STEM CELLS AND HEPATOCARCINOGENESIS

干细胞与肝癌发生

• 批准号: 7103671
• 负责人: STEWART SELL
• 金额: $ 26.34万
• 依托单位: ORDWAY RESEARCH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7103671
• 关键词: Adenoviridae; bone marrow transplantation; carcinogenesis; carcinogens; cell fusion; cell population study; cellular oncology; choline deficiency; diethylnitrosamine; disease /disorder model; epidermal growth factor; genetically modified animals; hepatocellular carcinoma; hepatotoxin; laboratory rat; liver cells; neoplastic process; preneoplastic state; propanols; stem cells; sulfur aminoacid; transfection /expression vector

Description (from applicant): One of the long standing unanswered questions in one of the most frequently studied models of carcinogenesis, chemical hepatocarcinogenesis, is what is the cell of origin of hepatocellular carcinomas (HCC)? The classic cellular pathway, championed by Emmanuel Farber, is that HCC develop from altered hepatocytes progressively through foci and preneoplastic nodules. However, studies on oval cells, which appear early during hepatocarcinogenesis, indicate that HCC may arise from "bipolar" liver progenitor cells located within terminal ducts or from pluripotent progenitor cells located adjacent to the ducts. In addition, recent studies on female mice and rats receiving bone marrow transplants from male donors indicated two possible origins of liver stem cells: from bipolar progenitor cells in the terminal ducts or from periductal stem cells. It is further postulated that these periductal progenitor cells may arise from circulating bone marrow stem cells either by differentiation into liver cells or that bone marrow cells may fuse with liver cells. In Specific Aim 1, the applicant proposes to develop a transgenic Fischer rat line expressing EGFP which can be used as a donor for bone marrow transplantation studies. In Specific Aim 2, three models of carcinogenesis: a. Continuous DEN, which features foci of altered hepatocytes preceding HCC with little or no oval cells will be used to determine if HCC arise from hepatocytes; b. Solt-Farber model, which features prominent proliferation of ductal oval cells to determine if HCC arise from bipolar ductal precursor cells; c. Choline-deficiency-ethionine, a model which features periductular proliferation of oval cells will be used to determine if preneoplastic lesions or HCC arise from periportal oval cells. In each of these protocols, DDPIV- (canalicular enzyme) female rats will receive a bone marrow transplant from DDPIV+, EGFP+, male donors. The origin of the populations of cells responding by proliferation will be identified by the presence of donor or recipient markers, and the types of cells identified through labeling with both liver lineage and littoral cell markers, when appropriate. In Specific Aim 3, the possibility of fusion of donor bone marrow stem cells with recipient liver cells will be tested and the possibility of fusion in etiology, progression or metastasis of HCC determined. Knowledge of the cellular origin of cancer is critical for understanding how cancer evolves and for developing prevention strategies.

描述（来自申请人）：最常见的癌变模型之一，化学肝癌发生的一个长期未解决的问题之一，是肝细胞癌（HCC）的起源细胞是什么？由伊曼纽尔·法伯（Emmanuel Farber）倡导的经典蜂窝路径是，HCC通过焦点和肿瘤结节逐渐改变肝细胞而发展。然而，对肝癌发生期间早期出现的椭圆形细胞的研究表明，HCC可能是由位于末端管道内的“双极”肝脏祖细胞或位于毗邻管道的多能祖细胞内的“双极”肝脏祖细胞引起的。此外，最近对雌性小鼠和大鼠接受骨髓移植的大鼠的研究表明，肝干细胞的两个可能起源：来自末端管道中的双极祖细胞或外围干细胞。进一步指出，这些外围祖细胞可能是由通过分化为肝细胞的骨髓干细胞引起的，或者骨髓细胞可能与肝细胞融合。在特定的目标1中，申请人建议开发一种表达EGFP的转基因Fischer大鼠线，该线可以用作骨髓移植研究的供体。在特定的目标2中，三种癌变模型：连续DEN具有在HCC前面改变的肝细胞的焦点，几乎没有或没有椭圆形细胞来确定HCC是否来自肝细胞。 b。 Solt-Farber模型，具有导管细胞的显着增殖，以确定HCC是否来自双极导管前体细胞。 c。胆碱缺乏 - 硫氨酸是一种具有椭圆形细胞外围的外围增殖的模型，用于确定肿瘤性病变或HCC是否来自周围椭圆形细胞。在这些方案中的每一种中，ddPiv-（管道酶）雌性大鼠将从ddpiv+，eGFP+，雄性供体接受骨髓移植。通过供体或受体标记的存在，通过增殖响应的细胞群体的起源将确定，以及在适当的情况下通过用肝谱系和沿海细胞标记标记的细胞类型。 在特定的目标3中，将测试供体骨髓干细胞与受体肝细胞的可能性，并且确定的HCC的病因，进展或转移的可能性。了解癌症的细胞起源对于了解癌症如何发展和制定预防策略至关重要。