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Nat Protoc. 2015 Aug;10(8):1264-74. doi: 10.1038/nprot.2015.080. Epub 2015 Jul 23.

An orthotopic mouse model of hepatocellular carcinoma with underlying liver cirrhosis.

Author information

1
1] Department of Radiation Oncology, Steele Laboratories for Tumor Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.
2
1] Department of Radiation Oncology, Steele Laboratories for Tumor Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
3
1] Department of Radiation Oncology, Steele Laboratories for Tumor Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Angiogenesis Laboratory, Cancer Center Amsterdam, Department of Medical Oncology, Vrije Universiteit (VU) University Medical Center, Amsterdam, the Netherlands.
4
Department of Radiation Oncology, Steele Laboratories for Tumor Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
5
1] Department of Radiation Oncology, Steele Laboratories for Tumor Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Duke University School of Medicine, Durham, North Carolina, USA.
6
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
7
Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

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(-/-)Stk3(F/-) (also known as Mst1(-/-)Mst2(F/-); F indicates a floxed allele) mice, and it results in the development of HCC tumors (hepatocarcinogenesis) concomitantly with liver cirrhosis.

PMID:
26203823
PMCID:
PMC4800979
DOI:
10.1038/nprot.2015.080
[Indexed for MEDLINE]
Free PMC Article

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