University Hospital Gasthuisberg Leuven, Belgium.
Acta Pharmacol Sin. 2010 Nov;31(11):1409-20. doi: 10.1038/aps.2010.142. Epub 2010 Oct 18.
Hepatocellular carcinoma (HCC) is a major health problem worldwide responsible for 500 000 deaths annually. A number of risk factors are associated with either the induction of the disease or its progression; these include infection with hepatitis B or C virus, alcohol consumption, non-alcoholic steatohepatitis and certain congenital disorders. In around 80% of the cases, HCC is associated with cirrhosis or advanced fibrosis and with inflammation and oxidative stress. In this review we focus firstly on the different risk factors for HCC and summarize the mechanisms by which each is considered to contribute to HCC. In the second part we look at the molecular processes involved in cancer progression. HCC development is recognized as a multistep process that normally develops over many years. Over this period several mutations accumulate in the cell and that stimulate malign transformation, growth, and metastatic behavior. Over the recent years it has become evident that not only the tumor cell itself but also the tumor microenviroment plays a major role in the development of a tumor. There is a direct link between the role of inflammation and cirrhosis with this microenviroment. Both in vitro and in vivo it has been shown that tumor formation and metastatic properties are linked to epithelial-mesenchymal transition (EMT), a process by which facillitates the tumor cell's attempts to migrate to a more favourable microenviroment. Several groups have analyzed the gene expression in HCC and its surrounding tissue by microarray and this has resulted in the molecular classification into a distinct number of classes. Here we also found a role for hypoxia induced gene expression leading to a clinically more aggressive gene expression in HCC. Molecular analysis also helped to identify important cellular pathways and possible therapeutic targets. The first molecule that in this way has shown clinical application for liver cancer is the multikinase inhibitor sorafenib, others are currently in different stages of clinical studies like the mTOR inhibitor everolimus.
肝细胞癌（HCC）是全球范围内的一个主要健康问题，每年导致 500 000 人死亡。许多危险因素与疾病的诱导或进展有关；这些因素包括乙型肝炎或丙型肝炎病毒感染、酒精摄入、非酒精性脂肪性肝炎和某些先天性疾病。在大约 80%的病例中，HCC 与肝硬化或晚期纤维化以及炎症和氧化应激有关。在这篇综述中，我们首先关注 HCC 的不同危险因素，并总结了每种危险因素被认为有助于 HCC 的机制。在第二部分，我们研究了癌症进展所涉及的分子过程。HCC 的发展被认为是一个多步骤的过程，通常需要多年的时间。在此期间，细胞中会积累多个突变，从而刺激恶性转化、生长和转移行为。近年来，人们已经清楚地认识到，不仅肿瘤细胞本身，而且肿瘤微环境在肿瘤的发展中起着重要作用。炎症和肝硬化与这种微环境之间存在直接联系。无论是在体外还是体内，都已经表明肿瘤的形成和转移特性与上皮-间充质转化（EMT）有关，这一过程有助于肿瘤细胞试图迁移到更有利的微环境。有几个小组通过微阵列分析了 HCC 及其周围组织的基因表达，并将其分子分类为许多不同的类别。在这里，我们还发现了缺氧诱导基因表达在 HCC 中导致更具临床侵袭性的基因表达的作用。分子分析还有助于确定重要的细胞途径和可能的治疗靶点。以这种方式，第一个在临床上应用于肝癌的分子是多激酶抑制剂索拉非尼，其他分子如 mTOR 抑制剂依维莫司目前正处于不同的临床研究阶段。
