Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, 3010, Australia.
The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, 3010, Australia.
BMC Cancer. 2019 Jul 18;19(1):707. doi: 10.1186/s12885-019-5916-6.
Hepatitis B virus (HBV) is the leading cause of liver cancer, but the mechanisms by which HBV causes liver cancer are poorly understood and chemotherapeutic strategies to cure liver cancer are not available. A better understanding of how HBV requisitions cellular components in the liver will identify novel therapeutic targets for HBV associated hepatocellular carcinoma (HCC).
The development of HCC involves deregulation in several cellular signalling pathways including Wnt/FZD/β-catenin, PI3K/Akt/mTOR, IRS1/IGF, and Ras/Raf/MAPK. HBV is known to dysregulate several hepatocyte pathways and cell cycle regulation resulting in HCC development. A number of these HBV induced changes are also mediated through the Wnt/FZD/β-catenin pathway. The lack of a suitable human liver model for the study of HBV has hampered research into understanding pathogenesis of HBV. Primary human hepatocytes provide one option; however, these cells are prone to losing their hepatic functionality and their ability to support HBV replication. Another approach involves induced-pluripotent stem (iPS) cell-derived hepatocytes. However, iPS technology relies on retroviruses or lentiviruses for effective gene delivery and pose the risk of activating a range of oncogenes. Liver organoids developed from patient-derived liver tissues provide a significant advance in HCC research. Liver organoids retain the characteristics of their original tissue, undergo unlimited expansion, can be differentiated into mature hepatocytes and are susceptible to natural infection with HBV.
By utilizing new ex vivo techniques like liver organoids it will become possible to develop improved and personalized therapeutic approaches that will improve HCC outcomes and potentially lead to a cure for HBV.
乙型肝炎病毒（HBV）是肝癌的主要病因，但 HBV 导致肝癌的确切机制尚不清楚，也没有针对肝癌的化疗策略。更好地了解 HBV 如何在肝脏中征用细胞成分，将为 HBV 相关的肝细胞癌（HCC）确定新的治疗靶点。
HCC 的发展涉及几个细胞信号通路的失调，包括 Wnt/FZD/β-catenin、PI3K/Akt/mTOR、IRS1/IGF 和 Ras/Raf/MAPK。HBV 已知会失调几个肝细胞通路和细胞周期调节，导致 HCC 的发展。HBV 诱导的许多这些变化也是通过 Wnt/FZD/β-catenin 途径介导的。缺乏合适的人类肝脏模型来研究 HBV，阻碍了对 HBV 发病机制的研究。原代人肝细胞提供了一种选择；然而，这些细胞容易失去其肝功能和支持 HBV 复制的能力。另一种方法涉及诱导多能干细胞（iPS）细胞衍生的肝细胞。然而，iPS 技术依赖于逆转录病毒或慢病毒进行有效的基因传递，并存在激活一系列癌基因的风险。源自患者肝脏组织的肝类器官在 HCC 研究中取得了重大进展。肝类器官保留了其原始组织的特征，可无限扩增，可分化为成熟肝细胞，并易受 HBV 的自然感染。
通过利用新的离体技术，如肝类器官，将有可能开发出改进的、个性化的治疗方法，改善 HCC 的预后，并可能为 HBV 带来治愈的希望。
