title: An inducible hepatocellular carcinoma model for preclinical evaluation of antiangiogenic therapy in adult mice.
abstract: The limited availability of experimental tumor models that faithfully mimic the progression of human tumors and their response to therapy remains a major bottleneck to the clinical translation and application of novel therapeutic principles. To address this challenge in hepatocellular carcinoma (HCC), one of the deadliest and most common cancers in the world, we developed and validated an inducible model of hepatocarcinogenesis in adult mice. Tumorigenesis was triggered by intravenous adenoviral delivery of Cre recombinase in transgenic mice expressing the hepatocyte-specific albumin promoter, a loxP-flanked stop cassette, and the SV40 large T-antigen (iAST). Cre recombinase-mediated excision of the stop cassette led to a transient viral hepatitis and resulted in multinodular tumorigenesis within 5 to 8 weeks. Tumor nodules with histologic characteristics of human HCC established a functional vasculature by cooption, remodeling, and angiogenic expansion of the preexisting sinusoidal liver vasculature with increasing signs of vascular immaturity during tumor progression. Treatment of mice with sorafenib rapidly resulted in the induction of vascular regression, inhibition of tumor growth, and enhanced overall survival. Vascular regression was characterized by loss of endothelial cells leaving behind avascular type IV collagen-positive empty sleeves with remaining pericytes. Sorafenib treatment led to transcriptional changes of Igf1, Id1, and cMet over time, which may reflect the emergence of potential escape mechanisms. Taken together, our results established the iAST model of inducible hepatocarcinogenesis as a robust and versatile preclinical model to study HCC progression and validate novel therapies.
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Runge
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.
authors.forename: Junhao
authors.initials: J
authors.lastname: Hu
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Wieland
authors.affiliation: Division of Bioinformatics and Functional Genomics, BioQuant Center, Heidelberg University, Heidelberg, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jan-Philip
authors.initials: JP
authors.lastname: Bergeest
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany. Department of Pathology, Heidelberg University, Heidelberg, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Mogler
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Neumann
authors.affiliation: Department for Dermatology, Venerology, and Allergy, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: Cyrill
authors.initials: C
authors.lastname: Géraud
authors.affiliation: Division of Molecular Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Arnold
authors.affiliation: Division of Bioinformatics and Functional Genomics, BioQuant Center, Heidelberg University, Heidelberg, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Rohr
authors.affiliation: Division of Medical Physics in Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Dorde
authors.initials: D
authors.lastname: Komljenovic
authors.affiliation: Department of Pathology, Heidelberg University, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Department for Dermatology, Venerology, and Allergy, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: Sergij
authors.initials: S
authors.lastname: Goerdt
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany. German Cancer Consortium, Heidelberg, Germany. augustin@angiogenese.de.
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D000077157:Sorafenib
chemical_list: D020533:Angiogenesis Inhibitors; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib