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）：在化学性肝癌这一最常研究的致癌模型之一中，长期悬而未决的问题之一是肝细胞癌（HCC）的起源细胞是什么？ Emmanuel Farber 倡导的经典细胞途径是，HCC 由改变的肝细胞逐渐通过病灶和癌前结节发展而来。然而，对肝癌发生早期出现的卵圆细胞的研究表明，HCC 可能源自位于终末导管内的“双极”肝祖细胞或邻近导管的多能祖细胞。此外，最近对接受雄性捐赠者骨髓移植的雌性小鼠和大鼠的研究表明，肝干细胞有两种可能的来源：来自终末导管中的双极祖细胞或来自导管周围干细胞。进一步假设这些导管周围祖细胞可能来自循环骨髓干细胞，或者通过分化为肝细胞，或者骨髓细胞可以与肝细胞融合。在具体目标1中，申请人提议开发表达EGFP的转基因Fischer大鼠系，其可用作骨髓移植研究的供体。在具体目标 2 中，三种致癌模型：连续 DEN 的特征是 HCC 之前肝细胞发生改变，几乎没有或没有卵圆细胞，将用于确定 HCC 是否源自肝细胞； b. Solt-Farber 模型，其特点是导管卵圆细胞显着增殖，以确定 HCC 是否源自双极导管前体细胞； c.胆碱缺乏-乙硫氨酸是一种以卵圆细胞导管周围增殖为特征的模型，将用于确定癌前病变或 HCC 是否由门静脉周围卵圆细胞引起。在每个方案中，DDPIV-（小管酶）雌性大鼠将接受来自 DDPIV+、EGFP+、雄性供体的骨髓移植。通过增殖作出反应的细胞群的起源将通过供体或受体标记物的存在来鉴定，并且在适当时通过用肝谱系和滨细胞标记物标记来鉴定细胞类型。 在具体目标3中，将测试供体骨髓干细胞与受体肝细胞融合的可能性，并确定融合在HCC病因、进展或转移方面的可能性。了解癌症的细胞起源对于了解癌症如何演变和制定预防策略至关重要。