文章：

肝癌细胞起源的功能和基因解构

Functional and genetic deconstruction of the cellular origin in liver cancer

原文发布日期：2015-10-23

DOI: 10.1038/nrc4017

类型: Review Article

开放获取: 否

要点：

1. Primary liver cancers (PLCs), including the most common subtypes, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), are characterized by molecular and phenotypic heterogeneity, which impedes therapeutic progress.
2. Chronic inflammation of the hepatic microenvironment is a hallmark feature of the majority of PLCs.
3. Although no clear oncogene addiction is recognized in PLCs, most common genetic alterations are detected in key cancer genes, such as TP53, WNT–CTNNB1 (which encodes β-catenin) and cell cycle-related genes. Other frequent changes are found in telomere maintenance (telomerase reverse transcriptase (TERT)), chromatin modifiers and inflammatory pathways.
4. Depending on the target cell of malignant transformation — that is, the cell of origin — a broad range of different phenotypes, from classic HCC and iCCA to mixed HCC–iCCA lesions, is observed.
5. The putative cellular origin in PLCs is diverse and not clearly defined. The differentiation state of the cell (or cells) of origin might determine the tumour biology.
6. Tumours that have progenitor cell traits display activation of adverse signalling pathways and a poor overall outcome.
7. Crosstalk between cancer cells and the altered hepatic tumour microenvironment can promote disease progression and might be a promising new therapeutic target.
8. The identification of novel cellular and molecular targets requires integrative approaches. Precision medicine using next-generation technologies (whole-exome and RNA sequencing, and methylation profiling) and integration of individual tumour characteristics will be needed to improve the dismal outcome for patients with PLC.

要点翻译：

1. 原发性肝癌（PLC）包括最常见的亚型——肝细胞癌（HCC）和肝内胆管癌（iCCA），其特点在于分子和表型的异质性，这种异质性阻碍了治疗进展。
2. 肝脏微环境的慢性炎症是大多数原发性肝癌的典型特征。
3. 尽管在原发性肝癌中未发现明确的癌基因成瘾现象，但在TP53、WNT-CTNNB1（编码β-连环蛋白）及细胞周期相关基因等关键癌症基因中检测到最常见的遗传改变。其他频繁出现的变异发生在端粒维持（端粒酶逆转录酶）、染色质修饰因子和炎症通路中。
4. 根据恶性转化的靶细胞（即起源细胞）不同，可观察到从经典肝细胞癌、肝内胆管癌到混合型肝癌等多种表型。
5. 原发性肝癌的推定细胞起源具有多样性且尚未明确界定。起源细胞的分化状态可能决定肿瘤的生物学特性。
6. 具有祖细胞特征的肿瘤显示不利信号通路的激活，并伴随总体预后不良。
7. 癌细胞与改变的肝脏肿瘤微环境之间的相互作用可促进疾病进展，这可能成为有前景的新治疗靶点。
8. 新型细胞和分子靶点的识别需要整合性研究方法。要改善原发性肝癌患者的不良预后，必须采用下一代技术（全外显子组测序、RNA测序和甲基化分析）进行精准医疗，并整合个体肿瘤特征。

英文摘要：

During the past decade, research on primary liver cancers has particularly highlighted the uncommon plasticity of differentiated parenchymal liver cells (that is, hepatocytes and cholangiocytes (also known as biliary epithelial cells)), the role of liver progenitor cells in malignant transformation, the importance of the tumour microenvironment and the molecular complexity of liver tumours. Whereas other reviews have focused on the landscape of genetic alterations that promote development and progression of primary liver cancers and the role of the tumour microenvironment, the crucial importance of the cellular origin of liver cancer has been much less explored. Therefore, in this Review, we emphasize the importance and complexity of the cellular origin in tumour initiation and progression, and attempt to integrate this aspect with recent discoveries in tumour genomics and the contribution of the disrupted hepatic microenvironment to liver carcinogenesis.

摘要翻译： 

在过去十年中，对原发性肝癌的研究特别强调了分化实质肝细胞（即肝细胞和胆管细胞（也称为胆管上皮细胞））的非凡可塑性、肝祖细胞在恶性转化中的作用、肿瘤微环境的重要性以及肝肿瘤的分子复杂性。尽管其他综述聚焦于促进原发性肝癌发生发展的遗传变异全景以及肿瘤微环境的作用，但肝癌细胞起源的关键重要性却远未被深入探讨。因此，本综述着重强调细胞起源在肿瘤启动与进展中的重要性与复杂性，并试图将这一方面与肿瘤基因组学的最新发现以及被破坏的肝脏微环境在肝癌发生中的贡献进行整合。

原文链接：

Functional and genetic deconstruction of the cellular origin in liver cancer