COX2 EXPRESSION IN GENITOURINARY CANCER AND DEVELOPMENT

环氧合酶(COX)在细胞代谢中起着关键作用，介导花生四烯酸转化为一系列具有生物活性的前列腺素。COX2是第二种丝裂原诱导亚型，发现的同时，人们意识到，服用包括阿司匹林和其他非类固醇抗炎药(NSAIDs)在内的环氧合酶抑制剂的患者克隆症和其他癌症的风险降低了近40%。最近的研究证实，COX2在包括结肠前列腺在内的特定上皮性癌细胞亚群中异常增加，在包括结肠、前列腺、膀胱在内的特定上皮性癌细胞亚群中异常增加。在各种实验模型中，COX2抑制剂显著减缓了这些肿瘤的生长。此外，观察到COX2基因敲除小鼠和子宫内暴露于COX2选择性非类固醇抗炎药的小鼠表现出严重的肾脏发育不全，这表明COX2在正常肾脏发育和维持正常肾脏发育和泌尿生殖功能方面发挥着特殊和关键的作用。COX2在生殖道中的表达是所有正常组织中最高的之一。COX2在生殖道中的表达是所有正常组织中最高的之一。COX2在正常生殖道和上皮性癌症的生长和发展中的特殊重要性的因素尚不清楚。本研究的目的是：1)建立一种由COX2启动子驱动的表达GFP报告基因的小鼠，以便于从发育中的小鼠和患有泌尿生殖系肿瘤的小鼠中分离出可表达COX2的细胞。具体目标#2是从发育中的生殖道和小鼠肿瘤组织中开发细胞系，这将允许区分COX2阳性和OX2阴性细胞的遗传和功能。这些细胞的分离应该提供了一种手段，可以识别导致COX2在癌症中异常上调的因素，以及COX2在胃肠道中正常的程序性表达。分离这些细胞将有助于鉴定由COX2高表达细胞合成的前列腺素类物质，这将阐明COX2抑制膀胱癌、前列腺癌和其他组织的进展的机制。

Cyclooxygenase (COX) play a critical role in cellular metabolism, mediating the conversion of arachidonate to a family of bioactive prostaglandins. The discovery of COX2, a second, mitogen inducible isoform, occurred almost simultaneously with realization that patients taking cyclooxygenase inhibitors including aspirin and other non-steroid anti-inflammatory drug (NSAIDs) had nearly a 40% risk reduction of clon and other cancers. Recent studies confirm that COX2 is aberrantly increased in specific epithelium cancer cell sub-populations including colonic prostate, aberrantly increased in specific epithelial cancer cell sub-populations including colonic, prostate, bladder. COX2 inhibitors significantly slow growth of these tumors in a variety of experimental models. Additionally, the observation that COX2 knockout mice and mice exposed to COX2 selective NSAIDs in utero exhibit sever renal dysgenesis suggests a specific and critical role for COX2 in the development and maintenance of normal renal development and genitourinary function. Expression of COX2 in the genitourinary tract is among the highest of any normal tissue. Expression of COX2 in the genitourinary tract is among the highest of any normal tissue. The factors contributing to the particular importance of COX2 in the normal genitourinary tract and in the growth and progression of epithelial cancers are uncharacterized. The aim of the proposed studies is to 1) develop a mouse expressing a GFP reporter driven by the COX2 promoter to facilitate the isolation of viable COX2 expressing cells from developing mouse and mice with genitourinary cancers. Specific Aim #2 is to develop cell lines from the developing genitourinary tract and murine neoplastic tissue which will allow genetic and functional distinction of COX2 positive and OX2 negative cells. The is9olation of these cells should provide a means of identifying those factors responsible for aberrant up-regulation of COX2 in cancers, and normal programmed expression of COX2 along the GU tract. Isolation of these cells will allow characterization of the prostanoid profile synthesized by COX2 over- expressing cells which should clarify how COX2 inhibitors progression of cancer in the bladder prostate, and other tissues.