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Page 2 of 11 Costa et al. Hepatoma Res 2018;4:35 I http://dx.doi.org/10.20517/2394-5079.2018.06

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Conclusion: Sorafenib shows promise as a treatment for reducing the aggressiveness of HCC as demonstrated by [ F]
FDG PET and immunohistochemistry.

Keywords: Animal model, hepatocellular carcinoma, liver steatosis, non-alcoholic fatty liver disease, positron emission
tomography, sorafenib

INTRODUCTION
Non-alcoholic, fatty liver disease (NAFLD) is associated with obesity and known to progress to non-
alcoholic, steatohepatitis (NASH), cirrhosis and then hepatocellular carcinoma (HCC), or directly progress
from NASH to HCC . Liver cancer is the 16th cause of global mortality and HCC accounts for up to 90% of
[1-3]
all primary liver cancers . Observational studies showed that diabetes, obesity, and iron overload are risk
[4,5]
factors for development of HCC and NAFLD .
[2]
Animal models are crucial to elucidate the physiopathology of HCC and to test potential therapeutic
targets . The ideal model of NAFLD-related HCC should replicate human HCC development, given a
[6,7]
high caloric diet, obesity, insulin resistance, dyslipidemia, similar hepatic markers, natural evolution of
HCC, genetic aspects and activation of the same signaling pathways . There are many animal models
[8,9]
for HCC that include genetically altered animals and orthotopic tumor implantation, however they are
not ideal to replicate NAFLD as they do not exhibit liver and metabolic changes [7,10] . Previous work used
a mixed experimental model of NAFLD-related HCC with fat and choline deficient diets together with
diethylnitrosamine (DEN) in drinking water to achieve HCC development within 16 weeks; a shorter period
than usual [7,11] . DEN has been used as a carcinogen and is capable of inducing HCC with intra- and inter-
tumor variability as it occurs in humans [12-14] .

Earlier studies performed with HCC patients, treated with sorafenib, demonstrated that higher values of
2-deoxy-2-[ F]-fluoro-D-glucose ([ F]FDG) uptake (expressed as SUVmax) were correlated with lower
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overall survival and more advanced HCC [15-21] . In HCC cell lines, the absence of p53 expression is indicative
of a worse prognosis, as is the increased [ F]FDG uptake . A recent metabolic study of HCC by positron
[22]
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emission tomography ([ F]FDG PET) showed that this imaging technique could be a prognostic tool, as
18
results correlate with long-term survival and early recurrence of HCC after liver transplantation [21,23] . This
tool can be used to identify the most undifferentiated and aggressive tumors to select patients who should
undergo liver transplantation .
[17]
Sorafenib was the first drug approved by the FDA for treatment of advanced HCC (BCLC C) [24,25] . The usual dose
for humans is 800 mg/day, providing an average of 127 μmol/L/h of plasmatic concentration (AUC ), while
0-12h
the equivalent dosage in rats is 5 mg/kg/day [26-28] . It had been showed that sorafenib (2.5 mg/kg/day) has the
capacity to prevent hepatic fibrosis, mitochondrial dysfunction, and reduce inflammation (interleukines 6
and 10) in NAFLD animal models . Furthermore, Yang et al. tested it for 8 weeks (5 mg/kg/day) and
[30]
[29]
demonstrated that sorafenib improved hepatic venous dysregulation, inhibited recruitment and activation
of leukocytes, and reduced splanchnic vasodilatation and ascites.

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This study aimed to evaluate the effect of sorafenib in a rat model of NAFLD related to HCC by using [ F]
FDG PET imaging as a tool to quantitate the degree of HCC differentiation in vivo.

METHODS
This study was approved by the ethical committee for animal use of the University of Sao Paulo Medical
School (protocol 108/14), following the current standards of small animal care.