Rogler C E, Chisari F V
Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York.
Semin Liver Dis. 1992 Aug;12(3):265-78. doi: 10.1055/s-2007-1007398.
For colorectal carcinomas, the rate of tumor development is proportional to the fourth to sixth power of elapsed time, suggesting that four to six independent events are necessary. Although similar calculations have not been made for HBV-associated HCCs, it is likely that this is also the case for HCCs, since individuals with persistent HBV infection do not usually develop HCC until they are 45 or greater years old. As evidence for specific genetic and epigenetic changes in HCCs accumulate, the important players in multistep hepatocarcinogenesis are becoming clearer. However, even though Myc family oncogenes are clearly implicated in woodchuck HCC, similar integrations have not been found in human HCCs. Therefore, although rodent and human systems have many similarities, we must realize that important differences may also exist. Regarding tumor suppressor genes, the evidence for p53 alterations in HCC is strong. A growing body of evidence suggests further that alterations in the retinoblastoma gene and one or more tumor suppressor genes on chromosome 11 are also involved in HCC. HBV integrations may certainly play a role in the generation of chromosome aberrations leading to loss of tumor suppressor alleles, since chromosomes 11 and 17 are the most common integration sites. Finally, the role of X proteins as participants in malignant transformation has been demonstrated for certain immortalized, nontransformed hepatocytes. Altered autocrine mechanisms of cell growth control, possibly involving IGF-II, are clearly implicated in HCC. Paracrine mechanisms for the control of hepatocyte growth and differentiated functions may also be altered as a result of the synthesis and secretion of a complex array of interleukins, HGF, and basic and acidic FGFs by cells in the inflammatory and cirrhotic lesions of precancerous livers. Whether the order of molecular changes in the hepatocyte is important for malignant progression is presently not clear. What is clear, however, is that hepatocarcinogenesis involves alterations in the concerted action of protooncogenes, growth factor, and tumor suppressor genes. How these factors interact will provide a more complete understanding of the mechanism or mechanisms of hepatic oncogenesis.
对于结直肠癌，肿瘤发生的速率与经过时间的四次方至六次方成正比，这表明需要四到六个独立事件。虽然尚未对乙肝相关肝癌进行类似计算，但肝癌可能也是这种情况，因为持续感染乙肝的个体通常直到45岁及以上才会发生肝癌。随着肝癌中特定基因和表观遗传变化的证据不断积累，多步骤肝癌发生过程中的重要参与者正变得越来越清晰。然而，尽管Myc家族癌基因显然与土拨鼠肝癌有关，但在人类肝癌中尚未发现类似的整合情况。因此，尽管啮齿动物和人类系统有许多相似之处，但我们必须认识到也可能存在重要差异。关于肿瘤抑制基因，肝癌中p53改变的证据很充分。越来越多的证据进一步表明，视网膜母细胞瘤基因以及11号染色体上一个或多个肿瘤抑制基因的改变也与肝癌有关。乙肝整合肯定可能在导致肿瘤抑制等位基因缺失的染色体畸变产生中起作用，因为11号和17号染色体是最常见的整合位点。最后，对于某些永生化、未转化的肝细胞，已证明X蛋白作为恶性转化参与者的作用。细胞生长控制的自分泌机制改变，可能涉及胰岛素样生长因子-II，显然与肝癌有关。由于癌前肝脏炎症和肝硬化病变中的细胞合成和分泌一系列复杂的白细胞介素、肝细胞生长因子以及碱性和酸性成纤维细胞生长因子，肝细胞生长和分化功能的旁分泌控制机制也可能发生改变。目前尚不清楚肝细胞中分子变化的顺序对恶性进展是否重要。然而，清楚的是，肝癌发生涉及原癌基因、生长因子和肿瘤抑制基因协同作用的改变。这些因素如何相互作用将使我们对肝脏肿瘤发生的机制有更全面的了解。
