The role of thromboxane A2 in bladder cancer

血栓素 A2 在膀胱癌中的作用

• 批准号: 6871187
• 负责人: Dennis K Watson
• 金额: $ 13.14万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6871187
• 关键词: angiogenesis; athymic mouse; autocrine; biological signal transduction; bladder neoplasm; cell growth regulation; cell line; cell migration; cell proliferation; cell surface receptors; human genetic material tag; human tissue; immunocytochemistry; neoplasm /cancer genetics; neoplastic process; oxidoreductase; oxidoreductase inhibitor; paracrine; protein structure function; receptor expression; thromboxanes

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. The clinical course in urinary bladder cancer has been difficult or impossible to predict: Unfortunately, recurrence, invasion, and metastasis, even after a seemingly successful treatment at early stage, are characteristic of bladder cancer. Our long-term goal is the identification of the alterations that are functionally critical for tumorigenesis and progression that will lead to more reliable patient stratification and outcome prediction and development of novel therapies. We have recently used a combination of genetic approaches to identify genes that may be functionally involved in the progression of bladder cancer. Thromboxane synthase (TXAS) was among the genes identified based upon its overexpression in a bladder cancer. Our preliminary data demonstrate that TXAS mRNA and protein are overexpressed in human bladder cancer and bladder cancer-derived cell lines. The frequency of TXAS overexpression is highest in high grade (G3) and late stage (T4) minors. We further determined that the Thromboxane A2 (TP) receptors are overexpressed in human bladder cancer and cell lines. Based upon our observations, we hypothesize that TXA2 contributes to metastatic bladder cancer via its control on cell proliferation, migration, and angiogenesis. We believe that TXA2-regulated pathways function in autocrine as well as paracrine pathways that affect the cancer cell and endothelial cells, respectively. We further hypothesize that inhibition of TP receptor signaling may provide a new therapeutic target for the treatment of bladder cancer. In this exploratory (R21) proposal, we will use pharmacological and molecular approaches to elucidate TXAS and TP receptor function in vitro and in vivo. Specifically, we will determine the effects of TP receptor antagonists or agonists and TXAS inhibitors on growth, migration, invasion of bladder cancer cells. These studies will be complemented by molecular loss of function and gain of function studies. We will evaluate clinical samples to determine whether the expression of TXAS and TP receptors is correlated with aggressive human bladder cancer. Collectively, these studies have the potential to reveal a new approach for the treatment of 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。膀胱癌的临床过程很难或不可能预测：不幸的是，复发，侵袭和转移，即使在早期阶段看似成功的治疗后，也是膀胱癌的特征。我们的长期目标是识别对肿瘤发生和进展具有重要功能的改变，这将导致更可靠的患者分层和结局预测以及新疗法的开发。我们最近使用了遗传学方法的组合，以确定可能在功能上参与膀胱癌进展的基因。血栓素合酶（TXAS）是基于其在膀胱癌中的过表达而鉴定的基因之一。我们的初步数据表明，TXAS mRNA和蛋白在人膀胱癌和膀胱癌衍生细胞系中过表达。TXAS过表达的频率在高级别（G3）和晚期（T4）未成年人中最高。我们进一步确定血栓素A2（TP）受体在人膀胱癌和细胞系中过表达。基于我们的观察，我们假设TXA2通过其对细胞增殖、迁移和血管生成的控制而促成转移性膀胱癌。我们认为，TXA2调节途径的功能，自分泌以及旁分泌途径，影响癌细胞和内皮细胞，分别。我们进一步假设，抑制TP受体信号传导可能为膀胱癌的治疗提供新的治疗靶点。在这个探索性的（R21）建议，我们将使用药理学和分子方法来阐明TXAS和TP受体的功能在体外和体内。具体而言，我们将确定TP受体拮抗剂或激动剂和TXAS抑制剂对膀胱癌细胞的生长，迁移，侵袭的影响。这些研究将通过分子功能丧失和功能获得研究进行补充。我们将评估临床样本以确定TXAS和TP受体的表达是否与侵袭性人类膀胱癌相关。总的来说，这些研究有可能揭示一种治疗膀胱癌的新方法。