The role of CAR and its application in bladder cancer

超出所提供的空间。预计今年美国将有超过5万例新病例和1万例死亡，膀胱癌是一个重大的健康问题。膀胱移行细胞癌（TCC）的不同形态、自然病史和预后表明，它不是一种单一的疾病，而是以三种不同的形式发生，每种形式都具有特征（即低级别乳头状癌、非侵袭性、原位癌、高级别浸润性）。最近的研究已经开始阐明这些不同表现的膀胱癌的形态学和生物学特征的潜在遗传决定因素。形态学改变之前的分子和遗传改变，是TCC发生和发展的原因。了解这些基因变化将最终改善TCC的诊断和基因治疗。最近报道了一种柯萨奇腺病毒受体（CAR）的鉴定，这是一种腺病毒5型的高受体。CAR的异质表达在几种TCC和前列腺癌细胞系中被检测到（cancer Res., 59,325, 1999和cancer Res., 60,5031, 2000）。这种表达是由于CAR基因转录下调所致。通过增加它们的CAR水平，耐药细胞可能对腺病毒感染变得高度敏感。因此，CAR不仅是监测基因治疗结果的替代标志物，而且可以提高基因治疗的效率。CAR的下调常见于TCC病变，而不见于邻近的正常组织，提示CAR可能在TCC的进展中发挥病理生理作用。此外，CAR与分化极化细胞中的紧密连接蛋白相关（PNAS, 98, 15191, 2001）。此外，CAR基因表达的增加可以抑制肿瘤细胞在体外和体内的生长。另一方面，降低几种TCC细胞系的CAR表达（使用反义载体）可以促进体外和体内生长速度。这些数据表明，CAR在TCC细胞中是一种肿瘤抑制剂（Cancer Res., 61,659,2001）。为了进一步阐明CAR在TCC细胞中的潜在机制，初步数据表明：(1)CAR是一种典型的细胞粘附分子；(2) CAR与紧密结复合体相关；(3) CAR的粘附活性与其生长抑制功能相当；(4)在TCC细胞中，CAR的胞内结构域对诱导其生长抑制信号至关重要；(5) CAR能够抑制环氧化酶2 （COX-2）的表达。基于这些结果，我们假设CAR可以通过重建TCC的细胞间相互作用来抑制细胞生长，其作用机制是抑制COX-2在TCC中的表达。由于CAR和COX-2的生物学在很大程度上是未知的，我们计划(1)从不同等级和阶段的TCC标本中建立CAR和COX-2之间的互惠关系；(2)揭示由CAR引发的激活其肿瘤抑制的下游途径，并确定能够激活CAR信号传导的任何其他配体；(3)确定CAR抑制COX-2的生物学意义；(4)通过增强其内源性CAR的表达来提高TCC基因治疗的疗效。这项研究的结果应该有助于我们了解CAR在TCC进展中的生物学作用，并制定TCC治疗的新策略。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. With over 50,000 new cases and 10,000 deaths expected this year in the U.S, bladder cancer is a significant health concern. Variable morphology, natural history, and prognosis demonstrate that transitional cell carcinoma (TCC) of the bladder is not a single disease, but occurs in three distinct forms, each possessing characteristic features (i.e., low grade papillary, noninvasive; carcinoma in situ; high grade, invasive). Recent studies have begun to elucidate the underlying genetic determinants of the morphologic and biologic characteristics of these different presentations of bladder cancer. Molecular and genetic alterations that precede morphologic changes, and which are responsible for tumorigenesis and progression of TCC. Understanding these genetic changes should eventually lead to improved diagnosis and gene therapy for TCC. Identification of a coxsackie and adenovirus receptor (CAR), a high receptor for adenovirus type 5, was recently reported. The heterogeneous expression of CAR is detected in several TCC and prostate cancer cell lines (Cancer Res., 59, 325, 1999 and Cancer Res, 60, 5031, 2000). This expression resulted from the down- regulation of CAR gene transcription. By increasing their CAR levels, resistant cells could become highly sensitive to adenoviral infection. Therefore, CAR not only is a surrogate marker to monitor the outcome of gene therapy, but also facilitate the efficiency of gene therapy. The Down-regulation of CAR is often seen ila TCC lesions but not in adjacent normal tissue, which suggests that CAR may play a pathophysiologic role in the progression of TCC. Also, CAR is associated with a tight junction protein in differentiated polarized cell (PNAS, 98, 15191, 2001). Moreover, increased CAR gene expression can inhibit the in vitro and in vivo growth of tumor cells. On the other hand, decreasing CAR expression (using antisense vector) in several TCC cell lines can facilitate the in vitro and in vivo growth rate. These data indicate that CAR is a tumor inhibitor in TCC cells (Cancer Res., 61, 6592, 2001). To further elucidate the underlying mechanism of CAR in TCC cells, preliminary data indicated that (1) CAR is a typical cell adhesion molecule; (2) CAR is associated with tight junction complex; (3) adhesion activity of CAR parallels its growth inhibitory function; (4) the intracellular domain of CAR is critical for inducing its growth inhibitory signal in TCC cells; (5) CAR is able to inhibit cyclooxygenase 2 (COX-2) expression. Based on these results, we hypothesize that CAR can inhibit cell growth by reestablishing intercellular interactions of TCC, and the mechanism of CAR action is to inhibit COX-2 expression in TCC. Since the biology of CAR and COX-2 is largely unknown, we plan to (1) establish a reciprocal relationship between CAR and COX-2 from TCC specimens of different grades and stages; (2) unveil downstream pathway(s) elicited by CAR that activates its tumor inhibition and to determine any other ligand(s) capable of activating CAR signaling; (3) determine the biologic significance of the suppression of COX-2 by CAR; (4) increase therapeutic efficacy of TCC gene therapy by enhancing its endogenous CAR expression. The outcome of this study should help us understand the biologic role of CAR in the progression of TCC and develop a new strategy for TCC therapy. PERFORMANCE SiTE ========================================Section End===========================================