Wang J H, Hinrichsen L I, Whitacre C M, Cechner R L, Sudilovsky O
Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106.
Cancer Res. 1990 Dec 1;50(23):7571-6.
In individual altered hepatic foci (AHF), aneuploidy occurs before malignant changes can be diagnosed histologically (O. Sudilovsky and T. K. Hei. Fed. Proc., 42:2225, 1983). In the current experiments Sprague-Dawley rats of both sexes were given i.p. injections of diethylnitrosamine (50 mg/kg body weight) 18 h after partial hepatectomy and were given a choline-sufficient diet (CS) for 1 wk. Four treatment groups were then formed and fed CS, CS containing 0.05% phenobarbital (PHB), choline-deficient diet (CD), and CD with 0.05% PHB. An extra female group received infusions of saline after the hepatectomy and fared CD. Control animals were partially hepatectomized, inoculated i.p. with saline, and placed on CS. The rats were sacrificed 16 wk later, liver sections were stained with a combined Feulgen-gamma-glutamyl transpeptidase stain, and the DNA content of gamma-glutamyl transpeptidase-positive foci was measured cytospectrophotometrically. There were no AHF in the control animals. Hepatocytes from control livers and cells adjacent to foci in treated livers had peaks corresponding to the 2C, 4C, and 8C range. In AHF the ploidy, however, was predominantly diploid, tetraploid, or heterogeneous. The ratio of diploid to tetraploid cells in foci of rats provided with CS + PHB was 5.5 and in those supplied with CD + PHB was 0.09. This suggested that dietary manipulations change the nuclear DNA distribution of AHF. Aneuploidy was also present, as expected, in 4 of 33 AHF in the animals placed on CD + PHB. It was observed as well in 2 of 26 AHF of rats given CD but in none of the 20 AHF fed CS + PHB. These data indicate that CD (which acts as both initiator and promoter) may be responsible for the appearance of aneuploidy. A general model, based on these results and the clonality of each individual focus, is proposed for the development of cells through the preneoplastic stage.
在单个改变的肝病灶（AHF）中，非整倍体在组织学上可诊断出恶性变化之前就已出现（O. Sudilovsky和T.K. Hei。《联邦程序》，42:2225，1983）。在当前实验中，对两性的Sprague-Dawley大鼠在部分肝切除术后18小时腹腔注射二乙基亚硝胺（50毫克/千克体重），并给予胆碱充足的饮食（CS）1周。然后形成四个治疗组，分别喂食CS、含0.05%苯巴比妥（PHB）的CS、胆碱缺乏饮食（CD）以及含0.05% PHB的CD。另外一组雌性大鼠在肝切除术后接受生理盐水输注并喂食CD。对照动物进行部分肝切除，腹腔注射生理盐水，并给予CS。16周后处死大鼠，肝切片用Feulgen-γ-谷氨酰转肽酶联合染色，并用细胞分光光度计测量γ-谷氨酰转肽酶阳性病灶的DNA含量。对照动物中没有AHF。对照肝脏的肝细胞以及处理过的肝脏中病灶附近的细胞具有对应于2C、4C和8C范围的峰值。然而，在AHF中，倍性主要为二倍体、四倍体或异质性。给予CS + PHB的大鼠病灶中二倍体细胞与四倍体细胞的比例为5.5，给予CD + PHB的大鼠病灶中该比例为0.09。这表明饮食操作改变了AHF的核DNA分布。正如预期的那样，在给予CD + PHB的动物的33个AHF中有4个出现了非整倍体。在给予CD的大鼠的26个AHF中有2个也观察到了非整倍体，但在给予CS + PHB的20个AHF中均未观察到。这些数据表明CD（既是启动剂又是促进剂）可能是导致非整倍体出现的原因。基于这些结果以及每个单个病灶的克隆性，提出了一个关于细胞通过癌前阶段发展的通用模型。
