Lapis K, Sarosi I, Bocsi J, Thorgeirsson U P
First Institute of Pathology and Experimental Cancer Research, Semmelweis University of Medicine, Budapest, Hungary.
Lab Invest. 1995 Jun;72(6):748-59.
Although the general conception is that hepatocyte- and bile duct-specific cytokeratin (CK) patterns are maintained throughout the neoplastic process, there is an increasing number of reports showing deviation from the rule. CK patterns have been found to be similar across species barriers, so it could be expected that studying the CK patterns of experimentally induced liver tumors may contribute to the elucidation of these controversies.
A CK immunohistochemical study was carried out on histologic sections from hepatocellular carcinomas (HCCs) and preneoplastic lesions from 118 monkeys chronically dosed with diethylnitrosamine (DEN), using mAbs to CK 8, CK 18, CK 7, and CK 19.
Normal monkey hepatocytes differed from human hepatocytes by displaying CK 19 in addition to the CK 8/CK 18 pairs, whereas the CK pattern of the bile duct epithelial cells was identical in monkey and human liver. In association with DEN-induced hepatocarcinogenesis, heterogeneity was observed in the CK expression, both in the HCCs and nontumorous parts of the livers. The majority of the HCC cases displayed one of the three CKs normally present in monkey hepatocytes, whereas positive expression of all three CKs (CK 8, CK 18, CK 19) and negative CK 7 was preserved in only 19.5% of the HCC cases. A so-called mixed staining pattern (negative and positive CK staining within the same tumor) was observed in approximately one-fourth of the cases. There was no correlation between the preservation of the hepatocyte-specific CK pattern and the degree of differentiation, tumor grade, or DNA ploidy of the HCCs. In approximately 10% of the primary tumors, CK 7 was expressed in the entire parenchymal cell compartment of the HCC nodules, whereas it was present in a mixed staining pattern in more than half of the cases. In lung metastases, CK 7 was less common, only expressed in approximately one-fourth of the cases. Alterations in the CK patterns were observed in the nonneoplastic hepatocytes of the tumor-bearing monkeys. These included mixed staining patterns in which the CKs appeared as positive and negative regenerating nodules side-by-side. As was observed in the HCCs, CK 7 was more commonly expressed in the nonneoplastic parenchyma in the form of mixed staining pattern than the other three CKs. Moreover, CK 7-negative HCCs occurred more frequently in CK 7-negative livers than in positive livers. Proliferation of CK 7- and CK 19-positive bile ductules and bile ductular-like (oval) cells was frequently associated with the DEN-induced liver injury and hepatocarcinogenesis.
This is the first report on CK expression in monkey liver. The findings show that the hepatocyte specific pattern is not always preserved during DEN-induced hepatocarcinogenesis and may therefore not be useful in differentiating between HCCs and cholangiocarcinomas.
尽管一般认为肝细胞和胆管特异性细胞角蛋白（CK）模式在整个肿瘤形成过程中保持不变，但越来越多的报告显示存在例外情况。已发现CK模式在不同物种间具有相似性，因此可以预期，研究实验诱导的肝肿瘤的CK模式可能有助于阐明这些争议。
对118只长期给予二乙基亚硝胺（DEN）的猴子的肝细胞癌（HCC）和癌前病变的组织学切片进行CK免疫组织化学研究，使用针对CK 8、CK 18、CK 7和CK 19的单克隆抗体。
正常猴肝细胞除了具有CK 8/CK 18外，还表达CK 19，这与人类肝细胞不同，而胆管上皮细胞的CK模式在猴肝和人肝中是相同的。在DEN诱导的肝癌发生过程中，在HCC和肝脏的非肿瘤部分均观察到CK表达的异质性。大多数HCC病例显示出猴肝细胞中通常存在的三种CK之一，而仅19.5%的HCC病例中保留了所有三种CK（CK 8、CK 18、CK 19）的阳性表达且CK 7阴性。在大约四分之一的病例中观察到一种所谓的混合染色模式（同一肿瘤内CK染色呈阴性和阳性）。肝细胞特异性CK模式的保留与HCC的分化程度、肿瘤分级或DNA倍体之间没有相关性。在大约10%的原发性肿瘤中，CK 7在HCC结节的整个实质细胞区中表达，而在超过一半的病例中呈混合染色模式。在肺转移瘤中，CK 7较少见，仅在大约四分之一的病例中表达。在荷瘤猴子的非肿瘤肝细胞中观察到CK模式的改变。这些改变包括混合染色模式，其中CK表现为阳性和阴性再生结节并排出现。正如在HCC中观察到的那样，CK 7以混合染色模式在非肿瘤实质中比其他三种CK更常见。此外，CK 7阴性的HCC在CK 7阴性的肝脏中比在阳性肝脏中更频繁地出现。CK 7和CK 19阳性的胆小管和胆小管样（卵圆）细胞的增殖经常与DEN诱导的肝损伤和肝癌发生相关。
这是关于猴肝中CK表达的首次报告。研究结果表明，在DEN诱导的肝癌发生过程中，肝细胞特异性模式并不总是保留，因此可能无助于区分HCC和胆管癌。
