HEPATIC OVAL CELLS IN CULTURE AND IN VIVO

描述：(改编自研究人员摘要)原发性胆道癌 肝内胆管细胞癌是一种高度恶性的疾病， 没有有效的治疗方法。虽然以高死亡率和高发病率为特征， 目前对其细胞和分子发病机制知之甚少 分化和生长调节，这似乎与 呋喃处理大鼠胆管癌变的研究。在中国诱发的肿瘤 这种独特的胆管癌变动物模型与它们的 产生粘蛋白的管状或“肠型”的形态和表型特征 人类肝脏的胆管细胞癌。在之前的授权期内，我们有 证明呋喃诱导的大鼠肿瘤上皮细胞 胆管细胞癌表现为显著的过度表达和激活 生长因子受体酪氨酸激酶。Neu，人类ErbB-2的大鼠同源物， 与增生和正常肝内胆管上皮的比较 细胞。此外，我们最近观察到环氧合酶-2(COX-2)是 一种新的大鼠胆管癌细胞系的显著上调 Neu在致瘤大鼠肝脏中的过表达 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，我们提供的数据有力地表明，CDX1，一种同源异型盒 肠道特异的转录因子，可能在 控制肠道血统中的细胞分化 人肝内肠型脉络膜癌的发病机制 呋喃处理的大鼠。根据这些最新发现，由于ErbB-2和 COX-2已被证明在相当比例的人类中过度表达 胆管细胞癌的发展，现在促使我们专注于完成 具体目标如下：(1)选择性地将Neu和COX-2作为 潜在重要的临床前抑制治疗策略 呋喃模型中胆管癌细胞的发展、生长和/或进展， (2)直接确定同源异型盒在肠道中的作用 转录因子，如CDX1和CDX2，在调节细胞分化中的作用 肝胆管肿瘤。总体而言，拟议的 研究不仅将提供有用的关于 胆管癌的发病机制在呋喃模型中的发展，但也 预计可能会产生重要的临床前信息 与预防和/或治疗人类胆管癌变有关。

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.