Liver carcinogenesis: rodent models of hepatocarcinoma and cholangiocarcinoma

Abstract

Hepatocellular carcinoma and cholangiocarcinoma are primary liver cancers, both represent a growing challenge for clinicians due to their increasing morbidity and mortality. In the last few years a number of in vivo models of hepatocellular carcinoma and cholangiocarcinoma have been developed. The study of these models is providing a significant contribution in unveiling the pathophysiology of primary liver malignancies. They are also fundamental tools to evaluate newly designed molecules to be tested as new potential therapeutic agents in a pre-clinical set. Technical aspects of each model are critical steps, and they should always be considered in order to appropriately interpret the findings of a study or its planning. The purpose of this review is to describe the technical and experimental features of the most significant rodent models, highlighting similarities or differences between the corresponding human diseases. The first part is dedicated to the discussion of models of hepatocellular carcinoma, developed using toxic agents, or through dietary or genetic manipulations. In the second we will address models of cholangiocarcinoma developed in rats or mice by toxin administration, genetic manipulation and/or bile duct incannulation or surgery. Xenograft or syngenic models are also proposed.

Fig. 1

Representative images of macroscopic (top) and microscopic H&E staining (bottom) appearance of CDAA (choline-deficient and iron-supplemented l-amino acid-defined) + CCl₄ (carbon tetrachloride)-induced HCC (hepatocellular carcinoma) nodules. Large nodules are visible on the surface of the mice livers after 6 month of CDAA diet associated with low dose chronic injection of CCl₄ (0.2 mg/kg of body weight, once a week). From: De Minicis et al., unpublished observations (2011).

Fig. 2

(A) Representative image of macroscopic appearance of TAA (thioacetamide)-induced IH-CCA (intrahepatic-cholangiocarcinoma) nodules. White-yellowish large nodules/arrows are consistently visible on the surface of the liver of treated animals after 24 weeks of 0.03% TAA administration to rats (left). Representative image of lung metastases due to TAA-induced IH-CCA. Bottom segments of left lung from a 24 week 0.03% TAA administration show clear evidence of nodules, metastases from IH-CCA (right). (From: Marzioni and Nilsson, unpublished observations (2011)). (B) Representative image of H&E staining of a TAA-induced IH-CCA nodule. Tumour is composed of deranged and irregular, duct forming tissue, together with a dense inflammatory infiltrate (original magnification 20x, left). Representative image of Sirius-Red staining of a TAA-induced IH-CCA nodule. Tumour shows an intense desmoplastic reaction, stained in red, similar to human disease (original magnification 20x, right). (From: Marzioni and Nilsson, unpublished observations, 2011). (C) Mz-ChA-1 cells (a CCA cell line) implanted subcutaneously in the flank of a nude mouse give rise to a clearly visible tumour. Tumour changes in size can be easily measured over time (top). Enlarged view of the same nodule (bottom). (From: Francis and Alpini, unpublished observations (2009)).