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 Tantigen (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. Cancer Res; 74(15); 4157-69. Ó2014 AACR.

In vivo screen identifies LXR agonism potentiates sorafenib killing of hepatocellular carcinoma

“…Next, we confirmed the specificity of sorafenib and GW3965 treatment by assessing gene expression levels of known markers of drug activity. Upregulation of GADD45B and downregulation of PDGFRB mRNA levels are indicative of sorafenib activity 22, 23 , and we observed these trends in sorafenib and combination groups. We also noted upregulation of the LXR target genes FASN and SREBF1 24, 25 in the GW3965 and combination groups, as expected (Figure 5C).…”

Mechanisms of Vessel Pruning and Regression

“…Only the expression of the pericyte marker aSMA was downregulated during regression and returned to baseline upon vessel regrowth (Mancuso et al, 2006). Persistence of pericytes along ebms after Sorafenibinduced tumor vessel regression was also observed in an inducible mouse model of hepatocellular carcinoma (Runge et al, 2014). Although no changes in the pericyte coverage of remaining vessels were observed under conditions of enhanced retinal vessel regression, pericytes have recently been reported to stay attached to ebms of regressed retinal vessels (Franco et al, 2015;Korn et al, 2014;Phng et al, 2009).…”

Bioprinting for cancer research

“…In addition, the results from testing on animal models may not accurately predict the result in human testing due to cross-species differences [84], causing many drugs to fail in the clinical trial stage. Furthermore, animal testing raises ethical concerns and this ethical framework is closely regulated to control the use of animals for scientific research [85].…”