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Evaluation of 11C-acetate and 18F-FDG PET/CT in mouse multidrug resistance gene-2 deficient mouse model of hepatocellular carcinoma.

Territo PR, Maluccio M, Riley AA, McCarthy BP, Fletcher J, Tann M, Saxena R, Skill NJ - BMC Med Imaging (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Radiology and Imaging Sciences, Indianapolis, IN, 46202, USA. pterrito@iupui.edu.

ABSTRACT

Background: Hepatocellular 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.

Methods: 18F-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.

Results: Hepatic18F-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.

Conclusions: Hepatic 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.

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LPA variant profile is modulated prior to HCC emergence in MDR2−/− mice. a) Serum levels of LPA and LPC variants were determined by LC/MS. There was a significant increase in 18:2 LPA and 20:4 LPA in MDR2−/− mice prior to the emergence of HCC at 12 mo. LPA variant levels were maximal at 12 mo. b) Calculation of the 20:4 LPC/20:4 LPA ratios showed a dramatic change indicative of increased ATX activity
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Fig5: LPA variant profile is modulated prior to HCC emergence in MDR2−/− mice. a) Serum levels of LPA and LPC variants were determined by LC/MS. There was a significant increase in 18:2 LPA and 20:4 LPA in MDR2−/− mice prior to the emergence of HCC at 12 mo. LPA variant levels were maximal at 12 mo. b) Calculation of the 20:4 LPC/20:4 LPA ratios showed a dramatic change indicative of increased ATX activity

Mentions: Serum 20:4LPA and 18:2LPA levels where significantly increased in MDR2−/− mice simultaneous with HCC emergence. Levels increased from 129 ± 87nM to 141 ± 116nM in FVB controls to 1177 ± 151 nM and 1331 ± 121nM in 12 m MDR2−/− mice for 20:4LPA and 18:2 LPA, respectively (p < 0.01, n = 10). There was no significant difference in LPA precursor LPC for either variant (p > 0.05, n = 10, Fig. 5a). This increase in LPA in the absence of an increase in precursor LPC demonstrates a definite increase in LPA biosynthesis verified by a marked increase in the LPA to LPC ratio for both 20:4LPA and 18:2LPA (Fig. 5b).Fig. 5


Evaluation of 11C-acetate and 18F-FDG PET/CT in mouse multidrug resistance gene-2 deficient mouse model of hepatocellular carcinoma.

Territo PR, Maluccio M, Riley AA, McCarthy BP, Fletcher J, Tann M, Saxena R, Skill NJ - BMC Med Imaging (2015)

LPA variant profile is modulated prior to HCC emergence in MDR2−/− mice. a) Serum levels of LPA and LPC variants were determined by LC/MS. There was a significant increase in 18:2 LPA and 20:4 LPA in MDR2−/− mice prior to the emergence of HCC at 12 mo. LPA variant levels were maximal at 12 mo. b) Calculation of the 20:4 LPC/20:4 LPA ratios showed a dramatic change indicative of increased ATX activity
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4493966&req=5

Fig5: LPA variant profile is modulated prior to HCC emergence in MDR2−/− mice. a) Serum levels of LPA and LPC variants were determined by LC/MS. There was a significant increase in 18:2 LPA and 20:4 LPA in MDR2−/− mice prior to the emergence of HCC at 12 mo. LPA variant levels were maximal at 12 mo. b) Calculation of the 20:4 LPC/20:4 LPA ratios showed a dramatic change indicative of increased ATX activity
Mentions: Serum 20:4LPA and 18:2LPA levels where significantly increased in MDR2−/− mice simultaneous with HCC emergence. Levels increased from 129 ± 87nM to 141 ± 116nM in FVB controls to 1177 ± 151 nM and 1331 ± 121nM in 12 m MDR2−/− mice for 20:4LPA and 18:2 LPA, respectively (p < 0.01, n = 10). There was no significant difference in LPA precursor LPC for either variant (p > 0.05, n = 10, Fig. 5a). This increase in LPA in the absence of an increase in precursor LPC demonstrates a definite increase in LPA biosynthesis verified by a marked increase in the LPA to LPC ratio for both 20:4LPA and 18:2LPA (Fig. 5b).Fig. 5

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Radiology and Imaging Sciences, Indianapolis, IN, 46202, USA. pterrito@iupui.edu.

ABSTRACT

Background: Hepatocellular 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.

Methods: 18F-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.

Results: Hepatic18F-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.

Conclusions: Hepatic 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.

Show MeSH
Related in: MedlinePlus