Journal Article

DKFZ-2017-04203

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png An inducible hepatocellular carcinoma model for preclinical evaluation of antiangiogenic therapy in adult mice.

Runge, A. (First author)DKFZ* ; Hu, J. ; Wieland, M.DKFZ* ; Bergeest, J.-P.DKFZ* ; Mogler, C.DKFZ* ; Neumann, A.DKFZ* ; Géraud, C. ; Arnold, B.DKFZ* ; Rohr, K.DKFZ* ; Komljenovic, D.DKFZ* ; Schirmacher, P.DKFZ* ; Goerdt, S. ; Augustin, H. (Last author)DKFZ*

2014
AACR Philadelphia, Pa.

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Please use a persistent id in citations: doi:10.1158/0008-5472.CAN-13-2311

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.

Keyword(s): Angiogenesis Inhibitors ; Phenylurea Compounds ; Niacinamide ; sorafenib

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Contributing Institute(s):

1. Vaskuläre Onkologie und Metastasierung (A190)
2. Molekulare Immunologie (D050)
3. Theoretische Bioinformatik (B080)
4. Medizinische Physik in der Radiologie (E020)
5. DKTK Heidelberg (L101)

Research Program(s):

1. 311 - Signalling pathways, cell and tumor biology (POF3-311) (POF3-311)

Appears in the scientific report 2014

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Database coverage:
; BIOSIS Previews ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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