Division of Experimental Pathology, Department of Pathology, University of Pittsburgh Medical Center and University of PittsburghPittsburgh, PAUSA.
Gene Expr. 2020 Nov 11;20(2):139-145. doi: 10.3727/105221620X15913805462476. Epub 2020 Jun 5.
The incidence of hepatocellular cancer (HCC) is gradually rising. HCC occurs as a sequela to various chronic liver diseases and ensuing cirrhosis. There have been many therapies approved for unresectable HCC in the last 5 years, including immune checkpoint inhibitors, and the overall response rates have improved. However, there are many cases that do not respond, and personalized medicine is lacking, making HCC an unmet clinical need. Generation of appropriate animal models have been key to our understanding of HCC. Based on the overall concept of hepatocarcinogenesis, two major categories of animal models are discussed herein that can be useful to address specific questions. One category is described as the outside-in model of HCC and is based on the premise that it takes decades of hepatocyte injury, death, wound healing, and regeneration to eventually lead to DNA damage and mutations in a hepatocyte, which initiates tumorigenesis. Several animal models have been generated, which attempt to recapitulate this complex tissue damage and cellular interplay through genetics, diets, and toxins. The second category is the inside-out model of HCC, where clinically relevant genes can be coexpressed in a small subset of hepatocytes to yield a tumor, which matches HCC subsets in gene expression. This model has been made possible in part by the widely available molecular characterization of HCC, and in part by modalities like sleeping beauty transposon/transposase, Crispr/Cas9, and hydrodynamic tail vein injection. These two categories of HCC have distinct pros and cons, which are discussed in this Thinking Out Loud article.
肝细胞癌 (HCC) 的发病率正在逐渐上升。HCC 是各种慢性肝病和随之而来的肝硬化的后遗症。在过去的 5 年中，已经有许多针对不可切除 HCC 的疗法获得批准，包括免疫检查点抑制剂，整体缓解率有所提高。然而，仍有许多病例没有反应，缺乏个性化治疗，这使得 HCC 成为一个未满足的临床需求。合适的动物模型的生成是我们理解 HCC 的关键。基于 HCC 发生的总体概念，本文讨论了两种主要的动物模型类别，它们可用于解决特定问题。一种类别被描述为 HCC 的“外向型”模型，其前提是需要数十年的肝细胞损伤、死亡、伤口愈合和再生，最终导致肝细胞中的 DNA 损伤和突变，从而引发肿瘤发生。已经生成了几种动物模型，它们试图通过遗传学、饮食和毒素来重现这种复杂的组织损伤和细胞相互作用。第二类是 HCC 的“内向型”模型，其中临床相关基因可以在一小部分肝细胞中共同表达，从而产生与 HCC 基因表达相匹配的肿瘤。这种模型的部分原因是 HCC 的广泛分子特征，部分原因是诸如睡眠美丽转座子/转座酶、Crispr/Cas9 和水力尾静脉注射等方式。这两种 HCC 类别各有优缺点，本文将对此进行讨论。
