Ogawa K, Solt D B, Farber E
Cancer Res. 1980 Mar;40(3):725-33.
This study was undertaken to answer the following question. Is the phenotypic diversity that is characteristic of hepatocellular carcinomas acquired early during carcinogenesis, or is it more likely to be a property added late in the process? This question was posed using a new model for the sequential analysis of hepatocarcinogenesis. This model utilizes a single initiating dose of a carcinogen, such as diethylnitrosamine, followed by the selective stimulation of the rare, initiated hepatocyte to proliferate under conditions in which the proliferation of the majority of uninitiated hepatocytes is inhibited. Under these conditions, discrete early foci of altered hepatocytes and hyperplastic foci and nodules are quite well synchronized for about 10 to 12 cell cycles, after which the synchrony is progressively lost. As phenotypic expressions, cell proliferation, judged by radioautography after the administration of [3H]thymidine and the activities of four enzyme markers, two positive ones, gamma-glutamyltranspeptidase and DT-diaphorase, and two negative ones, glucose-6-phosphatase and adenosine triphosphatase, all judged histochemically, were used. At the earliest time of observation, 7 days, and at subsequent time points thereafter, all histologically recognizable foci and nodules showed variable degrees of staining for each enzyme activity. Prior to selection, gamma-glutamyltranspeptidase activity was much more consistent than was that of the others; however, during and after the selection, the four markers showed almost the same consistency among developing lesions. During the period of selection, between 80 and 90% of hepatocytes in the proliferating nodules were labeled with [3H]thymidine, while only an occasional labeled hepatocyte was seen in the foci prior to selection and in the nodules following selection. In the postselection period, the majority of nodules acquired the histochemical and architectural properties of normal liver, while a minority persisted as typical hyperplastic nodules. This study suggests that phenotypes of carcinogen-altered hepatocytes are variable, but whether the histochemical diversity among the lesions is merely due to environmental variation or is a reflection of a more basic genotypic variability remains a fundamental question.
本研究旨在回答以下问题。肝细胞癌所特有的表型多样性是在致癌过程早期获得的，还是更有可能是在该过程后期才出现的特性？这个问题是通过一种用于肝癌发生顺序分析的新模型提出的。该模型利用单次致癌剂起始剂量，如二乙基亚硝胺，随后在大多数未起始肝细胞的增殖受到抑制的条件下，选择性刺激罕见的起始肝细胞进行增殖。在这些条件下，肝细胞改变的离散早期病灶以及增生性病灶和结节在大约10到12个细胞周期内相当好地同步，之后同步性逐渐丧失。作为表型表达，使用了细胞增殖（通过给予[3H]胸腺嘧啶核苷后的放射自显影判断）以及四种酶标志物的活性，其中两种为阳性，即γ-谷氨酰转肽酶和DT-黄递酶，两种为阴性，即葡萄糖-6-磷酸酶和三磷酸腺苷酶，所有这些均通过组织化学判断。在最早观察时间点（7天）以及此后的后续时间点，所有组织学上可识别的病灶和结节对每种酶活性均显示出不同程度的染色。在选择之前，γ-谷氨酰转肽酶活性比其他酶活性更为一致；然而，在选择期间及之后，这四种标志物在发育中的病变中显示出几乎相同的一致性。在选择期间，增殖结节中80%至90%的肝细胞被[3H]胸腺嘧啶核苷标记，而在选择前的病灶和选择后的结节中仅偶尔可见标记的肝细胞。在选择后阶段，大多数结节获得了正常肝脏的组织化学和结构特性，而少数结节则持续为典型的增生性结节。本研究表明，致癌物改变的肝细胞的表型是可变的，但病变之间的组织化学多样性仅仅是由于环境变化还是更基本的基因型变异性的反映，仍然是一个基本问题。
