HEPATIC OVAL CELLS IN CULTURE AND IN VIVO

描述：（改编自研究者摘要）原发性胆管癌 肝内胆管癌是一种高度恶性的疾病， 没有有效的治疗。虽然其特点是死亡率和发病率高， 关于这种疾病的细胞和分子发病机制， 分化和生长调节，这似乎是相关的， 在呋喃处理的大鼠中胆管癌的发展。诱导的肿瘤在 这种独特的胆管癌发生动物模型在它们的 形态学和表型特征产生粘蛋白的管状或“分泌型” 人肝胆管癌。在上一个资助期内，我们 证实了呋喃诱导的大鼠肿瘤上皮 胆管癌表现出显著的过度表达和激活， 生长因子受体酪氨酸激酶。Neu是人类ErbB-2的大鼠同源物， 与增生和正常肝内胆管上皮相比， 细胞另外，我们最近观察到环氧化酶-2（考克斯-2） 在一种新的大鼠胆管癌细胞系中显著上调 过表达Neu，以及在致瘤性neu转化的大鼠肝脏中 上皮干细胞样细胞，但在未转化的对照细胞中未检测到。 此外，我们已经提出的数据强烈表明，CDX 1，一个同源异型盒， 一种丝氨酸特异性转录因子，可能在 控制细胞分化沿着肠谱系， 肝内胆管型胆管癌的发病机制 呋喃处理的大鼠。根据这些最新的发现，由于ErbB-2和 考克斯-2已显示在显著百分比的人中过表达， 胆管癌的发展，现在促使我们专注于实现 （1）选择性地靶向Neu和考克斯-2， 潜在重要的临床前治疗策略， 在呋喃模型中胆管癌的发展、生长和/或进展， (2)以直接确定同源异型框蛋白特异性 转录因子，如CDX 1和CDX 2，在调节分化， 肝胆肿瘤总的来说，拟议的 这些研究不仅将提供有关 在呋喃模型中胆管癌发展的发病机制，但也 预计将产生重要的临床前信息， 与预防和/或治疗人胆管癌发生有关。

DESCRIPTION: (Adapted from the investigator's abstract) Primary biliary cancer in liver (cholangiocarcinoma) is a highly malignant disease of which there is no effective treatment. While characterized by high mortality and morbidity, little is actually known about the cellular and molecular pathogenesis of differentiation and growth regulation, which appear to be relevant to the development of cholangiocarcinoma in furan-treated rats. The tumors induced in this unique animal model of cholangiocarcingenesis closely resemble in their morphology and phenotypic features mucin-producing tubular or "intestinal-type" cholangiocarcinomas of human liver. During the previous grant period, we have demonstrated that neoplastic epithelium of furan-induced rat cholangiocarcinomas exhibit prominent overexpression and activation of the growth factor receptor tyrosine kinase. Neu, the rat homologue of human ErbB-2, when compared to hyperplastic and normal intrahepatic biliary ephithelial cells. in addition, we have recently observed that cyclooxygenase-2 (COX-2) is markedly up-regulated in a novel rat cholangiocarcinoma cell line overexpressing Neu, as well as in tumorigenic neu-transformd rat liver epithelial stem-like cells, but is not detected in untransformed control cells. Moreover, we have presented data strongly suggesting that CDX1, a homeobox intestine-specific transcription factor, may be playing a critical role in controlling cellular differentiation along the intestinal lineage in the pathogenesis of intestinal-type chalongiocarcinoma formed in the liver of furan-treated rats. Based on these recent findings, and because ErbB-2 and COX-2 have been shown to be overexpressed in significant percentages of human cholangiocarcinoma development, has now prompted us to focus on accomplishing the following specific aims: (1) to selectively target Neu and COX-2 as a potentially important preclinical therapeutic strategy for inhibiting cholangiocarcinoma development, growth, and/or progression in the furan model, (2) to directly determine the role played by homeobox intestine-specific transcription factors, such as CDX1 and CDX2, in regulating differentiation in hepatobiliary neoplasia. Overall, the findings generated by the proposed studies will not only provide useful new basic information about the pathogenesis of cholangiocarcinoma development in the furan model, but are also anticipated to yield important preclinical information potentially quite relevant for the prevention and/or therapy of human cholagiocarcinogenesis.