Abstract
BackgroundHepatocellular carcinoma (HCC) remains a global health problem with unique diagnostic and therapeutic challenges, including difficulties in identifying the highest risk patients. Previous work from our lab has established the murine multidrug resistance-2 mouse (MDR2) model of HCC as a reasonable preclinical model that parallels the changes seen in human inflammatory associated HCC. The purpose of this study is to evaluate modalities of PET/CT in MDR2−/− mice in order to facilitate therapeutic translational studies from bench to bedside.Methods18F-FDG and 11C-acetate PET/CT was performed on 12 m MDR2−/− mice (n = 3/tracer) with HCC and 12 m MDR2−/+ control mice (n = 3/tracer) without HCC. To compare PET/CT to biological markers of HCC and cellular function, serum alpha-fetoprotein (AFP), lysophosphatidic acid (LPA), cAMP and hepatic tumor necrosis factor α (TNFα) were quantified in 3-12 m MDR2−/− (n = 10) mice using commercially available ELISA analysis. To translate results in mice to patients 11C-acetate PET/CT was also performed in 8 patents suspected of HCC recurrence following treatment and currently on the liver transplant wait list.ResultsHepatic18F-FDG metabolism was not significantly increased in MDR2−/− mice. In contrast, hepatic 11C-acetate metabolism was significantly elevated in MDR2−/− mice when compared to MDR2−/+ controls. Serum AFP and LPA levels increased in MDR2−/− mice contemporaneous with the emergence of HCC. This was accompanied by a significant decrease in serum cAMP levels and an increase in hepatic TNFα. In patients suspected of HCC recurrence there were 5 true positives, 2 true negatives and 1 suspected false 11C-acetate negative.ConclusionsHepatic 11C-acetate PET/CT tracks well with HCC in MDR2−/− mice and patients with underlying liver disease. Consequently 11C-acetate PET/CT is well suited to study 1) HCC emergence/progression in patients and 2) reduce animal numbers required to study new chemotherapeutics in murine models of HCC.
Highlights
Hepatocellular carcinoma (HCC) remains a global health problem with unique diagnostic and therapeutic challenges, including difficulties in identifying the highest risk patients
Hepatocellular carcinoma (HCC) is a primary cancer of the liver that most often develops in identifiable patients with underlying liver disease, like hepatitis
More recently we have shown that HCC tumor burden can be reduced by administration of the commercially available lysophosphatidic acid (LPA) biosynthesis/signaling inhibitor BrP-LPA [6] and confirmed the use of MDR2−/− mice as a model for clinical pathologies [12,13,14,15,16]
Summary
Hepatocellular carcinoma (HCC) remains a global health problem with unique diagnostic and therapeutic challenges, including difficulties in identifying the highest risk patients. More recently we have shown that HCC tumor burden can be reduced by administration of the commercially available LPA biosynthesis/signaling inhibitor BrP-LPA [6] and confirmed the use of MDR2−/− mice as a model for clinical pathologies [12,13,14,15,16]. This current study builds on our use of macroscopic measurements of HCC as indicators of disease progression, and evaluates non-invasive markers and imaging in MDR2−/− mice in order to validate tools pursuant to accurately measuring response to chemotherapeutic agents in future studies
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