Animal Models of Hepatocellular Carcinoma: Current Applications in Clinical Research

Abstract

In the last decade, relevant advances have occurred in the treatment of hepatocellular carcinoma (HCC), with novel drugs entering the clinical practice, among which tyrosine kinase inhibitors (TKIs) such as lenvatinib, cabozantinib and regorafenib, and immune checkpoint inhibitors (ICPIs) either alone or in combination with VEGF inhibitors. Clinical trials have driven the introduction of such novel molecules into the clinics but, at present, no biomarker drives the choice of first-line options, which relies only upon clinical and imaging assessment. Remarkably, clinical and imaging-based evaluations do not consider the huge heterogeneity of HCC and do not allow to realize the potential of personalized treatments. Preclinical research still does not inform the design of clinical trials, even though many animal models mimicking specific subgroups of HCC are available and might provide relevant information. Although animal models directly informing the clinical practice, such as patients-derived xenografts, are not used to help the choice of treatment in advanced HCC, however, the preclinical research can count on a wide range of valuable models. Here we will review some HCC models which might turn informative for specific questions in defined patient subgroups, and we will describe recent preclinical studies for the mechanistic evaluation of immunotherapy-based treatment approaches. To this aim, we will mainly focus on two issues: (i) HCC models informative on NAFLD-NASH HCC and (ii) HCC models helping to elucidate mechanisms underneath immunotherapy. We have chosen these two settings since they represent, respectively, the most rapidly arising cause of chronic liver disease (CLD) and HCC in western countries and the most promising therapeutic option for advanced HCC.

Obesity, non-alcoholic fatty liver disease and hepatocellular carcinoma: current status and therapeutic targets

“…In this model, mice are given a low-dose of STZ through intraperitoneal or subcutaneous injection shortly after birth and then feed HFD at 4 weeks of age. This model leads to simple steatosis after 5 weeks, NASH after 7 weeks, followed by fibrosis after 9 weeks, adenomas after 12 weeks and evidence of HCC at approximately 16 weeks ( 196 ). The STAM model therefore rapidly induces NASH, however, the mice are lean and have insulin deficiency.…”

“…In this model, the treated mice exhibit obesity and hepatic steatosis after 8 weeks, IR, lobular inflammation and fibrosis after 12 weeks, and develop into HCC within 20 weeks ( 200 ). DEN is a procarcinogen and may be relevant in carcinogenesis, this may represent a substantial difference from its human counterpart ( 196 ).…”

Models of Liver Cancer in Vivo

“…Известно, что инбредные линии мышей различаются по своей способности к формированию спонтанных неоплазий печени [6]. Так, мыши линии C3H и CBA в высокой степени предрасположены к спонтанным опухолям печени, тогда как у линий LP, 129, DBA/2, BALB/c и C57BL отмечается низкая частота образования опухолей, однако данная информация была опубликована в конце 1930-х -начале 1940-х гг.…”

“…Так, мыши линии C3H и CBA в высокой степени предрасположены к спонтанным опухолям печени, тогда как у линий LP, 129, DBA/2, BALB/c и C57BL отмечается низкая частота образования опухолей, однако данная информация была опубликована в конце 1930-х -начале 1940-х гг. и на сегодняшний день могла утерять актуальность [6]. Данная модель рассматривается как плохо контролируемая и непредсказуемая система с низкой частотой заболеваемости, которая в настоящее время практически не используется, тем не менее, она может быть полезна для работ по идентификации генов предрасположенности к опухолям печени [7].…”

Lipidomic signatures of NAFLD/NASH progression to HCC in a murine model with conditional hepatocyte-specific Pten deletion

“…Liver-specific Pten knockout mice showed extensive hepatomegaly, with steatosis at 10 weeks of age, steatohepatitis with fibrosis was observed around 40 weeks. At 40-60 weeks, the incidence of spontaneous hepatoadenoma and HCC can reach 70-100% [19][20][21]. Thus, a unique feature of the liver-specific Pten-deficient mouse model is the recapitulation of the pathological processes from NASH to HCC in patients, histologically.…”