Quantitation of multistage carcinogenesis in rat liver
Quantitation of multistage carcinogenesis in rat liver
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DOI：
10.1177/019262339602400116
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发表时间：
1996-01-01
影响因子：
1.5
通讯作者：
Campbell, H
中科院分区：
文献类型：
--
作者：
Pitot, HC;Dragan, YP;Campbell, H
一个充分表征的多阶段癌发生模型是大鼠肝癌发生模型。在该系统中，起始、促进和进展阶段的组织病理学以及细胞和分子生物学已得到不同程度的阐明。假定单个起始肝细胞通过其肝癌发生的普遍标志物谷胱甘肽-S-转移酶 pi (GSTP) 的表达来鉴定。使用亚致癌剂量的二乙基亚硝胺 (DEN) 后 14 天内，0.5-1.0 X 10(6) GSTP 阳性“启动”肝细胞发育。在长期给予苯巴比妥等促进剂 4-8 个月的动物中，大约 1% 的这些细胞克隆性地发育为改变的肝病灶 (AHF)。 AHF 内的肝细胞在促进阶段表现出正常的二倍体核型，但根据促进剂的化学性质，表现出各种表型。持续给予促进剂导致肝细胞癌很少发生；然而，在促进阶段施用完全致癌剂或进展剂会导致大量的肝肿瘤。为了更准确地定量进展阶段的发展，已经寻找针对该阶段的选择性标记。转化生长因子-α（TGF-α）似乎是进展的标志。大约 500 个 TGF-α 阳性病变在开始和持续促进后自发形成，通常在 GSTP 阳性 AHF 内，但施用单剂量的进展剂（例如乙基亚硝基脲）可能会使该数字增加 3 倍或更多。一些药物，例如伽马射线和羟基脲，当以单次或几个紧密间隔的多次剂量施用时，不会导致TGF-α阳性病变数量增加，但其生长速度显着增加。通过使用定量体视学监测基因表达，可以对肝癌发生的各个阶段进行足够详细的分析和量化，以便将动物数据用于生物数学建模，以开发更准确的模型来估计人类癌症风险。
A well characterized model of multistage carcinogenesis is that of hepatocarcinogenesis in the rat. The histopathology as well as the cell and molecular biology of the stages of initiation, promotion, and progression have been elucidated to varying degrees in this system. Putatively single initiated hepatocytes are identified by their expression of the ubiquitous marker of hepatocarcinogenesis, glutathione-S-transferase pi (GSTP). 0.5-1.0 X 10(6) GSTP-positive ''initiated'' hepatocytes developed within 14 days after initiation with a subcarcinogenic dose of diethylnitrosamine (DEN). Approximately 1% of these cells develop clonally into altered hepatic foci (AHF) in animals administered promoting agents, such as phenobarbital, chronically for 4-8 mo. Hepatocytes within AHF during the stage of promotion exhibit normal diploid karyotypes but various phenotypes depending on the chemical nature of the promoting agent. Continued administration of the promoting agent results in the infrequent development of hepatocellular carcinomas; however, administration of a complete carcinogen or a progressor agent during the stage of promotion results in substantial numbers of hepatic neoplasms. In order to quantitate the development of the stage of progression more accurately, markers selective for this stage have been sought. Transforming growth factor-alpha (TGF-alpha) appears to be such a marker of progression. About 500 TGF-alpha-positive lesions develop spontaneously following initiation and continued promotion, usually within GSTP-positive AHF, but administration of a single dose of a progressor agent such as ethylnitrosourea may increase this number 3-fold or more. Some agents such as gamma radiation and hydroxyurea, when administered as single or a few closely spaced multiple doses, result in no increased number in TGF-a-positive lesions but a markedly enhanced increase in their growth rate. By monitoring gene expression using quantitative stereology, the stages of hepatocarcinogenesis can be analyzed and quantified in sufficient detail so that the animal data can be utilized in biomathematical modeling to develop more accurate models for estimation of human cancer risks.