An orthotopic mouse model of hepatocellular carcinoma with underlying liver cirrhosis

Abstract

Subcutaneous xenografts have been used for decades to study hepatocellular carcinoma (HCC). These models do not reproduce the specific pathophysiological features of HCCs, which occur in cirrhotic livers that show pronounced necroinflammation, abnormal angiogenesis and extensive fibrosis. As these features are crucial for studying the role of the pathologic host microenvironment in tumor initiation, progression and treatment response, alternative HCC models are desirable. Here we describe a syngeneic orthotopic HCC model in immunocompetent mice with liver cirrhosis induced by carbon tetrachloride (CCl4) that recapitulates key features of human HCC. Induction of substantial hepatic fibrosis requires 12 weeks of CCl4 administration. Intrahepatic implantation of mouse HCC cell lines requires 30 min per mouse. Tumor growth varies by tumor cell line and mouse strain used. Alternatively, tumors can be induced in a genetically engineered mouse model. In this setting, CCl4 is administered for 12 weeks after tail-vein injection of Cre-expressing adenovirus (adeno-Cre) in Stk4−/−Stk3F/− (also known as Mst1−/−Mst2F/−; F indicates a floxed allele) mice, and it results in the development of HCC tumors (hepatocarcinogenesis) concomitantly with liver cirrhosis.

A cell-autonomous tumour suppressor role of RAF1 in hepatocarcinogenesis

“…1i and j). As in most chemical models of hepatocarcinogenesis16, fibrosis or cirrhosis were not detected (Supplementary Fig. 1k).…”

Dual Programmed Death Receptor‐1 and Vascular Endothelial Growth Factor Receptor‐2 Blockade Promotes Vascular Normalization and Enhances Antitumor Immune Responses in Hepatocellular Carcinoma

“…In the macrophage‐stimulating 1 ( Mst1 –/– ) Mst2 f/– model adeno–cyclization recombination at a concentration of 10 7 pfu was injected through the tail vein in 3‐week‐old mice. To induce liver damage, 100 µL of 20% CCl 4 (Sigma‐Aldrich, St. Louis, MO) was administered orally from 8 to 12 weeks . When tumors reached ~5 mm in diameter, mice were randomly assigned to a treatment group (n = 6‐8).…”

“…The orthotopic HCC mouse models were described elsewhere. (30) The HCC cells (1 million 1:1 in Matrigel; Mediatech/Corning, Manassas, VA) were grafted into mice matching their genetic background-HCA-1 in C3H mice and RIL-175 in C57Bl/6 mice. Tumor growth was monitored by high-frequency ultrasonography twice a week.…”

Tumor regulation of the tissue environment in the liver

“…HCC growth in inflamed or cirrhotic livers. New murine HCC models take these two components into account (Reiberger, et al, 2015). After cirrhosis induction through carbon tetrachloride administration, tumor cells are either implanted orthotopically into the liver or initiated in genetically engineered models using viral expression of Cre recombinase.…”