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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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Serum AFP and cAMP and hepatic TNFα are modulated contemporaneously with HCC in MDR2−/− mice. Serum AFP and cAMP and hepatic TNFα were quantified in MDR2−/− mice prior to emergence of HCC at 12 mo. a) Serum AFP levels increased in MDR2−/− mice concomitant with the emergence of HCC. b) Serum cAMP levels significantly reduced prior to the emergence of HCC. c) Hepatic TNFα levels were significantly increased prior to emergence of HCC. D-E) Representative micrographs of MDR2−/− (D) FVB and (E) control mouse livers. Collagen staining (blue) was markedly increased in 12 mo MDR2−/− mice when compared to 12 mo MDR2−/+ controls
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Fig2: Serum AFP and cAMP and hepatic TNFα are modulated contemporaneously with HCC in MDR2−/− mice. Serum AFP and cAMP and hepatic TNFα were quantified in MDR2−/− mice prior to emergence of HCC at 12 mo. a) Serum AFP levels increased in MDR2−/− mice concomitant with the emergence of HCC. b) Serum cAMP levels significantly reduced prior to the emergence of HCC. c) Hepatic TNFα levels were significantly increased prior to emergence of HCC. D-E) Representative micrographs of MDR2−/− (D) FVB and (E) control mouse livers. Collagen staining (blue) was markedly increased in 12 mo MDR2−/− mice when compared to 12 mo MDR2−/+ controls

Mentions: Serum AFP levels are typically raised in patients with HCC, although the sensitivity and specificity of this biomarker is low [34]. In MDR2−/+mice, that don’t develop HCC, serum AFP levels were not significantly increased when compared to FVB controls (Fig. 2a). In contrast, and similarly observed in humans with HCC, serum AFP was significantly (p = 0.048, n = 10) increased in MDR2−/− mice (58 ± 15 ng/ml) when compared to control mice (35 ± 5 ng/ml) (Fig. 2a); however, this increase was not uniform across all mice studied. Serum AFP levels were significantly elevated (40 ± 9 ng/ml) in 63 % of MDR2−/− mice, with little correlation between serum AFP levels and tumor burden (R2 = 0.17, n = 10).Fig. 2


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)

Serum AFP and cAMP and hepatic TNFα are modulated contemporaneously with HCC in MDR2−/− mice. Serum AFP and cAMP and hepatic TNFα were quantified in MDR2−/− mice prior to emergence of HCC at 12 mo. a) Serum AFP levels increased in MDR2−/− mice concomitant with the emergence of HCC. b) Serum cAMP levels significantly reduced prior to the emergence of HCC. c) Hepatic TNFα levels were significantly increased prior to emergence of HCC. D-E) Representative micrographs of MDR2−/− (D) FVB and (E) control mouse livers. Collagen staining (blue) was markedly increased in 12 mo MDR2−/− mice when compared to 12 mo MDR2−/+ controls
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Serum AFP and cAMP and hepatic TNFα are modulated contemporaneously with HCC in MDR2−/− mice. Serum AFP and cAMP and hepatic TNFα were quantified in MDR2−/− mice prior to emergence of HCC at 12 mo. a) Serum AFP levels increased in MDR2−/− mice concomitant with the emergence of HCC. b) Serum cAMP levels significantly reduced prior to the emergence of HCC. c) Hepatic TNFα levels were significantly increased prior to emergence of HCC. D-E) Representative micrographs of MDR2−/− (D) FVB and (E) control mouse livers. Collagen staining (blue) was markedly increased in 12 mo MDR2−/− mice when compared to 12 mo MDR2−/+ controls
Mentions: Serum AFP levels are typically raised in patients with HCC, although the sensitivity and specificity of this biomarker is low [34]. In MDR2−/+mice, that don’t develop HCC, serum AFP levels were not significantly increased when compared to FVB controls (Fig. 2a). In contrast, and similarly observed in humans with HCC, serum AFP was significantly (p = 0.048, n = 10) increased in MDR2−/− mice (58 ± 15 ng/ml) when compared to control mice (35 ± 5 ng/ml) (Fig. 2a); however, this increase was not uniform across all mice studied. Serum AFP levels were significantly elevated (40 ± 9 ng/ml) in 63 % of MDR2−/− mice, with little correlation between serum AFP levels and tumor burden (R2 = 0.17, n = 10).Fig. 2

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