Sepulveda A R, Finegold M J, Smith B, Slagle B L, DeMayo J L, Shen R F, Woo S L, Butel J S
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030.
Cancer Res. 1989 Nov 1;49(21):6108-17.
alpha-1-Antitrypsin (AAT) is the major antiprotease in human plasma; it is synthesized primarily in hepatocytes and to a lesser extent in several nonhepatic tissues. Under the control of regulatory elements of the human AAT gene, expression of SV40-large tumor antigen (T-ag) in transgenic mice occurred in the liver, stomach, pancreas, and kidney. Among seven founder transgenic animals, six developed liver carcinoma, four showed gastric neoplasia, and one developed pancreatic carcinoma. In three animals the kidneys showed glomerular or tubular epithelial hyperplasia but no malignancy. A stable transgenic line, 1812, was established. Members of this line reproducibly develop liver tumors by 10 weeks of age but do not exhibit any phenotypic changes in other tissues. Histological changes leading to liver tumor formation occurred with predictable kinetics and could be classified into four distinct stages: (a) embryonal/fetal stage, no recognizable histological changes; (b) newborn to 2 weeks of age, hyperplastic hepatocytes with reduced amounts of cytoplasm but no nuclear alterations; (c) between 3 and 8 weeks of age, diffuse liver cell dysplasia without observable tumor nodules; and (d) 8 weeks of age and thereafter, hepatocellular carcinomas in a background of liver dysplasia. Embryonic and newborn liver tissue showed uniform, high level expression of T-ag in the majority of hepatocytes by immunohistochemistry, whereas the dysplastic and tumoral stages were characterized by considerable variation in both the intensity of T-ag staining and the proportion of T-ag-positive cells. Immunoprecipitation analyses showed that T-ag was complexed with cellular protein p53 in all tumor samples. This study showed that SV40 T-ag expression in the liver resulted in cellular hyperplasia and dysplasia; additional event(s) apparently were required for progression to neoplasia. Those cooperating events occurred with predictable kinetics. This transgenic mouse system displays several similarities with human liver disease and provides a practical model for the study of separate steps in hepatocarcinogenesis.
α-1抗胰蛋白酶（AAT）是人类血浆中的主要抗蛋白酶；它主要在肝细胞中合成，在几种非肝组织中合成较少。在人类AAT基因调控元件的控制下，转基因小鼠中SV40大T抗原（T-ag）在肝脏、胃、胰腺和肾脏中表达。在七只转基因奠基动物中，六只发生了肝癌，四只出现了胃肿瘤，一只发生了胰腺癌。在三只动物中，肾脏出现了肾小球或肾小管上皮增生，但无恶性病变。建立了一个稳定的转基因品系1812。该品系的成员在10周龄时可重复性地发生肝肿瘤，但在其他组织中未表现出任何表型变化。导致肝肿瘤形成的组织学变化以可预测的动力学发生，可分为四个不同阶段：（a）胚胎/胎儿期，无明显的组织学变化；（b）新生至2周龄，肝细胞增生，细胞质减少，但无核改变；（c）3至8周龄之间，弥漫性肝细胞发育异常，无可见肿瘤结节；（d）8周龄及以后，在肝发育异常背景下出现肝细胞癌。免疫组织化学显示，胚胎和新生肝组织在大多数肝细胞中呈现均匀、高水平的T-ag表达，而发育异常和肿瘤阶段的特征是T-ag染色强度和T-ag阳性细胞比例均有显著差异。免疫沉淀分析表明，在所有肿瘤样本中，T-ag与细胞蛋白p53形成复合物。这项研究表明，肝脏中SV40 T-ag的表达导致细胞增生和发育异常；进展为肿瘤显然还需要其他事件。这些协同事件以可预测的动力学发生。这个转基因小鼠系统与人类肝脏疾病有几个相似之处，为研究肝癌发生的各个步骤提供了一个实用模型。
