of the downstream effectors (tumor suppressor PTEN and pro-angiogenic pleiotrophin) responsible for its induced malignant phenotype and 3. Determine whether tissue expression of TXAS, TP beta receptor, urinary TXB2, urinary TP beta receptor, and down-stream effectors exhibit prognostic significance in the progression of human bladder cancer. The proposed studies utilize a combination of molecular and cellular techniques, mouse models when appropriate and clinical studies. These approaches provide a comprehensive analysis of possible tumor-related functions of TP beta receptor-signaling, and may identify a new therapeutic target for bladder cancer, and maybe other cancers.