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.