title: Model Matters: Differences in Orthotopic Rat Hepatocellular Carcinoma Physiology Determine Therapy Response to Sorafenib.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Institut für Radiologie.
authors.forename: Claudia
authors.initials: C
authors.lastname: Groß
authors.affiliation: Institut für Pathologie.
authors.forename: Katja
authors.initials: K
authors.lastname: Steiger
authors.affiliation: Institut für Radiologie.
authors.forename: Sufyan
authors.initials: S
authors.lastname: Sayyed
authors.affiliation: Institut für Radiologie.
authors.forename: Irina
authors.initials: I
authors.lastname: Heid
authors.affiliation: Institut für Pathologie und.
authors.forename: Annette
authors.initials: A
authors.lastname: Feuchtinger
authors.affiliation: Institut für Pathologie und.
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
authors.affiliation: Abteilung für Strahlenzytogenetik, Helmholtz-Zentrum München, Neuherberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Heß
authors.affiliation: Abteilung für Strahlenzytogenetik, Helmholtz-Zentrum München, Neuherberg, Germany.
authors.forename: Kristian
authors.initials: K
authors.lastname: Unger
authors.affiliation: Abteilung für Strahlenzytogenetik, Helmholtz-Zentrum München, Neuherberg, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: Zitzelsberger
authors.affiliation: Institut für Radiologie.
authors.forename: Marcus
authors.initials: M
authors.lastname: Settles
authors.affiliation: Institut für Pathologie.
authors.forename: Anna Melissa
authors.initials: AM
authors.lastname: Schlitter
authors.affiliation: Institut für Radiologie.
authors.forename: Juliane
authors.initials: J
authors.lastname: Dworniczak
authors.affiliation: II. Medizinische Klinik.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Altomonte
authors.affiliation: II. Medizinische Klinik.
authors.forename: Oliver
authors.initials: O
authors.lastname: Ebert
authors.affiliation: Nuklearmedizinische Klinik, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaiger
authors.affiliation: Institut für Radiologie.
authors.forename: Ernst
authors.initials: E
authors.lastname: Rummeny
authors.affiliation: Abteilung für Gastroenterologie und Hepatologie, Universität Zürich, Zurich, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Steingötter
authors.affiliation: Institut für Pathologie, Institut für Pathologie, Medizinische Universität Innsbruck, Innsbruck, Austria.
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.affiliation: Institut für Radiologie, rbraren@tum.de.
authors.forename: Rickmer
authors.initials: R
authors.lastname: Braren
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D002471:Cell Transformation, Neoplastic; D055028:Comparative Genomic Hybridization; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D008114:Liver Neoplasms, Experimental; D008279:Magnetic Resonance Imaging; D008297:Male; D060787:Neoplasm Grading; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D000077157:Sorafenib
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D015415:Biomarkers; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib