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 histological characteristics of human HCC established a functional vasculature by cooption, remodeling and angiogenic expansion of the pre-existing 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.
This research output has an Altmetric Attention Score of 4. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 07 May 2020.
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#11,442,951
of 34,350,842 outputs
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Outputs of similar age
#89,793
of 270,750 outputs
Outputs of similar age from Cancer Research
#106
of 176 outputs
Altmetric has tracked 34,350,842 research outputs across all sources so far. This one has received more attention than most of these and is in the 65th percentile.
So far Altmetric has tracked 35,807 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 8.7. This one is in the 47th percentile – i.e., 47% of its peers scored the same or lower than it.
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