INSTABILITY OF TUMOR PROMOTION IN HEPATOCARCINOGENESIS

肝癌发生过程中肿瘤促进的不稳定性

• 批准号: 2683469
• 负责人: Henry C Pitot, Jr.
• 金额: $ 24.82万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2683469
• 关键词: antioxidants; apoptosis; chemical carcinogenesis; enzyme activity; fasting; flow cytometry; gene induction /repression; glutathione transferase; hepatocellular carcinoma; hepatocyte growth factor; in situ hybridization; laboratory rat; neoplasm /cancer genetics; retinoids; tissue /cell culture; transforming growth factors; tumor necrosis factor alpha; tumor promoters

DESCRIPTION: The long-term objective of the studies outlined in this proposal is to better our understanding of the cell and molecular mechanisms involved in the stages of initiation and promotion in multistage hepatocarcinogenesis in the rat. A series of five experiments will be performed to test the thesis that single glutathione-S transferase, placental form (PGST)-positive (+) hepatocytes comprise a significant part of the initiated cell population. During the stage of promotion altered hepatic foci (AHF) comprise only about 1% of the number of single PGST+ hepatocytes. Reasons for this difference will be sought in determining ploidy characteristics of the single PGST+ hepatocytes as well as the phenotypic distributions of AHF induced by different promoting agents. The operational reversibility of AHF growth during the stage of promotion will be investigated by combining the removal of the -promoting agent after 4 months of administration, together with two sequential periods of short-term fasting in order to obtain the most effective loss of AHF within a relatively short time period. Parameters involved in the acute loss of hepatocytes within AHF by this procedure will be studied by determining the most effective format of the fasting period(s), the effect of the time of tumor promotion prior to the fasting period, the effect of continued administration of the promoting agent during the fasting period, and the effects of omission and addition of the same or other promoting agents or inhibitors of the stage of promotion during the refeeding period on the AHF number and growth. Since apoptosis is reportedly a principal mechanism in the loss of cells from AHF upon removal of the promoting stimulus, as well as in liver on acute fasting, we will investigate both in vivo and in hepatocyte culture in normal hepatocytes and those of AHF levels of the growth factors, TGF-(, HGF, and TGF-(1, as well as TNF-(, and their receptors during and following the period of fasting and promoting agent removal. The effect of fasting on the expression of members of the Bcl-2 and Bax gene families will also be investigated. From these studies we hope to better establish the cell biology of the stage of initiation and develop a better understanding of mechanisms involved in the reversibility of the stage of tumor promotion as induced by a combination of removal of the promoting agent and acute dietary restriction in the form of fasting.

描述：研究中概述的研究的长期目标 建议是更好地理解细胞和分子机制 参与多阶段的启动和促进阶段 大鼠中的肝癌发生。 一系列五个实验将是 进行的是测试单个谷胱甘肽-S转移酶的论点 胎盘形式（PGST） - 阳性（+）肝细胞包括重要部分 启动细胞种群。 在晋升阶段发生了变化 肝灶（AHF）仅占单个PGST+数量的1％ 肝细胞。 确定这种差异的原因将寻求 单个PGST+肝细胞的倍性特征以及 不同促进剂引起的AHF的表型分布。 这 在晋升阶段，AHF增长的运营可逆性将 可以通过合并4次后启动剂的去除来研究 几个月的给药，以及两个短期顺序的时间 禁食以在A内获得最有效的AHF损失 相对较短的时间。 急性损失涉及的参数 通过确定该过程，将研究AHF内AHF的肝细胞 禁食期的最有效格式，时间的影响 禁食期之前的肿瘤促进 在禁食期间给予促进剂， 遗漏的效果以及添加相同或其他促进剂或 在AHF的促进阶段的抑制剂 数量和增长。 据报道，由于凋亡是一种主要机制 除去促进刺激时，AHF的细胞丧失， 与急性禁食中的肝脏一样，我们将在体内和 正常肝细胞和AHF水平的肝细胞培养 增长因子TGF-（，HGF和TGF-（1，以及TNF-（及其） 禁食和促进剂期间和之后的受体 移动。 禁食对Bcl-2成员表达的影响 和Bax基因家族也将进行研究。 从这些研究中我们希望 更好地建立开始阶段的细胞生物学并发展 更好地理解涉及的机制 肿瘤促进的阶段，由去除的组合诱导 禁食形式促进剂和急性饮食限制。