Satdarshan P Monga. “Inside-out” or “Outside-in”: Choosing the Right Model of Hepatocellular Cancer. Gene Expr. 2020 Jun 5. doi: 10.3727/105221620X15913805462476. Online ahead of print. PMID: 32503685. DOI: 10.3727/105221620X15913805462476
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 which 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 co-expressed 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.
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