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@ARTICLE{Runge:128185,
author = {A. Runge$^*$ and J. Hu and M. Wieland$^*$ and J.-P.
Bergeest$^*$ and C. Mogler$^*$ and A. Neumann$^*$ and C.
Géraud and B. Arnold$^*$ and K. Rohr$^*$ and D.
Komljenovic$^*$ and P. Schirmacher$^*$ and S. Goerdt and H.
Augustin$^*$},
title = {{A}n inducible hepatocellular carcinoma model for
preclinical evaluation of antiangiogenic therapy in adult
mice.},
journal = {Cancer research},
volume = {74},
number = {15},
issn = {1538-7445},
address = {Philadelphia, Pa.},
publisher = {AACR},
reportid = {DKFZ-2017-04203},
pages = {4157 - 4169},
year = {2014},
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.},
keywords = {Angiogenesis Inhibitors (NLM Chemicals) / Phenylurea
Compounds (NLM Chemicals) / Niacinamide (NLM Chemicals) /
sorafenib (NLM Chemicals)},
cin = {A190 / D050 / B080 / E020 / L101},
ddc = {610},
cid = {I:(DE-He78)A190-20160331 / I:(DE-He78)D050-20160331 /
I:(DE-He78)B080-20160331 / I:(DE-He78)E020-20160331 /
I:(DE-He78)L101-20160331},
pnm = {311 - Signalling pathways, cell and tumor biology
(POF3-311)},
pid = {G:(DE-HGF)POF3-311},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:24906623},
doi = {10.1158/0008-5472.CAN-13-2311},
url = {https://inrepo02.dkfz.de/record/128185},
}