title: 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(-/-)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.
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Reiberger
authors.affiliation: 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.
authors.forename: Yunching
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Rakesh R
authors.initials: RR
authors.lastname: Ramjiawan
authors.affiliation: Department of Radiation Oncology, Steele Laboratories for Tumor Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Tai
authors.initials: T
authors.lastname: Hato
authors.affiliation: 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.
authors.forename: Christopher
authors.initials: C
authors.lastname: Fan
authors.affiliation: Department of Radiation Oncology, Steele Laboratories for Tumor Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Rekha
authors.initials: R
authors.lastname: Samuel
authors.affiliation: Department of Radiation Oncology, Steele Laboratories for Tumor Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Roberge
authors.affiliation: Department of Radiation Oncology, Steele Laboratories for Tumor Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Peigen
authors.initials: P
authors.lastname: Huang
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Gregory Y
authors.initials: GY
authors.lastname: Lauwers
authors.affiliation: Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.affiliation: Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.affiliation: Department of Radiation Oncology, Steele Laboratories for Tumor Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.affiliation: Department of Radiation Oncology, Steele Laboratories for Tumor Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D006528:Carcinoma, Hepatocellular; D008103:Liver Cirrhosis / Q000139:chemically induced*; D008113:Liver Neoplasms; D008114:Liver Neoplasms, Experimental; D008809:Mice, Inbred C3H; D014183:Transplantation, Heterologous
chemical_list: D002251:Carbon Tetrachloride