Multimodal imaging of a humanized orthotopic model of hepatocellular carcinoma in immunodeficient mice.

The development of multimodal strategies for the treatment of hepatocellular carcinoma requires tractable animal models allowing for advanced in vivo imaging. Here, we characterize an orthotopic hepatocellular carcinoma model based on the injection of luciferase-expressing human hepatoma Huh-7 (Huh-7-Luc) cells in immunodeficient mice. Luciferase allows for an easy repeated monitoring of tumor growth by in vivo bioluminescence. The intrahepatic injection was more efficient than intrasplenic or intraportal injection in terms of survival, rate of orthotopic engraftment, and easiness. A positive correlation between luciferase activity and tumor size, evaluated by Magnetic Resonance Imaging, allowed to define the endpoint value for animal experimentation with this model. Response to standard of care, sorafenib or doxorubicin, were similar to those previously reported in the literature, with however a strong toxicity of doxorubicin. Tumor vascularization was visible by histology seven days after Huh-7-Luc transplantation and robustly developed at day 14 and day 21. The model was used to explore different imaging modalities, including microtomography, probe-based confocal laser endomicroscopy, full-field optical coherence tomography, and ultrasound imaging. Tumor engraftment was similar after echo-guided intrahepatic injection as after laparotomy. Collectively, this orthotopic hepatocellular carcinoma model enables the in vivo evaluation of chemotherapeutic and surgical approaches using multimodal imaging.

Scientific reports. 2016 Oct 14*** epublish ***

Tao Wu, Emilie Heuillard, Véronique Lindner, Ghina Bou About, Mihaela Ignat, Jean-Philippe Dillenseger, Nicolas Anton, Eugénie Dalimier, Francine Gossé, Gael Fouré, Franck Blindauer, Céline Giraudeau, Hussein El-Saghire, Mourad Bouhadjar, Cynthia Calligaro, Tania Sorg, Philippe Choquet, Thierry Vandamme, Christophe Ferrand, Jacques Marescaux, Thomas F Baumert, Michele Diana, Patrick Pessaux, Eric Robinet

INSERM, U 1110, 67000 Strasbourg, France., Pathology Department, University Hospital of Strasbourg, 67000 Strasbourg, France., Mouse Clinical Institute, 67400 Illkirch, France., Pôle Hépatodigestif, Unité Hépatologie, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France., University of Strasbourg, 67000 Strasbourg, France., LLTech SAS, 75014 Paris, France., IHU-Strasbourg, Institute of Image-Guided Surgery, 67000 Strasbourg, France., French Blood Agency Bourgogne/Franche-Comté, 25000 Besançon, France.