Model Matters: Differences in Orthotopic Rat Hepatocellular Carcinoma Physiology Determine Therapy Response to Sorafenib

Abstract

Purpose: Preclinical model systems should faithfully reflect the complexity of the human pathology. In hepatocellular carcinoma (HCC), the tumor vasculature is of particular interest in diagnosis and therapy. By comparing two commonly applied preclinical model systems, diethylnitrosamine induced (DEN) and orthotopically implanted (McA) rat HCC, we aimed to measure tumor biology noninvasively and identify differences between the models.Experimental Design: DEN and McA tumor development was monitored by MRI and PET. A slice-based correlation of imaging and histopathology was performed. Array CGH analyses were applied to determine genetic heterogeneity. Therapy response to sorafenib was tested in DEN and McA tumors.Results: Histologically and biochemically confirmed liver damage resulted in increased 18 F-fluorodeoxyglucose (FDG) PET uptake and perfusion in DEN animals only. DEN tumors exhibited G1-3 grading compared with uniform G3 grading of McA tumors. Array comparative genomic hybridization revealed a highly variable chromosomal aberration pattern in DEN tumors. Heterogeneity of DEN tumors was reflected in more variable imaging parameter values. DEN tumors exhibited lower mean growth rates and FDG uptake and higher diffusion and perfusion values compared with McA tumors. To test the significance of these differences, the multikinase inhibitor sorafenib was administered, resulting in reduced volume growth kinetics and perfusion in the DEN group only.Conclusions: This work depicts the feasibility and importance of in depth preclinical tumor model characterization and suggests the DEN model as a promising model system of multifocal nodular HCC in future therapy studies.

Pre-clinical and clinical investigations of metabolic zonation in liver diseases: The potential of microphysiology systems

“…76 The rodent does not adequately replicate the underlying conditions that lead to the prerequisite liver damage necessary for HCC. 77 The absence of an optimal rodent model for HCC has led to use of the standard subcutaneous tumor models for efficacy testing and these have not been effective in identifying new drugs. 77 Finally, humans are more prone to drug-induced cholestasis from BSEP inhibitors due to an increased production of toxic glycine-conjugated bile acids compared with the production of less toxic taurine-conjugated bile acids found in the rodent.…”

“…77 The absence of an optimal rodent model for HCC has led to use of the standard subcutaneous tumor models for efficacy testing and these have not been effective in identifying new drugs. 77 Finally, humans are more prone to drug-induced cholestasis from BSEP inhibitors due to an increased production of toxic glycine-conjugated bile acids compared with the production of less toxic taurine-conjugated bile acids found in the rodent. 78 These differences suggest that the use of human cell-based liver models is likely necessary to expand our understanding of human liver diseases.…”

Relative Initial Weight Is Associated with Improved Survival without Altering Tumor Latency in a Translational Rat Model of Diethylnitrosamine-Induced Hepatocellular Carcinoma and Transarterial Embolization

“…Small animal models typically carry lower costs than large animal models, but until recently had been thought too small to allow for selective endovascular treatments (7). Xenograft models of HCC allow for reproducible tumors that are easily detected with short latencies, but fail to accurately recreate the tumor microenvironment of underlying liver injury that characterizes human disease (8–11). Similarly, orthotopic tumor models lack the phenotypic background of cirrhosis as well as the arterial dependence of HCC that characterizes human pathogenesis.…”

Efeito do sorafenibe na carcinogênese hepática experimental secundária à doença hepática gordurosa não alcoólica

“…O DEN é um carcinógeno utilizado há muito tempo em modelos experimentais de CHC por representar a complexidade da doença em humanos. Apesar da variabilidade intra e intertumoral do modelo, o seu uso é promissor no estudo pré-clínico de futuras terapias para CHC avançado (69,70) . (64,68) .…”

“…Eles viram que em 95% dos modelos utilizados para avaliar esta eficácia foram em xenotransplantes humanos. Apesar da maior parte das linhagens celulares mostrarem ação robusta do sorafenibe em camundongos, outras, como a McA-RH7777, não responderam a este fármaco (70) . (70) .…”