Peraino C, Staffeldt E F, Carnes B A, Ludeman V A, Blomquist J A, Vesselinovitch S D
IARC Sci Publ. 1984(56):37-55.
A new experimental system was used to examine the stages of chemically induced hepatic neoplasia in the rat. The treatment protocol involved the intraperitoneal injection of a single non-necrogenic dose of carcinogen [N-nitrosodiethylamine (NDEA) or benzo[a]pyrene (BP)] into male and female rats within one day after birth, followed by dietary exposure to promoter (0.05% phenobarbital) from weaning. Rats were killed at intervals, and their livers were examined for tumours and for histochemically detectable foci of altered hepatocytes. Six histochemical markers were used. Through serial frozen-sectioning techniques and computer-assisted image analysis, foci containing between one and six markers were identified, and their average sizes were calculated. The same complement of histochemical tests was applied to the primary hepatic tumours observed in this study. The data showed that (1) the new treatment protocol was highly efficient in foci and tumour production; (2) growth rates and incidence levels of foci were directly related to hepatocarcinogenic effectiveness (NDEA greater than BP), whereas both carcinogens had similar effects on foci phenotypic properties; (3) after their formation, foci at a given level of phenotypic complexity did not become progressively more complex; (4) incidence levels of foci were sex-dependent (females greater than males), but growth rates of foci were the same for both sexes; (5) growth rates and growth capacities (ranges of possible growth rates) of foci were directly related to phenotypic complexity levels of foci; (6) frequencies and phenotypic complexities of foci were inversely related; the reverse was true for tumours, although 10% of the tumours were relatively simple (three markers or fewer); (7) marker frequency distribution patterns were completely different in foci and in tumours. From these observations, we suggest that the foci are not direct tumour progenitors but, instead, are manifestations of a mosaic of subtumorigenic effects of the carcinogenic stimulus on cellular functions associated with the control of cell division and phenotypic character. The observed foci and tumour characteristics suggest that these carcinogen-induced cellular changes define elements of the mechanism whereby a specific neoplastic transformation site is rendered more accessible to carcinogenic attack.
一种新的实验系统被用于研究大鼠化学诱导性肝肿瘤形成的各个阶段。治疗方案包括在出生后一天内对雄性和雌性大鼠腹腔注射单一非致死剂量的致癌物[N-亚硝基二乙胺（NDEA）或苯并[a]芘（BP）]，随后从断奶开始给予促癌剂（0.05%苯巴比妥）饮食暴露。大鼠在不同时间点处死，检查其肝脏是否有肿瘤以及是否存在组织化学可检测到的肝细胞改变灶。使用了六种组织化学标记物。通过连续冰冻切片技术和计算机辅助图像分析，识别出含有一至六种标记物的病灶，并计算其平均大小。将相同的组织化学检测方法应用于本研究中观察到的原发性肝肿瘤。数据表明：（1）新的治疗方案在病灶和肿瘤产生方面效率很高；（2）病灶的生长速度和发生率与肝癌致癌效力直接相关（NDEA大于BP），而两种致癌物对病灶表型特性的影响相似；（3）病灶形成后，在给定表型复杂性水平下的病灶不会逐渐变得更复杂；（4）病灶的发生率存在性别差异（雌性大于雄性），但病灶的生长速度在两性中相同；（5）病灶的生长速度和生长能力（可能的生长速度范围）与病灶的表型复杂性水平直接相关；（6）病灶的频率和表型复杂性呈负相关；肿瘤情况则相反，尽管10%的肿瘤相对简单（三种标记物或更少）；（7）标记物频率分布模式在病灶和肿瘤中完全不同。基于这些观察结果，我们认为病灶不是直接的肿瘤祖细胞，而是致癌刺激对与细胞分裂控制和表型特征相关的细胞功能产生的亚致癌效应的镶嵌表现。观察到的病灶和肿瘤特征表明，这些致癌物诱导的细胞变化定义了一种机制的要素，通过该机制特定的肿瘤转化位点更容易受到致癌攻击。
